Narcolepsy and depression and the neurobiology of gammahydroxybutyrate

Progress in Neurobiology 89 (2009) 193–219

Contents lists available at ScienceDirect

Progress in Neurobiology journal homepage: www.elsevier.com/locate/pneurobio

Narcolepsy and depression and the neurobiology of gammahydroxybutyrate Mortimer Mamelak a,b,* a b

Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada Baycrest Hospital, 3560 Bathurst Street, Toronto, Ontario, Canada M6A 2E1

A R T I C L E I N F O

A B S T R A C T

Article history: Received 14 January 2009 Received in revised form 24 May 2009 Accepted 28 July 2009

A voluminous literature describes the relationship between disturbed sleep and depression. The breakdown of sleep is one of the cardinal features of depression and often also heralds its onset. Frequent arousals, periods of wakefulness and a short sleep onset REM latency are typical polysomnographic features of depression. The short latency to REM sleep has been attributed to the combination of a monoaminergic deficiency and cholinergic supersensitivity and these irregularities have been proposed to form the biological basis of the disorder. A similar imbalance between monoaminergic and cholinergic neurotransmission has been found in narcolepsy, a condition in which frequent awakenings, periods of wakefulness and short sleep onset REM latencies are also characteristic findings during sleep. In many cases of narcolepsy, this imbalance appears to result from a deficiency of hypocretin but once established, whether in depression or narcolepsy, this disequilibrium sets the stage for the dissociation or premature appearance of REM sleep and for the dissociation of the motor inhibitory component of REM sleep or cataplexy. In the presence of this monoaminergic/cholinergic imbalance, gammahydroxybutyrate (GHB) may acutely further reduce the latency of REM sleep and induce cataplexy, in both patients with narcolepsy or depression. On the other hand, the repeated nocturnal application of GHB in patients with narcolepsy improves the continuity of sleep, prolongs the latency to REM sleep and prevents cataplexy. Evidence to date suggests that GHB may restore the normal balance between monoaminergic and cholinergic neurotransmission. As such, the repeated use of GHB at night and the stabilization of sleep over time makes GHB an effective treatment for narcolepsy and a potentially effective treatment for depression. ß 2009 Elsevier Ltd. All rights reserved.

Keywords: Narcolepsy Depression Gammahydroxybutyrate Sleep GHB Receptors GABAB Receptors Sodium oxybate

Contents 1. 2. 3. 4.

5.

Introduction . . . . . . . . . . . . . . . . . Narcolepsy: clinical presentation Quality of life . . . . . . . . . . . . . . . . Diagnostic considerations . . . . . . 4.1. Genetics. . . . . . . . . . . . . . . 4.2. Polysomnography . . . . . . . 4.3. Hypocretin deficiency . . . . Hypocretin physiology. . . . . . . . . 5.1. Diurnal variations . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

194 194 195 196 196 196 196 197 197

Abbreviations: AMPA, alpha-amino-3-hydroxy-s-methyl-4-isoxazole proprionic acid; ATP, adenosine triphosphate; BDNF, brain derived neurotrophic factor; CGIc, clinical global impression of change; CREB, cyclic-AMP response element binding protein; CSF, cerebrospinal fluid; D-APS, D( )-2 amino-5-phosphonopentanoic acid; DAT, dopamine transporter; DLA, dog leukocyte antigen; EEG, electrocencephalogram; ESS, Epworth sleepiness scale; GABA, gamma-aminobutyric acid; GABAA, GABAA receptor; GABAB, GABAB receptor; GHB, gammahydroxybutyrate; GPCRs, G-protein coupled receptors; GR, glucocorticoid receptor; GTPg [35S], guanosine 5-O-(3-[35S] thio triphosphate; GTPase, guanosine triphophatase; HOCPCA, 3-hydroxycyclopent-1-enecarboxylic acid; HEK, human embryonic kidney; HLA, human leukocyte antigen; MAO, monoamine oxidase; MAOI, MAO inhibitor; MSLT, multiple sleep latency test; MWT, multiple wakefulness test; NADPH, nicotinamide adenine dinucleotide phosphate; NCS-382, (5-hydroxy-5,7,8,9tetrahydro-6H-benzo[a] [7] annulen-6-ylidene)ethanoic acid; NMDA, N-methyl-D-aspartate; NREM, non-rapid eye movement sleep; QNB, quinuclidinyl benzilate; peri-LCa, perilocus coeruleus-alpha; PGO, pontine-geniculate-occipital; REM, rapid eye movement sleep; SPECT, single photon emission computed tomography; SSRIs, selective serotonin reuptake inhibitors; THCA, trans-g-hydroxy-crotonic acid; TCAs, tricyclic antidepressants; VLPO, ventrolateral preoptic nucleus; Xyrem, sodium oxybate. * Correspondence address: Baycrest Hospital, Department of Psychiatry, 3560 Bathurst Street, Toronto, Ontario, Canada M6A 2E1. Tel.: +1 416 236 5650; fax: +1 416 493 0170. E-mail address: [email protected]. 0301-0082/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.pneurobio.2009.07.004

194

6. 7.

8. 9.

10.

11. 12. 13. 14. 15. 16.

M. Mamelak / Progress in Neurobiology 89 (2009) 193–219

5.2. Effects on arousal mechanisms . . . . . . . . . . . . . . . . . . . . . . . 5.3. Effects on motor activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hypocretin: therapeutic applications . . . . . . . . . . . . . . . . . . . . . . . . The treatment of narcolepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1. The stimulants: amphetamine, methylphenidate, modafinil 7.2. Novel experimental alerting agents . . . . . . . . . . . . . . . . . . . . 7.3. The antidepressants: tricyclics, SSRIs and MAO inhibitors . . The treatment of narcolepsy and cataplexy with GHB. . . . . . . . . . . GHB and its receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.1. The GHB receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.2. The GABAB receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.3. GABAB: second messengers . . . . . . . . . . . . . . . . . . . . . . . . . . GABAB and the regulation of neurotransmitter release . . . . . . . . . . 10.1. Hypocretin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.2. Histamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.3. Dopamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.4. Noradrenaline and serotonin . . . . . . . . . . . . . . . . . . . . . . . . . 10.5. Acetycholine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.6. Glutamate and GABA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . GHB and slow wave sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Functions of slow wave sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neurotransmitter circuits in sleep and wakefulness . . . . . . . . . . . . Neurotransmitter disequilibrium in cataplexy . . . . . . . . . . . . . . . . . GHB and the neurochemistry of cataplexy . . . . . . . . . . . . . . . . . . . . GHB and the neurochemistry of depression . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Harry Stack Sullivan, that great icon of American psychiatry, once wrote that ‘‘a good night’s sleep’’ might be all that was necessary to save some of his patients from the incipient dangers of decompensation (Sullivan, 1965). Sullivan recognized that the breakdown of sleep often forecast the recurrence of severe states of depression and other forms of mental illness and he was impressed with sleep’s therapeutic efficacy in many of these cases. However, working in the nineteen thirties and forties, he hesitated to induce sleep in his mentally ill patients because of the hazards associated with the use of the hypnotic drugs then available to him, their low lethal threshold, their addictive potential and their dangerous withdrawal reactions. Was there a better way to tap the magic power of sleep? In the 1960s, Laborit and his colleagues, seeking to get gammaaminobutyric acid (GABA) across the blood–brain barrier, began their seminal studies on the central effects of gammahydroxybutyric acid (GHB), a molecule conceived as a potential precursor of GABA (Laborit, 1964) and later also shown to be a metabolite of GABA (Roth and Giarman, 1969). GHB proved to have strong hypnotic effects and was almost immediately applied to treat drug dependency states and barbiturate intoxication (Muyard and Laborit, 1977). In animal studies, tolerance to its hypnotic effects failed to develop with long term use (Vickers, 1969) and GHB was also shown to be able to promote both REM and slow wave sleep (Godbout and Montplaisir, 2002), in distinction to most of the common hypnotics then in use which suppressed these two sleep states. When given to healthy human subjects at bedtime, the normal sequence of NREM and REM sleep occurred; delta sleep tended to be prolonged and REM sleep appeared after a normal latency (Lapierre et al., 1990; Yamada et al., 1967). It seemed reasonable to try to improve the sleep of depressed patients with GHB since a deficiency of slow wave sleep was considered one of the features of severe depression (Peterson and Benca, 2006; Shaffery et al., 2003) and of other major psychiatric disorders (Benca et al., 1992; Benson, 2006). An initial trial of GHB in a cohort of depressed patients unexpectedly demonstrated that it could

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

198 198 199 199 200 201 201 202 203 203 205 206 207 207 207 207 207 208 208 208 209 210 210 211 212 213 213

induce a prolonged sleep onset REM period that might last for almost an hour and that was followed by an equally prolonged period of slow wave sleep (Mamelak et al., 1973, 1977). One patient reported feeling paralyzed and unable to move soon after she had ingested GHB. The drug had induced a state with clinical and electroencephalographic features that greatly resembled narcolepsy. Although the clinical and polysomnographic features of narcolepsy were well known, its pathogenesis remained mysterious. It appeared as if the orchestration of sleep had been lost in this disease and that the different components of sleep were adrift around the nycthemeron. Given both the REM and NREM sleep promoting effects of GHB, the possibility of using this agent to ‘‘glue’’ these components together again and anchor them in the night was considered. The very first attempts met with success. GHB consolidated sleep at night, alleviated drowsiness during the day and virtually eliminated daytime attacks of cataplexy (Broughton and Mamelak, 1976, 1979, 1980). 2. Narcolepsy: clinical presentation Narcolepsy is characterized by excessive daytime drowsiness and is typically associated with cataplexy and other REM sleep phenomena such as sleep paralysis and hypnagogic hallucinations. Very comprehensive descriptions of the disease and its clinical manifestations have recently been published and only certain features will be highlighted here. (ASDA, 1997; AASM, 2005; Nishino, 2007). Narcolepsy is estimated to occur in 0.02–0.18% of the general population. Its prevalence appears to be highest in Japan and most commonly begins in the second decade of life. Cataplexy may first appear together with excessive daytime drowsiness or after a delay of months or years. Fluctuating levels of continuous drowsiness during the day or repeated naps and, at times irresistible lapses into sleep of short duration, best describe the excessive sleepiness of narcolepsy. Cataplexy, often considered the one unique feature of narcolepsy, may be defined as a sudden bilateral loss of motor tone provoked by strong emotion and corresponds to the dissociated activation of the motor atonic

M. Mamelak / Progress in Neurobiology 89 (2009) 193–219

component of REM sleep. The frequency of cataplexy may range from an isolated event during the course of a year in some patients to countless attacks in a single day in others. Sleep paralysis, hypnagogic hallucinations, automatic behaviors and nocturnal sleep disruption are other commonly associated features of narcolepsy. Hypnagogic hallucinations are vivid visual, tactile, kinetic and auditory perceptual experiences which occur at sleep onset often with the realistic awareness of someone in the bedroom or at the bedside. These threatening ghost like apparitions, common in narcolepsy, are to be distinguished from the threatening moral auditory admonitions of schizophrenic hallucinations. At times, the visual hallucinations of narcolepsy may intrude into the day and disrupt ongoing activities, like driving. Sleep paralysis is a transient generalized inability to move or speak during the transition between wakefulness and sleep at night although it may also occur upon awakening in the morning. Sleep paralysis may last from one to several minutes and can be frightening. It is often accompanied by the sensation of an inability to breathe. Episodes often occur together with hypnagogic hallucinations. Sleep onset paralysis and hypnagogic hallucinations almost always correspond with sleep-onset REM periods. These two symptoms are defined as auxiliary symptoms and along with cataplexy and excessive sleepiness constitute the narcoleptic tetrad. Narcoleptic patients may report lapses of memory and automatic behaviors without awareness of sleepiness. Nocturnal sleep disruption with frequent awakenings are also characteristic features of the disease. Only 10–15% of patients with narcolepsy experience the classic tetrad of symptomatic abnormalities. The majority, about 70%, have cataplexy, the most specific symptom of the disease. About a third of patients suffer from hypnagogic hallucinations while a quarter have sleep paralysis. The presenting symptom in the majority of patients is excessive daytime drowsiness alone or in combination with hypnagogic hallucinations and or sleep paralysis. Cataplexy rarely precedes the onset of excessive daytime drowsiness. 3. Quality of life In 1934, in a now classic review of narcolepsy, Daniels emphasized that the social and economic consequences of the disease were frequently as troubling to the patient as the specific narcoleptic symptoms (Daniels, 1934). To obtain quantitative data on these features of the disease, Broughton and Ghanem created a questionnaire that specifically surveyed the effects of narcolepsy on work, education and interpersonal relationships as well as on memory, driving and recreation (Broughton and Ghanem, 1976). The questionnaire was applied to 43 patients. Over 60% reported that narcolepsy had interfered with their performance at work and close to 20% indicated that they had lost their jobs because of their disease. Excessive drowsiness during the day had impaired their capacity to concentrate, attend and learn. Sleepiness and fatigue had affected their personal lives and, in some cases had led to the breakdown of relationships and marriages. Driving a car was a particular challenge and more than 70% of the patients surveyed had fallen asleep at the wheel. Over 60% reported near accidents because of drowsiness and a number of those surveyed had given up driving. Recreational activities were also frequently adversely affected by the disease. Falling asleep reading, watching television or at the movies were almost universal experiences but many also fell asleep during more social activities like playing cards. Patients with narcolepsy often related that they were simply too tired to engage in recreational activities. Broughton and his colleagues later reported that narcolepsy impaired psychosocial functions like work and recreation even more than epilepsy (Broughton et al., 1984). Other investigators found that narcolepsy was more

195

debilitating than untreated sleep apnea (Vignatelli et al., 2004). Persistent drowsiness, sleep attacks and unpredictable episodes of weakness were symptoms not easily overcome. In recent years, the effect of narcolepsy on the quality of life and the advantages of treatment has been examined in large case series. Daniels et al. (2001), surveyed 500 patients with narcolepsy in the United Kingdom with three different questionnaires. The Ullanlinna Narcolepsy Scale was used to determine the severity and frequency of narcolepsy symptoms, a specifically designed questionnaire was used to determine the impact of the disease on work, school, relationships and recreation and the overall health status of these patients was assessed with the SF-36, a widely used and validated questionnaire which quantifies subjective reports of health in terms of functional and emotional status and generally well being. Daniels et al. also determined the prevalence and severity of depression in their cases with the Beck Depression Inventory. Thirty-seven percent of the 313 subjects who responded to the survey reported that they had lost or left a job because of narcolepsy. Over 50% experienced problems with concentration during classroom work. Nearly 20% thought that narcolepsy had caused a relationship to end. The response to the SF-36 questionnaire revealed that patients with narcolepsy had significantly lower scores on all scales than age and sex matched normal subjects. The greatest difference was role limitation due to physical problems, i.e., narcolepsy caused problems with everyday life, but it also sapped the energy and vitality of these patients, and created emotional problems. Fully 57% of this narcoleptic population were depressed. The majority of the patients in this study were taking stimulant and/or anticataplexy medication. However, no matter what medication combination was being used, health status was not restored to normal. Although one study with the wake promoting agent modafinil demonstrated that the use of this drug did raise scores on SF-36 measures of physical energy, vitality and social and emotional function, the majority of scores did not reach normal levels (Beusterien et al., 1999). A recent Norwegian study (Ervik et al., 2006) also concluded that narcolepsy had a clear negative effect on the quality of life which was not adequately addressed by conventional treatments for drowsiness and cataplexy. Weaver and Cuellar (2006), studied the effects on psychosocial variables of treating patients with narcolepsy with sodium oxybate. They examined 285 patients with narcolepsy randomized to treatment with either placebo or 4.5 g, 6.0 g and 9.0 g of sodium oxybate at night. Sodium oxybate was administered in divided doses at 4-h intervals during the night. The Functional Outcomes of Sleep Questionnaire (FOSQ) was used to measure the impact of treatment on activity level, vigilance, intimacy and sexual relationships, general productivity and social outcome. In this validated questionnaire, a total score is generated from the mean item scores of each subscale. Seventy-eight percent of the study subjects were using stimulants concurrently and approximately 30% of participants were on antidepressants. Sodium oxybate had a positive effect on most components of the quality of life as demonstrated by an increased total score on the FOSQ and as well improved scores on subscales that measured activity level, vigilance, general productivity and social outcome. A dose response was demonstrated with the greatest effect demonstrated at 9.0 g. These observations complemented an earlier study which demonstrated that sodium oxybate significantly decreased excessive daytime drowsiness and the incidence and severity of cataplexy. The authors of this report emphasized that their findings were not only statistically significant but also clinically important. Sodium oxybate substantially improved daily functioning even in the 50% of subjects in this study who were being treated with the stimulant, modafinil. Thus, sodium oxybate appeared to further enhance functioning in study subjects receiving other

196

M. Mamelak / Progress in Neurobiology 89 (2009) 193–219

concurrent treatments for narcolepsy. Levels of excessive daytime drowsiness fell into the normal range in many patients treated with this agent. 4. Diagnostic considerations The diagnosis of narcolepsy is usually straightforward, especially when a young person presents with the full narcoleptic tetrad and an episode of cataplexy is witnessed by the examiner (ASDA, 1997; AASM, 2005; Nishino, 2007). Often, however, the description of symptoms leaves room for doubt. Excessive daytime drowsiness, for example, may be associated with a number of other conditions such as sleep deprivation, shift work, sleep apnea, head injury and idiopathic hypersomnia. Daytime sleepiness must also be distinguished from the fatigue and tiredness which occur with a wide variety of medical and psychiatric disorders. Cataplexy can be confused with weakness brought on by emotion. Cataplexy has also been reported in association with a variety of neurological conditions such as head trauma and brain tumours as well as with rare conditions such as the Coffin–Lowry syndrome, the Mobius syndrome, Niemann–Pick disease, type C and Norrie disease (Nishino and Kanbayashi, 2005). It has been argued that a favorable response to treatment with a tricyclic antidepressant like clomipramine is required to fully satisfy the diagnosis of cataplexy (Honda, 1988). Sleep paralysis is common in the population and occurs independently of narcolepsy in many individuals who keep irregular sleep hours. Sleep paralysis may also be familial. Hypnagogic hallucinations may be difficult to distinguish from ordinary dreaming at sleep onset. Thus, in many cases, clinical presentation alone may be insufficient for diagnosis. 4.1. Genetics Most cases of narcolepsy–cataplexy are sporadic. A major genetic factor linked to this disorder is located in the MHC DQ region of chromosome 6. More than 85% of all narcoleptic patients with definite cataplexy share a specific HLA allele, HLA DQB1* 0602. HLA DQB1* 0602 and another HLA gene allele located nearby, HLA DQA1* 0102 have been identified as the narcolepsy susceptibility genes (Mignot, 1998; Mignot et al., 2001). The link between narcolepsy and the DQB1* 0602 and DQA1* 0102 alleles is one of the strongest HLA associations in medicine. Yet these alleles alone are neither necessary nor sufficient for the development of narcolepsy. Twelve to 25% of the general population carry exactly the same alleles, yet only 0.02–0.18% of the general population has narcolepsy. Typical cases of narcolepsy with cataplexy have been described in which these alleles were not present. Even some concordant twin pairs have been found DQB1* 0602 negative. Indeed, some of the rare cases of familial narcolepsy have also been found to be DQB1* 0602 negative and other genetic links have been identified in these cases (Nishino, 2007). To date, dogs with narcolepsy have not been shown to share any single DLA locus reactivity. Rather, narcolepsy in the dog has been shown to be caused by a mutation in the hypocretin receptor 2 gene. In humans, however, mutations in hypocretin related genes are rare and only a single case with early onset at 6 months was found which was associated with a single point mutation in the preprohypocretin gene (Peyron et al., 2000). Thus, HLA testing alone can also not be used to confirm the diagnosis of narcolepsy/cataplexy and despite the apparent genetic susceptibility to narcolepsy, family history is usually of little diagnostic value. Although the risk of developing narcolepsy with cataplexy among first degree relatives of a patient with the disease is 10–40 times that in the general population, only 1–2% of first degree relatives manifest the disorder (ASDA, 1997; AASM, 2005; Mignot, 1998; Nishino, 2007). Indeed, only about 25–31% of

identical twins are concordant for the disorder. Environmental factors thus appear to contribute to the development of the disorder or may be required to induce it. Head trauma, shift work, sleep deprivation and various infections have been proposed as triggering agents. 4.2. Polysomnography Although narcolepsy with cataplexy can be diagnosed on purely clinical grounds, all night polysomnography followed by multiple sleep latency testing (MSLT) the next day may be useful to confirm the diagnosis whether or not cataplexy is present. All night recordings typically demonstrate a nocturnal sleep latency of less than 10 min and a nocturnal REM sleep latency of less than 20 min, while the MSLT reveals an average daytime sleep latency of less than 8 min on four or five twenty minute nap opportunities spaced 2 h apart during the day as well as two or more sleep onset REM periods during these naps. Five naps are employed when REM sleep occurs only once during the first four naps. Narcolepsy without cataplexy may be diagnosed when multiple sleep onset REM periods are found on the MSLT. It should be noted that narcolepsy without cataplexy, as defined above, has a much lower HLA DQB1* 0602 association than narcolepsy with cataplexy. This allele occurs in only about 40% of these patients suggesting that narcolepsy with cataplexy is a more specific entity. This conclusion is underscored by a recent study on a randomly selected sample of community adults consisting of 289 men and 267 women between the ages of 35 and 70. A mean sleep latency during the day of less than 8 min and 2 or more sleep onset REM periods were observed in 5.9% of the men and 1.1% of the women, all without cataplexy (Mignot et al., 2006). The authors of this study concluded that there was either a high incidence of a syndrome that resembled narcolepsy without cataplexy in the general population or a large number of false positives on daytime sleep latency testing. These conclusions were more recently corroborated by another group of investigators (Singh et al., 2006). Problems with the specificity of sleep laboratory studies in the diagnosis of narcolepsy are compounded further by observations that patients using antidepressants and particularly the newer compounds which do not suppress REM such as bupropion or mirtazapine as well as patients with sleep apnea or male patients who work shift are all likely to have multiple daytime sleep onset REM periods (Mignot et al., 2006; Singh et al., 2006). Mentally depressed patients frequently present with REM sleep soon after sleep onset at night (Argyropoulos and Wilson, 2005) and may also have multiple REM sleep periods during the day (Kupfer et al., 1981) although this last observation was not confirmed in more systematic studies (Mignot et al., 2006; Nofzinger et al., 1991). However, clinically, self-reports of dissociated REM sleep phenomena such as sleep paralysis and cataplexy are significantly more frequent in severely depressed patients (Szklo-Coxe et al., 2007). Multiple REM sleep periods during the day can also be induced by placing normal subjects on a 2-h sleep–wake schedule around the clock (Carskadon and Dement, 1980). Sleep laboratory findings must therefore be interpreted in the context of other clinical findings. 4.3. Hypocretin deficiency Patients with narcolepsy have normal amounts of REM and NREM sleep during a 24 h period but differ from their normal counterparts by more frequent and abnormal transitions between the three vigilance states, wakefulness, REM and NREM sleep. During the past decade, genetic studies of the canine model of narcolepsy as well as studies in knockout mice and in mice and rats with induced degenerative changes in specific neuronal tracts have

M. Mamelak / Progress in Neurobiology 89 (2009) 193–219

demonstrated that malfunction of the hypocretin (orexin) system alters the organization of sleep and wakefulness in these animals in a manner similar to that of human narcolepsy (Sakurai, 2007; Sutcliff and de Lecea, 2002). The hypocretins consist of two neuropeptides, hypocretin-1 and hypocretin-2, that are derived from the same precursor gene and that are synthesized by neurons located almost exclusively in the lateral, posterior and perifornical hypothalamus (Nambu et al., 1999; Peyron et al., 1998), a region classically implicated in mammalian feeding behavior (Willie et al., 2001). These neuropeptides were named hypocretins when it was discovered that their structure resembles the gut hormone secretin (de Lecea et al., 1998). The name orexin was independently applied when it was demonstrated that these peptides could stimulate appetite in mice when injected into the cerebral ventricles (Sakurai et al., 1998). Hypocretin neurons were shown to have widespread projections to all levels of the neuraxis (Peyron et al., 1998; Nambu et al., 1999) and were soon recognized to integrate arousal, locomotion and food consumption in the interests of energy balance (Sakurai, 2005). Mammals respond to starvation by staying awake and searching for food. The duration of sleep is reduced. On the other hand, a large meal, satiation and energy abundance induces sleep. Indeed, the duration of sleep after a meal has been shown to correlate with the energy content of the food (Nicolaidis and Danguir, 1984). The hypocretin neuronal system is intimately engaged in these homeostatic events. Hypocretin neurons become more excitable in response to hypoglycemia or ghrelins, a stomach derived peptide which promotes feeding, but are inhibited by high energy signals such as are glucose and appetite suppressants such as leptin (Burdakov and Alexopoulos, 2005; Sakurai, 2005; Yamanaka et al., 2003). Two hypocretin receptors, type 1 and type 2, have been identified but with markedly different distributions within the nervous system (Marcus et al., 2001; Trivedi et al., 1998). Hypocretin-1 has a much greater affinity for the hypocretin-1 receptor than for the hypocretin-2 receptor. The hypocretin-2 receptor, on the other hand, has an equal affinity for both hypocretin peptides (Sakurai et al., 1998; Willie et al., 2001). Of the brain stem regions involved in sleep state control, the locus cerulerus is predominantly served by the type I receptor while the dorsal raphe is equally served by both receptors (Marcus et al., 2001; Trivedi et al., 1998). In familial canine narcolepsy, cataplexy and sleep wake instability occur in association with a mutation of the hypocretin receptor type 2 gene (Lin et al., 1999). Similarly, mice lacking the type 2 receptor, but not the type 1 receptor, also have narcolepsy like characteristics (Willie et al., 2001) but the behavioural and electroencephalographic phenotype of mice lacking the type 2 receptor is less severe than that found in orexin neuropeptide knockout mice which lack both receptors and which display a phenotype strikingly similar to that of human narcolepsy with cataplexy and frequent transitions into REM sleep from wakefulness (Chemelli et al., 1999). Rats expressing a polyglutamine ataxin-3-transgene in hypocretin neurons develop a selective postnatal loss of hypothalamic-hypocretin positive neurons and also present with cataplexy like episodes and abnormal transitions into REM sleep (Beuckmann et al., 2004). Thus, in mice, rats and the dog, studies strongly suggest a link between hypocretin insufficiency and the behavioural and polysomnographic features of narcolepsy (Baumann and Bassetti, 2005). The majority of HLA-DQB1* 0602 positive patients with narcolepsy–cataplexy have CSF hypocretin-1 levels less than or equal to 110 pg/ml, i.e., less than one-third the mean normal control values. Hypocretin-2 has been difficult to assay in the CSF (Taheri et al., 2002). Low or undetectable CSF levels of hypocretin-1 are required for cataplexy (Mignot et al., 2002; Nishino et al., 2001). Reduced but detectable CSF hypocretin-1 levels can be found in a variety of clinical disorders that present with excessive

197

daytime drowsiness but without cataplexy (Mignot et al., 2002; Nishino and Kanbayashi, 2005). The virtual absence of hypocretin1 in the CSF of patients with cataplexy almost certainly reflects the loss of most of the 50,000–100,000 hypothalamic neurons containing the hypocretin neuropeptides that can be found normally in the human brain (AASM, 2005; Lodi et al., 2004; Thannickal et al., 2000). On average, post-mortem studies demonstrate that only about 10% of the normal number of hypocretin containing neurons remain in the brains of patients with narcolepsy (Thannickal et al., 2000). The reason for the neuronal loss in the hypothalamus has not been established but an autoimmune process has been proposed given the strong HLA association of the disease (Silber et al., 2007; Zeitzer et al., 2006). Gliosis is not confined to regions normally containing hypocretin cell somas but is most strongly correlated with the density of the hypocretin-2 receptor rather than the density of the hypocretin-1receptor or the density of the hypocretin cell somas suggesting that the hypocretin-2 receptor or a closely associated antigen may be the target for an immune attack (Thannickal et al., 2003; Siegel, 2004). The rare neurological disorders and mid-brain tumors that cause cataplexy all appear to alter or damage the function of the hypothalamus (Nishino and Kanbayashi, 2005). Nevertheless, it must be kept in mind that up to 11% of patients with narcolepsy and cataplexy have normal CSF hypocretin-1 levels (Baumann and Bassetti, 2005). Some familial cases actually have elevated CSF hypocretin-1 levels (Nishino et al., 2001). This may indicate that CSF levels do not perfectly reflect hypocretin neurotransmission or that hypocretin-1-deficiency alone is insufficient for the development of cataplexy. Cataplexy has not been reported in either patients with acute severe brain trauma (Baumann et al., 2005) or the Guillain–Barre syndrome (Nishino et al., 2003) in both of which CSF hypocretin-1levels are vanishingly low. Time may be required for hypocretin deficiency to exercise its full effects. Even in orexin neuropeptide knockout mice, a few weeks must pass for the narcoleptic syndrome to appear in full force (Chemelli et al., 1999). Thus, adaptive changes in the neural control of motor tone which develop overtime in the absence of hypocretin may be required for cataplexy but these adaptive changes could be generated in other ways and could account for cataplexy in the 11% of patients with this disorder who are not hypocretin-1 deficient. For example, cataplexy has been observed following the withdrawal of antidepressants from depressed patients who do not have narcolepsy (Nissen et al., 2005). Antidepressant drug withdrawal is known to further promote the dissociation of REM sleep which is so often a feature of depression (Argyropoulos and Wilson, 2005; Wilson and Argyropoulos, 2005). Depression, itself appears to be associated with an increased incidence of cataplexy and specifically of sleep paralysis (Szklo-Coxe et al., 2007) even though CSF hypocretin levels are normal in this disorder (Salomon et al., 2003). The common occurrence of sleep paralysis in otherwise normal individuals, which like cataplexy, consists of motor atonia during wakefulness also suggests that the dissociation of REM sleep and motor atonia can occur without any abnormalities in the hypocretin system. Hypocretin deficiency may therefore be only one of a number of ways by which the motor atonic component of REM sleep may be sensitized. 5. Hypocretin physiology 5.1. Diurnal variations Because of the fragmentation of the three arousal states, wakefulness, NREM and REM sleep in hypocretin deficient animals and man, a great effort has been made to understand how sleep wake states and motor control are regulated by the hypocretins. A

198

M. Mamelak / Progress in Neurobiology 89 (2009) 193–219

diurnal pattern of hypocretin neurotransmission has been demonstrated in the rat brain (Fujiki et al., 2001; Nishino, 2007; Yoshida et al., 2001). Levels of hypocretin-1 in rat brain CSF (Fujiki et al., 2001) and extracellular levels in the rat lateral hypothalamus and medial thalamus (Yoshida et al., 2001) were found to increase during the active dark period and decline towards the end of the light rest phase. It was then demonstrated that the expression of the transcription factor FOS in rat perifornical hypocretin neurons correlated positively with the amount of wakefulness and negatively with the amounts of NREM and REM sleep during the preceding 2 h (Estabrooke et al., 2001). These studies were supplemented by studies in cats which examined FOS immunoreactivity in hypothalamic-hypocretin neurons and found that a majority of these neurons expressed FOS during active wakefulness but not during quiet wakefulness. Surprisingly, a large portion of the hypocretinergic neurons were FOS immunoreactive during carbachol induced active sleep (Torterolo et al., 2001). Using microdialysis in freely moving cats, another group of investigators found that hypocretin-1 release from the perifornical hypothalamus was significantly higher during active wakefulness than during slow wave sleep and significantly higher in both the perifornial hypothalamus and basal forebrain during rapid eye movement sleep than during slow wave sleep (Kiyashchenko et al., 2002). There was evidence that hypocretin-1 release was far greater during active wakefulness than during quiet wakefulness. The elevated levels of hypocretin during active wakefulness and REM sleep were thought to be consistent with a role for hypocretin in motor planning. Central motor systems have been shown to reach discharge levels equal or greater than those of active waking during REM sleep and have minimal discharge during slow wave sleep (Siegel, 2000). On the other hand, recording from hypocretin neurons in head fixed rats revealed that these neurons discharge during active waking when postural tone is high in association with movements, decrease discharge during quiet waking in the absence of movement and virtually cease firing during sleep when postural tone is low or absent. During REM sleep, they remain relatively silent in association with postural muscle atonia and most often despite phasic muscular twitches. Their firing rate increases towards the end of REM sleep and thereby herald the return of waking and muscle tone (Lee et al., 2005). The different species and methods employed in these studies may account for the discrepant observations about hypocretin physiology especially in REM sleep. In the squirrel monkey which, like humans, consolidates sleep into a single daily episode, hypocretin-1 levels in the cisternal CSF peak in the latter third of the day and decline during sleep. Levels remain low during the initial 1–3 h of wakefulness despite elevated levels of motor activity (Zeitzer et al., 2003). In man, hypocretin-1 levels vary slightly but significantly across the diurnal cycle but are lowest at midday and highest in the middle of the night while subjects are mostly asleep. These unexpected findings have been attributed to a delay in equilibration between higher CSF compartments and the lumbar sac (Salomon et al., 2003). Further studies are in order. 5.2. Effects on arousal mechanisms Hypocretin has been shown to promote wakefulness by exciting the nonspecific thalamocortical projection neurons that stimulate and maintain cortical activation through widespread projections to the cerebral cortex (Bayer et al., 2002). Dense excitatory projections to brainstem arousal systems such as the noradrenergic locus ceruleus (Hagan et al., 1999; Horvath et al., 1999), the serotonergic dorsal raphe (Liu et al., 2002) and the histaminergic tuberomammillary nucleus (Bayer et al., 2001) have also been identified. Hypocretin neurons have been found to project to the ventral tegmental area (Peyron et al., 1998) and

specifically to the recently discovered wake active dopaminergic neurons in the periaqueductal gray matter (Lu et al., 2006). Hypocretin may directly excite dopaminergic neurons in the midbrain ventral tegmental area (Korotkova et al., 2003). It has also been shown to excite cholinergic neurons in the brain stem (Burlet et al., 2002) and basal forebrain (Eggermann et al., 2001). Some evidence suggests that its actions on the histaminergic tuberomammillary nucleus are singularly important to its wake promoting actions (Huang et al., 2001; Yamanaka et al., 2002). The decline or absence of hypocretin neuronal activity during NREM sleep, attributed to the activity of GABA afferents from the basal forebrain and preoptic area (Alam et al., 2005; Eggermann et al., 2003; Gaus et al., 2002), corresponds to the decline in activity in monoaminergic and cholinergic centers during this state. Since hypocretin activates the monoaminergic neurons that normally inhibit the sleep active neurons in the preoptic area, the absence of hypocretin would tend to promote sleep (Saper et al., 2001). Indeed, a dual orexin receptor antagonist, ACT-078573, which blocks both hypocretin receptors, has been shown to effectively promote sleep in rats, dogs and humans (Brisbare-Roch et al., 2007). Hypocretin has also been shown to have the capacity to evoke the release of the excitatory neurotransmitter glutamate and the inhibitory neurotransmitter GABA at specific sites in the nervous system (Follwell and Ferguson, 2002; van den Pol et al., 1998). The release of these neurotransmitters may modify or even block hypocretin’s excitatory effects. For example, recent work has demonstrated that hypocretin-1 can inhibit cholinergic neurons in the brain stem by activating GABA containing local interneurons and GABA containing neurons in the substantia nigra pars reticulata (Takakusaki et al., 2005). Increased levels of the inhibitory neurotransmitter, GABA, can be found in the locus ceruleus and dorsal raphe during REM sleep (Nitz and Siegel, 1997a,b). This may help account for the inhibition of noradrenergic and serotonergic neurons during this sleep state even in the presence of the normally excitatory peptide hypocretin (Kiyashchenko et al., 2002). 5.3. Effects on motor activity The activation of arousal systems by hypocretin is paralleled by concomitant effects at many levels of the neuraxis that maintain motor tone and promote motor activity. In the absence of hypocretin, these facilitatory effects on the arousal and motor systems may diminish or be lost. For example, the hyperlocomotion and stereotypy that can be produced by hypocretin-1 are mediated by the dopaminergic system and can be blocked by dopamine D1 or D2 antagonists (Nakamura et al., 2000). In narcolepsy, however, the sensitivity of the dopaminergic system is altered and low doses of agents that are normally inert may increase or block cataplexy. In the narcoleptic dog, infusion of the D2 dopamine receptor agonist quinpirole into the ventral tegmental area or into the globus pallidus/putamen produces an increase in cataplexy while raclopride, a D2 dopamine receptor antagonist has the opposite effect. These findings suggest that the mesolimbic dopaminergic system is hypersensitive to autoreceptor agonists in canine narcolepsy (Nishino et al., 1991; Reid et al., 1996) an in keeping with this, an increase in D2 dopamine receptors in the rostral caudate and amygdala of these animals has been reported (Bowersox et al., 1987) as well as signs of reduced dopamine turnover (Mefford et al., 1983). A similar increase in striatal D2 receptor binding together with a marked reduction in dehydroxyphenylacetic acid, a dopamine metabolite, was demonstrated in the post-mortem human narcoleptic brain (Kish et al., 1992). More recently, Eisensehr et al. (2003) used SPECT to demonstrate an increase in D2 receptor bindings in vivo in patients with narcolepsy. They found that the increase was pre-synaptic

M. Mamelak / Progress in Neurobiology 89 (2009) 193–219

and that it correlated with the incidence of cataplexy. They argued that methodological problems accounted for the failure of other groups to discover this relationship (MacFarlane et al., 1997; Rinne et al., 1995; Staedt et al., 1996). The increased sensitivity of D2 dopamine receptors to its agonist may reflect an adaptive response to an overall decrease in dopaminergic activity in the absence of hypocretin and reveals a role for dopamine in the control of motor tone that is not otherwise apparent. A similar adaptive response to the absence of hypocretin may occur in the noradrenergic and serotonergic neurons. The release of noradrenaline and serotonin at motor neuron pools from descending tracts emanating from the locus cerulerus and dorsal raphe normally contributes to the maintenance of motor tone (Lai et al., 2001). Noradrenergic and serotonergic neuronal activity are both reduced during REM sleep when muscle tone is low (Siegel, 2000). With the loss of hypocretin, the release of both transmitters may be even further reduced. Thus, while locus ceruleus activity is virtually absent during REM sleep in the rat (Aston-Jones and Bloom, 1981), it may be even lower in REM sleep or cease entirely, in the narcoleptic dog during cataplexy (Wu et al., 1999). In canine narcolepsy and in the human form of the disorder, antidepressant drugs that inhibit the reuptake of noradrenaline are more effective than dopaminergic or serotonergic uptake inhibitors for reducing cataplexy (Mignot et al., 1993; Nishino and Mignot, 1997). The a1b adrenergic receptor most likely mediates the anticataplectic effects of the noradrenergic reuptake inhibitors. In both the narcoleptic dog and man, prazocin, an alpha-1 adrenergic antagonist, increases cataplexy (Guilleminault et al., 1988; Mignot et al., 1989). Studies at the a-2 adrenergic receptor, although not as convincing, also suggest that agents that promote the release of noradrenaline inhibit cataplexy while the opposite holds true for agents that decrease the availability of noradrenaline (Nishino and Mignot, 1997). Reduced noradrenergic neuronal activity may account for the elevated number of a-2 adrenoreceptors in the locus ceruleus in canine narcolepsy (Fruhstorfer et al., 1989). Although noradrenaline and serotonin act in concert with other agents to control muscle tone (Kodama et al., 2003) a drop in the availability of these transmitters and specifically, noradrenaline, again possibly as a result of the absence of hypocretin, contributes to the instability of the motor system in narcolepsy. Destruction of a small region in the pontine reticular formation just ventral to the locus ceruleus, the peri-LCa, eliminates all aspects of REM sleep (Jouvet and Delorme, 1965; Luppi et al., 2004). Bilateral injections of carbachol, a cholinergic agonist, into this region induces REM sleep after a very short delay. Ascending cholinergic neurons from the dorsal and rostral region of the periLCa are responsible for cortical activation during REM sleep. A set of glutamatergic neurons found in all parts of the peri-LCa that is also activated by carbachol projects caudally to the ventromedial bulbar reticular formation where it synapses with descending glycinergic premotor neurons. The release of glycine hyperpolarizes these motor neurons and, with assistance from GABA, produces the atonia of REM sleep (Kodama et al., 2003; Luppi et al., 2004). Coincident with the phasic events of REM sleep such as the rapid eye movements or PGO spikes, additional descending volleys, mediated by the medial and descending vestibular nuclei, stimulate pre- and post-synaptic circuits to respectively enhance the motor atonia of REM sleep and produce its muscular twitches (Pompeiano, 1967). In canine narcolepsy, cholinergic hypersensitivity is a feature of both the pontine and basal forebrain cholinergic systems. The infusion of low doses of carbachol, a muscarinic M2 receptor agonist into either region can elicit cataplexy (Nishino et al., 1995) and upregulation of these receptors has been found in the brainstem (Boehme et al., 1984). In normal dogs much higher doses are required for the same response (Nishino et al., 1995).

199

Although it has been more difficult to demonstrate the development of cholinergic supersensitivity in the human form of the disease (Nishino and Mignot, 1997), this increased sensitivity may, again, betray the loss of normal cholinergic neuronal activation by hypocretin. The key role of hypocretin in the regulation of motor control by neurons in the pontine reticular formation is illustrated by the two- to threefold increase in the duration of REM sleep and the induction of cataplexy when microdialysis perfusion of this region is conducted with hypocretin-2 receptor antisense (Thakkar et al., 1999). A number of studies have also specifically examined the capacity of hypocretin to act directly at the level of the motoneuron. In the brain stem, the application of hypocretin to the trigeminal and hypoglossal motor nuclei produces an increase in masseter muscle tone and genioglossus muscle activity respectively but the actions of hypocretin at these sites may be mediated by glutamate. In both cases, pretreatment with D-AP5, an N-methyl-D-aspartic acid (NMDA) glutamate receptor antagonist, abolishes the excitatory response (Peever et al., 2003). Stimulation of the hypothalamus has been shown to produce a complex sequence of depolarizing-hyperpolarizing potentials in spinal motoneurons and it has been tentatively concluded that hypocretin acts both pre- and post-synaptically (Yamuy et al., 2004). The evidence to date suggest that hypocretin acts pre-synaptically to release the putative neurotransmitter glutamate, while other findings demonstrate that the juxtacellular application of hypocretin depolarizes motoneurons and often produces high frequency discharge. Preliminary work has identified hypocretin receptors on motoneurons (Yamuy et al., 2000). 6. Hypocretin: therapeutic applications Given the physiological effects of hypocretin, it is not surprising that experiments have been undertaken to determine whether hypocretin can be therapeutic in narcolepsy. In one study the intravenous infusion of hypocretin-1, which was shown in mice to rapidly enter the brain from the blood by diffusion (Kastin and Akerstrom, 1999), produced a dose related reduction in the frequency of cataplexy in the dog with narcolepsy in which the disease is caused by a mutation in the hypocretin-2 receptor (John et al., 2000). The duration of wakefulness was prolonged and the waking state was accompanied by an increase in the dog’s activity level. Most impressive, the periods of sleep also become longer, more continuous and stable. Other investigators, however, have not been able to reproduce these findings (Fujiki et al., 2003) and, in distinction to Kastin and Akerstrom, reported that the blood– brain barrier was impermeable to hypocretin-1. On the other hand, when hypocretin-1 was delivered intracerebroventricularly to mice whose hypocretin neurons had been ablated, the duration of wakefulness was strikingly increased and episodes of cataplexylike behavioural arrests were almost completely suppressed (Mieda et al., 2004). The potential effectiveness in narcolepsy of an agent like hypocretin-1 that stimulates wakefulness and muscle tone makes it all the more puzzling that GHB, a hypnotic and anesthetic agent which induces hypotonia of the skeletal muscles (Vickers, 1969) and, at times, full blown cataplexy (Price et al., 1981) can alleviate the symptoms of narcolepsy. 7. The treatment of narcolepsy Guidelines for the treatment of narcolepsy and future approaches to its management have recently been published (Billiard, 2008; Morgenthaler et al., 2007; Wise et al., 2007). Although keeping to a regular sleep schedule, taking brief naps during the day and avoiding heavy meals and especially large

200

M. Mamelak / Progress in Neurobiology 89 (2009) 193–219

quantities of carbohydrate can mitigate the symptoms of narcolepsy, most patients with narcolepsy, and especially those with frequent attacks of cataplexy, come to rely on drugs. In one survey, over 90% of patients reported using medication to control their symptoms (American Narcolepsy Association, 1992). While a nap may relieve sleepiness for an hour or two (Roehrs et al., 1986), it is hardly a practical solution for those trying to hold down a job or participate in social and recreational activities and family life. Amphetamine was first introduced to treat narcolepsy in 1935 (Prinzmetal and Bloomberg, 1935) and the tricyclic antidepressants (TCA) were added in 1960 soon after they became available (Akimoto et al., 1960). Stimulants and antidepressants have since been the twin pillars of treatment. 7.1. The stimulants: amphetamine, methylphenidate, modafinil Amphetamine, a racemic mixture of L- and D-amphetamine has its primary molecular targets both the vesicular monoamine transporters and the plasma monoamine dopamine, norepinephrine and serotonin transporters. Amphetamine relies on its ability to act as a substrate for these transporters and ultimately to increase the extracellular levels of monoamines. Amphetamine achieves this increase by inducing synaptic vesicle depletion, which increases intracellular monoamine levels and also by promoting reverse transport (efflux) through plasma membrane monoamine transporters (Fleckenstein et al., 2007; Nishino and Mignot, 2007; Robertson et al., 2009). The exact mechanism by which amphetamine promotes wakefulness remains to be elucidated but studies in control and narcoleptic dogs suggest that dopamine is the key agent (Kanbayashi et al., 2000; Nishino et al., 1998). The wake promoting effect of amphetamine is maintained even after the severe reduction of brain norepinephrine (Jones et al., 1977). Amphetamine requires the dopamine transporter (DAT) for its wake promoting effects. DAT knockout mice are totally insensitive to its wake promoting properties (Wisor et al., 2001). Thus, an increase in the concentration of dopamine in the synaptic cleft appears necessary for the alerting actions of amphetamine. Accordingly, it has been found that the intracerebroventricular infusion of D1 and D2 dopamine receptor agonists in sleeping rats induces a dose dependent increase in wake time (Isaac and Berridge, 2003). A recent study has shown that amphetamine infusions directly into mesial basal forebrain initiate and maintain alert wakefulness and that this site appears to be distinct from sites previously associated with amphetamine induced locomotion (Berridge et al., 1999). Although amphetamine is utilized clinically for its wake promoting actions, it also produces a compensatory increase in sleep and sleep intensity as its effects wear off (Oswald, 1970; Tecce and Cole, 1974). Both the L- and D-isomers of amphetamine have been used to treat narcolepsy but the D-isomer has been found to be slightly more potent (Parkes, 1976) and dextroamphetamine is now commonly used in clinical practice in daily doses that range between 5 mg and 60 mg. Its half life is about 12 h and the drug is usually prescribed in divided doses during the day although slow release preparations are also available. In addition to its effects on drowsiness, dextroamphetamine will also relieve cataplexy to some extent perhaps because it can also release noradrenaline. Emotional lability, headaches, palpitations, tremors, dry eyes, sweating and insomnia are the typical side effects although changes in mood, suspiciousness and frank paranoia are the most troubling adverse events. The alerting effect of dextroamphetamine wears off in time. It remains to be determined whether this is because of the development of tolerance or because the drug causes sleep deprivation by preventing sleep during the day and then rebound sleepiness when it wears off but in clinical practice

dextroamphetamine may regain much of its effectiveness if the drug is discontinued for a day or two and this drug holiday slept away. While the development of tolerance is common, dependence on amphetamine rarely occurs in patients with narcolepsy (Mitler et al., 1993). Methylphenidate (Ritalin1), a 1:1 racemic mixture of L- and Dmethylphenidate, is a piperidine derivative that is structurally related to amphetamine and that has pharmacological properties that are essentially the same as amphetamine (Hoffman and Lefkowitz, 1996). However, methylphenidate has little effect on granular dopamine storage and primarily blocks dopamine reuptake (Fukui et al., 2003; Mignot and Nishino, 2005; Nishino and Mignot, 2007). It was first introduced for the treatment of narcolepsy by Yoss and Daly in 1959 and soon became more popular than amphetamine perhaps because its short 2 h half life allowed it to be used on an as needed basis. Methylphenidate also made it possible for patients with narcolepsy to nap during the day if they wished (Nishino and Mignot, 1997). However, extended release formulations of methylphenidate that have a duration of action of about 8 h are now also commonly prescribed. Daily doses range from 10 mg to 60 mg. Although methylphenidate’s side effect profile is similar to that of the amphetamines, it is considered to have a better therapeutic index, i.e., the risk of adverse events in less when taken at therapeutic doses (Banerjee et al., 2004). The development of drug dependency is uncommon. During the past decade, modafinil (Provigil1; Alertec1) has become the drug of first choice in many centers for the treatment of excessive daytime drowsiness in narcolepsy (Boutrel and Koob, 2004). In the United States, modafinil has also been approved for the treatment of shift work sleep disorder and as an adjunct in the treatment of residual drowsiness in sleep apnea/hypopnea (Czeisler et al., 2005; Keating and Raffin, 2005). Its mechanism of action and its clinical properties and applications have recently been reviewed (Gerrard and Malcolm, 2007; Kumar, 2008). Modafinil, like the other stimulants discussed earlier, is a 1:1 racemic mixture of L- and D-isomers in which the half life of the Disomer is about 3–4 times longer than the L-isomer (10–14 h vs. 3– 4 h). The longer acting D-isomer is currently being developed as a distinct agent for the treatment of excessive drowsiness in narcolepsy (Harsh et al., 2006). Modafinil’s mechanism of action is slowly being unraveled. Studies have demonstrated that modafinil’s wake promoting effects can be blocked both by dopamine receptor agonists like quinpirole that inhibit the release of dopamine as well as by a-1 adrenergic antagonists like terazocin that block noradrenaline (Wisor and Eriksson, 2005). Nevertheless, in distinction to the amphetamines, modafinil retains its wake promoting effects in the face of D1/D2 dopamine receptor antagonists (Duteil et al., 1990; Lin et al., 1992; Wisor and Eriksson, 2005). It also remains effective in the absence of all noradrenaline transporter bearing forebrain noradrenergic projections (Wisor and Eriksson, 2005). The cell membrane dopamine transporter is the only documented binding site for modafinil in the central nervous system (Mignot et al., 1994) and modafinil has been shown to increase the extracellular concentration of dopamine in the prefrontal cortex (de Saint Hilaire et al., 2001) and in the caudate (Wisor et al., 2001). The binding of modafinil to the dopamine transporter is weak and the increased release of dopamine may occur indirectly (Nishino and Mignot, 2007). But, since there is evidence that dopamine may stimulate adrenergic receptors in different areas of the brain (Cornil et al., 2002; Crochet and Sakai, 2003; Malenka and Nicoll, 1986) and that dopamine and noradrenaline are nearly equipotent at activating second messenger pathways through a-1 adrenergic receptors (Zhang et al., 2004), it has been proposed that dopamine may stimulate adrenergic receptors at anatomical sites where dopaminergic projections are present in abundance in close

M. Mamelak / Progress in Neurobiology 89 (2009) 193–219

apposition to adrenergic receptors (Wisor and Eriksson, 2005). Wake promoting adrenergic receptors and dopamine transporter bearing dopaminergic terminals are found together in the basal forebrain cholinergic complex, cerebral cortex and thalamus (Berridge et al., 2003; Jones, 2004; McCormick, 1992) but not in the locus ceruleus, lateral dorsal tegmentum and pedunculopontine tegmentum (Siegel, 2000). This anatomical specificity for modafinil’s action has been used to explain modafinil’s capacity to promote wakefulness and not to activate brainstem adrenergic pathways to prevent cataplexy. Acting through a-1 noradrenergic pathways, modafinil may foster alertness by potentiating the activity of cortically projecting neurons of the basal forebrain (Berridge et al., 2003). Modafinil has also been shown to potentiate noradrenergic inhibition of the sleep active neurons of the ventrolateral preoptic area (Gallopin et al., 2004). Modafinil may also promote alertness indirectly by elevating extracellular histamine levels in the anterior hypothalamus (Ishizuka et al., 2003) or by activating the tuberomammilary nucleus (Scammell et al., 2000). It suppresses cortical GABA release (Tanganelli et al., 1995) and may also indirectly elevate brain extracellular glutamate levels (Ferraro et al., 1998). As well, modafinil may be capable of activating the hypocretin system (Scammell et al., 2000) although it is unlikely that modafinil acts through this system since the wake promoting effects of modafinil have been shown to be greater in hypocretin-null mice (Willie et al., 2005). The exact mechanism by which modafinial promotes alertness, therefore, awaits definition but it is of some interest that aside from its actions on central neurotransmission, modafinil’s alerting effects have been related to its neuroprotective and antioxidant properties (Gerrard and Malcolm, 2007). Curiously, modafinil shares these properties with another alerting agent-GHB (Mamelak, 2007). The usual adult daily dose of modafinil is between 200 mg and 400 mg divided between morning and noon. The commonest side effects are headaches and nausea. Modafinil, however, may decrease the peak plasma concentrations of ethinyl estradiol and women, therefore, are advised to seek alternative or additional methods of contraception while taking modafinil and for 1 month after stopping it. Tolerance to modafinil’s alerting effects is slow to develop and, in one study, was not observed after 40 weeks of treatment (Mitler et al., 2000). Although modafinil’s alerting and performance enhancing effects in the face of sleep loss may be no greater than that of caffeine (Wesenstein et al., 2002) tolerance to caffeine’s psychostimulant effects may develop in time (Fredholm et al., 1999). 7.2. Novel experimental alerting agents The stimulant properties of histamine-3 receptor antagonists are currently being explored. Other investigators have examined the alerting effects of thyrotropin releasing hormone agonists and there has naturally been great interest in the possible development of hypocretin peptide supplementation, hypocretin receptors agonists, hypocretin gene therapy and even hypocretin cell transplantation (Mignot and Nishino, 2005). These initiatives may radically alter the future treatment of excessive daytime drowsiness and narcolepsy. But, for the time being, clinical practice relies mostly on the three stimulants described earlier despite the fact that none of the these stimulants can restore alertness to normal levels (Mitler et al., 1993; Mitler et al., 1994), whether measured subjectively with the Epworth Sleepiness Scale or more objectively with the multiple wakefulness test. 7.3. The antidepressants: tricyclics, SSRIs and MAO inhibitors The effects of the antidepressants on central neurotransmission and on sleep have been extensively studied and it has been found

201

that their capacity to increase the synaptic availability of noradrenaline and serotonin appears to be associated, at least initially with suppression of REM sleep and with an increase in sleep fragmentation (Mayers and Baldwin, 2005; Wilson and Argyropoulos, 2005). In time, usually after a number of weeks, these effects wear off with both the tricyclic antidepressants (TCAs) and the selective serotonin reuptake inhibitors (SSRIs) although REM sleep suppression with the MAO inhibitors appears to last as long as theses drugs are prescribed. The REM sleep suppressing effects of the antidepressants have been exploited to treat the auxiliary symptoms of narcolepsy, cataplexy, sleep paralysis and hypnagogic hallucinations, all 3 of which are based on the dissociated activation of REM sleep (Akimoto et al., 1960; Guilleminault et al., 1976; Hishikawa et al., 1966). An increase in synaptic noradrenaline may be the key neurotransmitter regulating the level of muscle tone in the dog with narcolepsy (Mignot et al., 1993; Nishino et al., 1993; Nishino and Mignot, 1997). For example, locus ceruleus noradrenergic neurons are silent during REM sleep and cataplexy in these animals but serotonergic neurons retain some activity during cataplexy (Wu et al., 1999, 2003). The anticataplectic actions of both the TCAs and the SSRIs in canine narcolepsy have been attributed to adrenergic reuptake inhibition. Serotonin reuptake blockers were only effective at high doses and dopaminergic reuptake blockers were entirely ineffective. Many antidepressants are known to be metabolized significantly by hepatic first pass into demethylated compounds that have longer half lives and higher affinities for adrenergic reuptake sites. Thus, the demethylated metabolite of chlorimipramine, the most powerful serotonin reuptake inhibitor of all the TCAs (Wilson and Argyropoulos, 2005) and the demethylated metabolite of the SSRI, fluoxetine, were both found more effective against cataplexy in the dog than the parent compound. There is some evidence that the antidepressant actions of both the TCAs and SSRIs also owe their effectiveness for the most part to the inhibition of noradrenaline reuptake. Genetically modified mice which are unable to synthesize noradrenaline and adrenaline fail to respond to the behavioural effects of most antidepressants including the SSRIs with the exception of citalopram, the most selective of the SSRIs (Cryan et al., 2004). In 5HTIA knockout mice, the REM suppressing effect of the citalopram was absent (Monaca et al., 2003). Further studies are necessary to determine if noradrenaline is the key neurotransmitter controlling REM sleep and cataplexy in species other than the dog. In man, clomipramine is the most effective anticatplectic TCA and the most powerful REM sleep suppressing agent in this class of drugs (Chen, 1979; Wilson and Argyropoulos, 2005). Effective doses of clomipramine range between 10 mg and 150 mg (Guilleminault et al., 1976; Nishino and Mignot, 1997; Parkes and Schachter, 1979). The TCAs reduce the incidence and severity of cataplexy within 1 or 2 days (Gross, 1969; Linnoila et al., 1980) but tolerance tends to develop after a few months and necessitates an increase in the dose (Linnoila et al., 1980). The side effects of the TCAs are well described and have been attributed to their actions, usually antagonistic, at muscarinic cholinergic, a-1 and a-2 adrenergic, H-1 histaminergic and 5HT 1A and 5HT2 serotonergic receptors (Wilson and Argyropoulos, 2005). The TCAs may cause sedation, hypotension, seizures, weight gain, and sexual dysfunction, and their muscarinic cholinergic effects in particular, produce dry mouth, urinary retention and constipation. These cholinergic side effects contraindicate their use in patients with glaucoma. The TCAs also have quinidine-like properties which may depress the myocardium and prolong cardiac conduction time. Sudden withdrawal of the TCAs, the SSRIs and the MAO inhibitors as well leads to a rebound increase in REM sleep (Wilson and Argyropoulos, 2005). In patients with narcolepsy and cataplexy, withdrawal can lead to a severe rebound increase in

202

M. Mamelak / Progress in Neurobiology 89 (2009) 193–219

cataplexy and the development of status cataplecticus (MartinezRodriguez et al., 2002; Parkes and Schachter, 1979). As noted earlier, cataplexy on withdrawal of antidepressants has even been observed in depressed patients who don’t have narcolepsy (Nissen et al., 2005). The rebound increase in REM sleep and cataplexy has been ascribed to a rebound increase in cholinergic neurotransmission (Wilson and Argyropoulos, 2005). This, in turn, has been attributed to the prolonged suppression of cholinergic tone and the development of cholinergic supersensitivity after the chronic exposure of the cholinergic neuronal system to high levels of noradrenaline and serotonin. In current practice, the SSRIs are more popular than the TCAs for the treatment of cataplexy because they have fewer side effects. These drugs reduce the overall duration of REM sleep during the night and delay the first entry into REM sleep but, as with the TCAs, these sleep effects fade within weeks. A rebound increase in REM sleep follows their withdrawal (Wilson and Argyropoulos, 2005). Although the SSRIs are able to control cataplexy, the general consensus has been that these drugs are less potent than the TCAs (Nishino and Mignot, 1997). Fluoxetine is commonly prescribed is doses between 20 and 60 mg/day. The typical side effects of the SSRIs are nausea, headaches and sexual dysfunction. The MAO inhibitors (MAOIs) increase monoamine transmission by inhibiting the enzyme monoamine oxidase. Two forms of the enzyme exist, MAOA and MAOB. The older MAOIs, phenelzine, pargyline, tranylcypromine produce nonselective irreversible inhibition of both forms of the enzyme. Although these drugs are effective treatments for the auxiliary symptoms of narcolepsy and may even improve alertness, they are hardly ever prescribed today because of their poor safety profile (Nishino and Mignot, 1997; Wyatt et al., 1971). Selegeline, a selective irreversible MAOB inhibitor that counts L-amphetamine and L-methamphetamine among its metabolites, has been shown to reduce daytime sleepiness and to improve cataplexy (Hublin et al., 1994; Mayer et al., 1995; Nishino and Mignot, 1997; Roselaar et al., 1987). Lower doses of this drug are reasonably safe, but the higher more effective doses may require the same dietary precautions as the nonselective MAO inhibitors to prevent a tyramine induced hypertensive crisis. 8. The treatment of narcolepsy and cataplexy with GHB The properties of sodium oxybate and its use in the treatment of narcolepsy have recently been the subject of a number of excellent reviews (Castelli, 2008; Pardi and Black, 2006; Robinson and Keating, 2007; Scharf, 2006; Wong et al., 2004). GHB’s capacity to alleviate the symptoms of narcolepsy and cataplexy was first reported by Broughton and Mamelak in 1976. The essential features of its clinical and polysomnographic effects in this disease were documented in follow up studies by the same investigators (Broughton and Mamelak, 1979, 1980). The oral administration of GHB in divided doses between 3.75 g and 6.25 g for 7–10 nights to patients with narcolepsy who had been free of all medication for at least 2 weeks led to a reduction in both the incidence and intensity of cataplexy and the duration of sleep during the day. Subjective drowsiness, however, persisted. Night sleep was perceived as deeper and less restless. Nightmares and hallucinations were eliminated although dreaming persisted. The 48 h continuous polysomnographic recordings that were conducted in these studies at baseline and then again at the end of the drug treatment period revealed that the nocturnal application of GHB significantly increased the duration of slow wave sleep at the expense of stage I sleep. The duration of REM sleep was unchanged but REM density was significantly decreased and REM sleep latency was dramatically decreased. REM sleep fragmentation was reduced and although the total sleep time at night was unchanged, sleep at

night was less fragmented with significantly fewer periods lasting less than 15 min. During the day, the durations of both slow wave sleep and REM sleep were significantly reduced and, discounting the increase in drowsiness or stage I sleep, there was an overall and significant reduction in the duration of daytime sleep. There were significantly fewer daytime sleep periods that lasted 45 min or more. All in all, the lines between the states of sleep and wakefulness, blurred in untreated patients, became more distinct after treatment with GHB. GHB appeared to reintegrate the three vigilance states. These findings were soon corroborated and extended by other investigators who collected large case series (Mamelak et al., 1986; Scharf et al., 1985) and reported that tolerance failed to develop to GHB over time in contrast to treatment with conventional stimulant and antidepressant drugs. These investigators also found that adverse effects were few and usually easily managed. At this time, in the year 2009, many patients with narcolepsy and cataplexy have been using GHB nightly for more than 20 years. (One 85-year-old woman has been using the drug nightly since 1977.) Double blind placebo controlled trials which confirmed GHB’s effectiveness in narcolepsy and cataplexy were carried out by Scrima et al. (1989, 1990) as well as by Lammers et al. (1993). In 2002, GHB (Xyrem1, sodium oxybate) was approved by the United States Food and Drug Administration for the treatment of cataplexy. Three years later, in 2005 approval was granted for the treatment of excessive daytime drowsiness. Approval followed the completion of a series of large multicentre clinical trials. In the first of these trials (US Xyrem, 2002), 136 patients with narcolepsy and cataplexy remained on their stable dose of stimulant medication but were gradually withdrawn from their anticataplectic and hypnotic medication and, following a washout period, patients having at least three attacks of cataplexy per week were assigned to receive either placebo or 3 g, 6 g or 9 g of GHB for 4 weeks in equally divided doses at bedtime and again 2.5–4 h later. Symptomatic response was assessed using patient diaries and the Clinical Global Impression of Change (CGIc) scale while daytime drowsiness was measured with the Epworth Sleepiness Scale (ESS). At baseline, the incidence of cataplexy among study subjects ranged from 3 to 249 attacks per week. The median number was 21. The weekly incidence of cataplexy decreased in all four treatment groups over the 4 weeks period but was greatest in the three groups treated with GHB. The magnitude of the anticataplectic response was dose related and a significant 69% reduction in the incidence of cataplexy compared to baseline was reached with the 9 g dose. The ESS improved in all GHB treatment groups, again, in a dose related manner and again reached significance with the 9 g dose. Indeed, at this dose, the subjective measure of sleepiness on the ESS fell into the normal range in a number of patients. A dose related response was also found with the CGIc that also became significant with 9 g. At this does, 80% of patients reported that they were much improved or very much improved after 4 weeks of nightly treatment with GHB compared with 32% in the placebo group. There was also a significant reduction in the number of inadvertent naps or sleep attacks during the day in both the 6 g and 9 g treatment groups. At the 9 g dose, there was also a significant decrease in the number of nocturnal awakenings. All doses of GHB reduced the incidence of sleep paralysis and hypnagogic hallucinations. Most adverse events occurred within the first few days following the start of treatment and tended to decrease with time. The adverse events that occurred at a significant level and in a dose related manner consisted of nausea, vomiting, dizziness and enuresis. Clinical experience outside of these trials has shown that some patients may sleep walk on GHB and may also be confused at night if they wake before the drug is eliminated. There has also been a concern about the sodium load delivered with each dose of GHB especially

M. Mamelak / Progress in Neurobiology 89 (2009) 193–219

in patients with hypertension. In some cases the increased sodium intake has lead to water retention. One hundred and eighteen of the patients who participated in the initial 4-week trial elected to join a 12-month extension trial (US Xyrem, 2003). All patients began treatment at 6 g per night in equally divided doses as before. Based on the clinical response, the investigator could choose to decrease the total nightly dose to 4.5 g or 3 g or increase it to 7.5 g or 9 g. Patients were permitted to use a stable dose of a stimulant throughout the trial. The data from this open label study revealed that all doses between 3 g and 9 g produce significant long term improvements in the incidence of cataplexy. This improvement was rapidly progressive during the first month but the incidence of cataplexy fell further during the course of the year. The findings indicated that GHB was progressively more effective with time and that it was effective over time at even the lowest 3 g dose. With long term use, even this low dose controlled cataplexy in many patients. There was also a significant improvement in daytime sleepiness for all treatment groups that was maximal after 2 months and stable for the remainder of the 12-month study. Thus, patients on stimulants felt even more alert with the added use of GHB and were better able to concentrate. The quality of sleep at night was also significantly improved. In the course of this long term study, dizziness was the only side effect which occurred at a significant level. There was no evidence for dose escalation to suggest the development of tolerance to the therapeutic effects of GHB or any tendency to abuse it. Another study demonstrated that the abrupt withdrawal of GHB from patients with narcolepsy who had received nightly doses of 3–9 g for 7–44 months led only to the gradual return of the symptoms of the disease. There was no rebound increase in cataplexy (US Xyrem, 2004). Thus, withdrawal from clinically appropriate doses of GHB was a relatively benign event. This stands in contrast to the abrupt discontinuation of higher recreational doses of GHB, estimated to range between 43 and 144 g/day, which can lead to a severe withdrawal syndrome which resembles the one noted after the withdrawal of alcohol and sedative hypnotic drugs (Tarabar and Nelson, 2004; Weerts et al., 2005). Disabling insomnia, anxiety, tremulousness progressing on to delirium have been described. Although the withdrawal of high doses of GHB rarely causes seizures, a prolonged period of delirium lasting as long as 2 weeks can occur. The abuse liability of GHB has been found to be intermediate to other commonly abused sedative hypnotics (Carter et al., 2006a). The lowest daily dose of GHB associated with withdrawal symptoms is reported to be 18 g and is at least twice as high as the highest dose recommended for the treatment of narcolepsy (Snead and Gibson, 2005). Activation of the GABAB receptor may be important for GHB dependence (Weerts et al., 2005). Reviews about GHB’s toxicology and about the mechanisms mediating its potential for abuse and addiction have recently been published (Carter et al., 2009; Castelli, 2008; Wong et al., 2004). The effects of GHB on sleep architecture were examined in a study on 25 patients with narcolepsy and cataplexy (Mamelak et al., 2004). These patients were gradually withdrawn from all sedative hypnotic and antidepressant drugs over a 2-week period that was followed by another 2-week washout period before the study began. All patients continued on their usual stable daily stimulant dose. They then received 4.5 g of GHB each night in divided doses for 4 weeks followed by escalating doses of 6, 7.5 and 9.0 g at subsequent 2-week intervals. Periodic polysomnographic studies recorded the effects of these increasing doses on the sleep architecture. The multiple wakefulness test (MWT) and the ESS were used to determine the effect on daytime sleepiness. As in earlier studies, GHB at bedtime initially further reduced the already shortened REM sleep latency and increased the overall

203

duration of REM sleep in the 4 h that followed. After 4 weeks, however, this effect was no longer observed and, indeed, escalating doses of GHB progressively depressed the duration of REM sleep and increased the duration of slow wave sleep. Delta power, a measure of the amplitude and frequency of the slow delta waves induced by GHB was significantly increased and even more so following the second dose during the night. The total sleep time at night was not increased, even with the highest dose, although the number of nocturnal awakenings declined significantly as the dose was increased. Despite the failure to increase the total sleep time, GHB demonstrated a dose related improvement in the capacity to stay awake during the day as well as in the subjective sense of alertness. At the highest 9 g dose, 6 subjects rated their sleepiness in the normal range (ESS score <11.0). Such low scores were not found in any of the subjects before treatment. GHB augmented levels of alertness beyond that achieved by stimulants alone. This effect was objectively confirmed with the MWT. A significant increase in mean sleep latency during the day was observed after 4 weeks of treatment with 4.5 g nightly and the latency to sleep was even more prolonged at the 9 g dose. These observations were extended in a multicentre placebo controlled parallel group trial that involved 228 patients who were maintained on their stimulant medications but withdrawn from all anticataplectic and hypnotic drugs and treated for 8 weeks with either placebo or 4.5 g, 6.0 g or 9.0 g of GHB in divided doses at night (Xyrem International, 2005a; Xyrem International, 2005b). After 8 weeks, patients treated with 9 g of sodium oxybate nightly displayed a significant median increase of greater than 10 min in the MWT and dose related decreases in median ESS scores and frequency of inadvertent naps which were significant at the 6 g and 9 g doses. The improvements in excessive daytime sleepiness were incremental to those achieved by concomitant stimulants alone (Xyrem International, 2005b). Compared to placebo, these doses of sodium oxybate all also produced statistically significant median decreases in the weekly incidence of cataplexy (Xyrem International, 2005a). Significant improvements in the CGIc were found in each group treated with sodium oxybate. Given these findings, a second double blind controlled trial was undertaken on 270 patients with narcolepsy to compare the impact of GHB on daytime sleepiness with that of modafinil (Black and Houghton, 2006). The patients in this double blind placebo controlled trial were randomly assigned to one of four treatment groups: (1) placebo, (2) GHB alone, at 6 g for 4 weeks followed by 9 g for another 4 weeks, (3) modafinil alone at the patient’s current dose and (4) GHB, 6 g and 9 g, as in group 2 together with modafinil as in group 3. Measures of daytime sleepiness with the multiple wakefulness test demonstrated that modafinil and GHB were each equally effective in maintaining alertness but even greater levels of alertness were achieved when modafinil and GHB were used together suggesting that the drug combination produced an additive effect. Patients treated with GHB or with GHB and modafinil had significantly fewer sleep attacks at the end of the trial compared to patients treated with modafinil alone or placebo. GHB alone also produced a significant decrease in the Epworth Sleepiness Scale and, again, a somewhat greater decrease occurred when GHB at night was combined with modafinil during the day. 9. GHB and its receptors 9.1. The GHB receptor GHB has been shown to bind to a family of specific GHB receptors and to act as a weak partial agonist at the GABAB receptor. Two specific binding sites for GHB, a high affinity site with a Kd between 30 and 580 nM and a low affinity site with a Kd between 2.6 and 16 mM, have been identified in crude rat brain

204

M. Mamelak / Progress in Neurobiology 89 (2009) 193–219

membranes as well as in human synaptosomal membranes obtained from brains at post-mortem (Benavides et al., 1982; Maitre et al., 1983; Maitre, 1997; Snead and Liu, 1984). Optimal binding at the high affinity site occur at pH 5.5 and drops off rapidly at each side of this value (Benavides et al., 1982). Neither GABA nor a host of other agents such as baclofen, muscimol, bicuculline, dopamine, naloxone, valproic acid or other antiepileptic drugs are able to displace [3H] GHB from its high affinity binding site. However, trans-g-hydroxy-crotonic acid (THCA), a structural analog and possible metabolite of GHB which has a similar distribution in the brain to that of GHB (Vayer et al., 1988), binds more effectively than GHB to the high affinity receptor at certain sites in the brain and less effectively at other sites suggesting that several isoforms of the GHB receptor may exist (Hechler et al., 1990). High affinity GHB binding sites have not been identified in peripheral tissues like liver and kidney (Andriamampandry et al., 2003; Snead and Liu, 1984) even though ample quantities of GHB are present in these organs (Nelson et al., 1981; Tedeschi et al., 2003). In the vertebrate nervous system, high and low affinity binding sites appear to exist only on neurons and not on glia (Maitre, 1997). With the use of autoradiography, the greatest concentration of high affinity binding sites is found in the hippocampus and specifically in the CA1 field. Regions innervated by dopaminergic terminals such as the putamen, caudate, nucleus accumbens and olfactory system also have high binding site concentrations. The frontal, parietal, temporal and cingulate cortices, amygdala and thalamus have lower concentrations in both the rat and human brain and the hypothalamus, cerebellum and pons-medulla appear devoid of binding sites (Castelli et al., 2000; Hechler et al., 1989, 1992; Maitre, 1997). Other investigators, however, using synaptic membranes prepared from various parts of the human brain and methods other than autoradiography, have identified binding in the hypothalamus and pons (Snead and Liu, 1984). The receptor has been shown to be distinct from the GABAB receptor, pre-synaptically located and G-protein linked (Ratomponirina et al., 1995; Snead, 1992, 2000) although some recent studies have failed to confirm this link (Castelli et al., 2003; Kaupmann et al., 2003; Odagaki and Yamauchi, 2004). The GHB receptor has recently been cloned from both the rat and human brain (Andriamampandry et al., 2003, 2007). In the rat, GHB receptor mRNA was detected in the brain and not in any other organ. Three distinct bands were present suggesting the existence of a family of GHB receptors. Receptor mRNA was identified in all regions of the rat brain in which GHB binding sites were identified as well as in the cerebellum. Thus, it was suggested that the distribution of receptor mRNA does not coincide with its expression in different brain regions. GHB analogs such as THCA and similar compounds that bind to the high affinity receptor in vivo in the rat brain bind to the cloned GHB receptor in transfected cells, but GABA, baclofen and glutamate are unable to displace [3H] GHB from its binding site in these cells. Despite these observations, doubts have been raised about the authenticity of this cloned receptor (Bettler et al., 2004). NCS-382, for example, a commonly used high affinity GHB receptor antagonist, failed to displace [3H] GHB from the cloned receptor. Does NCS-382, then, bind to another member of this receptor family? Moreover, although the cloned protein was reported to activate G proteins and to have seven putative transmembrane regions like other G-protein coupled receptors (GPCRs), the amino terminal part of the receptor was identified as a member of the tetraspanin gene family and no additional GPCR topology was visible at the carboxyl end. In response to these objections, it has been argued that the structure of the cloned receptor closely resembles the interaction between tetraspanins and partner proteins like GPCR which have been described in the central nervous system (Kemmel et al., 2006). However, additional

discordant information about this receptor has come from immunohistological studies. Several peptides belonging to the extracellular domain of the cloned rat GHB receptor were used to raise antibodies against it (Kemmel et al., 2006). With this technique, the distribution of receptor protein in the brain was found to closely resemble the distribution of high affinity GHB binding sites but the majority of the Purkinje cells in the cerebellum were also strongly stained. Receptor staining was not found on glia, and, in contrast to the findings with other methods, appeared to be localized to post-synaptic dendrites. Two isoforms of the GHB receptor have recently been cloned from the human brain (Andriamampandry et al., 2007). Both are thought to function as GPCRs although their structures do not conform to the typical seven transmembrane model. Their activation in transfected cells opens cation channels but not the same ones activated by the rat GHB receptor. To explain this discrepancy, it has been suggested that human and rat GHB receptors are coupled to different signal transduction pathways. One isoform of the human receptor, termed GHBh1, desensitizes rapidly on application of low concentration of GHB. NCS-382 has been shown to be an antagonist at the other isoform, termed C12 K32. The function of the GHB receptors remains elusive (Andriamampandry et al., 2007; Crunelli et al., 2006b). In a clonal neurohybridoma cell line, NCS-20, in which a functional GHB system has been demonstrated (Kemmel et al., 1998), GHB reduces Ca2+ entry when the cell membrane is depolarized by a voltage clamp or a high concentration of K+. A similar effect has been found in synaptosomes. But when the membrane is at its resting potential, physiological concentrations of GHB, between 5 and 25 mM, promote the entry of Ca2+ through T-type channels which, in turn, open Ca2+ activated K+ channels to hyperpolarize the cell membrane (Kemmel et al., 2003). This hyperpolarizing effect is reduced or lost with higher doses and suggests that the receptor is desensitized at these higher doses. Maitre has proposed that GHB functions normally to regulate the release of GABA, i.e., that the excessive release of GABA leads to the formation of GHB which in turn acts on pre-synaptic GHB receptors to increase the membrane potential and inhibit the further release of GABA. This control mechanism fails when high doses of GHB, like those used clinically, are given. These high doses downregulate the GHB receptor and eliminate the tonic inhibitory control of GHB receptors on the GABA pre-synaptic element. As a result, both GABA release and GABAergic tone are increased leading to sedation and sleep (Maitre et al., 2002). Some evidence in favour of this hypothesis was presented by Banerjee and Snead (1995) who employed microdialysis to demonstrate that GHB in doses of 250–1500 mM reduced the basal extracellular release of GABA in the rat thalamic ventrobasal nucleus. There was no effect on glutamate. However, GHB inhibited the K+ evoked release of both GABA and glutamate at this site. Other investigators, using neurophysiological techniques have also demonstrated that GHB does not uniquely regulate GABA release. Thus, Cammalleri et al. (2002), demonstrated that GHB in concentrations between 100 and 1200 mM reduced GABAA mediated inhibitory post-synaptic potentials in the CA-1 region of the hippocampus in the presence of GABAB blockade. This effect was prevented by the GHB receptor antagonist NCS-382 and was attributed to an action on the receptor at the pre-synaptic site. Brancucci et al. (2004a), also found that similar concentrations of GHB depressed the frequency and amplitude of spontaneous inhibitory post-synaptic currents in the substanita nigra pars compacta. These effects were again GABAB independent and were prevented with NCS-382. But, these investigators also demonstrated that the effects of GHB in these concentrations were not limited to the inhibition of

M. Mamelak / Progress in Neurobiology 89 (2009) 193–219

GABA release from pre-synaptic sites but could also be shown to inhibit the release of glutamate. Berton et al. (1999) demonstrated that GHB could inhibit excitatory post-synaptic potentials in the hippocampus in the face of GABAB blockade and that this effect was prevented by NCS-382 but in this instance GHB was thought to act at pre-synaptic sites to reduce glutamate release. Brancucci et al. (2004b), also showed that GHB could inhibit spontaneous excitatory post-synaptic currents but, in this case, recorded from dopaminergic neurons in the substantia nigra pars compacta. This effect was again attributed to a decrease in glutamate release and was observed in the presence of GABAB blockade and prevented by NCS-382. The need for the high doses of GHB, in excess of the physiological range, to define the role of the GHB receptors was explained by the optimal binding of GHB to its receptor at pH 5.5 while the electrophysiological studies were carried out at the physiological range of pH 7.4 (Cammalleri et al., 2002). The studies presented by Berton, Cammalleri and Branucci which, as will be described later have been challenged by other investigators (Gervasi et al., 2003), did not examine whether receptor desensitization occurred in response to the supraphysiological doses employed and thus the place of receptor desensitization in the sedative effects of GHB with the pharmacological doses used clinically remains to be clarified. A recent study in succinic semialdehyde dehydrogenase null mice, in which very high levels of GHB can be found in the brain, other tissues and urine, failed to demonstrate any changes in the binding of GHB or the GHB receptor antagonist, NCS-382, to the GHB receptor but did reveal a decrease in the binding of a specific GABAB receptor antagonist (Buzzi et al., 2006; Mehta et al., 2006). In this experimental model, GHB appeared to down regulate the GABAB receptor but not the GHB receptor. The role of the GHB receptor in the control of glutamate release has also been directly examined with microdialysis (Castelli et al., 2003). GHB in very low doses of 500 nM infused into the hippocampus increased the release of glutamate while a 1 mM solution had the opposite effect. Increased release was blocked by the GHB receptor antagonist NCS-382 while inhibition was blocked by a GABAB antagonist. These results suggest that the GHB receptor mediates the release of glutamate in response to low endogenous levels of GHB and that GABAB receptors mediate the inhibition of glutamate release in response to high pharmacological doses. However, the findings cited above by Berton et al. (1999) suggested that in the hippocampus high doses, 600 mM, also inhibited glutamate release yet in these experiments the inhibition was not mediated by GABAB receptors and could be prevented by NCS-382. Different test methods and different test sites may account in part for these discrepant findings but they highlight some of the challenges encountered in the search for the function of the GHB receptor. Progress in this regard is hindered but the absence of a specific GHB receptor antagonist. NCS-382, a semirigid compound structurally related to GHB, and commonly used as a GHB receptor antagonist, is a good ligand but not a selective antagonist. It may also inhibit GHB dehydrogenase and it appears capable of either eliciting qualitatively similar effects to GHB or even enhancing some of its actions (Carai et al., 2001; Carter et al., 2003). For example, NCS-382 actually enhances the loss of the righting reflex produced by GHB (Carai et al., 2001). These properties confound the interpretation of the test results obtained with this compound (Carai et al., 2001; Castelli et al., 2004; Gervasi et al., 2003). The development of structural analogues of GHB that bind selectively to the GHB receptor and not to the GABAB receptor and that cannot be metabolized to GABA heralds a new phase in studies on the function of the GHB receptors (Carter et al., 2005a,b; Wu et al., 2003). Two such structural analogues, THCA and NCS-435,

205

which displace [3H] GHB from GHB receptors with the same affinity as GHB but, unlike GHB, cannot displace [3H] baclofen from GABAB receptors, are able to raise extracellular glutamate levels in a dose related manner (Castelli et al., 2003). In this respect, they duplicate the effects of low doses of GHB. The effects of these analogues on glutamate release could be blocked by NCS-382, which had no effect on glutamate release on its own, but not by GABAB antagonists. As well, these analogues, in doses of 1000 mg/ kg or greater could not induce the loss of the righting reflex in mice which can easily be achieved by comparable doses of GHB. Thus, the use of structural analogues may yield useful insights into the function of the GHB receptor and may, perhaps, lead to new therapeutic agents. The R-isomer of HOCPCA (3-hydroxycyclopent-1-enecarboxylic acid) is the most potent ligand so far developed with a 39-fold greater affinity for the GHB receptor than GHB (Wellendorf et al., 2005). 9.2. The GABAB receptor While the physiological functions of the low concentrations of GHB found naturally in the brain, about 2–20 nM/g (Nelson et al., 1981; Snead and Morley, 1981) and the functions of the specific high affinity receptor to which it binds with a Kd of 30–580 nM remain uncertain, gathering evidence suggests that GHB’s striking effects when given to man and laboratory animals in pharmacological doses are mediated by the GABAB receptor, a heteromeric assembly of two subunits, GABAB1 and GABAB2 (Jones et al., 1998; Kaupmann et al., 1998). Thus, in laboratory rats, the intraperitoneal administration of GHB in doses between 100 and 400 mg/ kg raises brain tissue levels above 250 nM/g (Bernasconi et al., 2002; Snead, 1991) and reliably reduces body temperature, alters the synthesis and release of many neurotransmitters, hyperpolarizes cell membranes, produces EEG slow wave activity and induces sedation, sleep and coma. These pharmacological effects can be reproduced by baclofen, a specific GABAB agonist and can be blocked by GABAB antagonists but not by NCS-382 (Bernasconi et al., 2002; Carai et al., 2001). Indeed, in mice lacking the gene for the GABA1 subunit of the GABAB receptor and in which the GABAB2 subunit is also down regulated (Prosser et al., 2001; Queva et al., 2003; Schuler et al., 2001), GHB fails to produce its expected pharmacological effects (Carai et al., 2001; Kaupmann et al., 2003; Queva et al., 2003) despite an unchanged spatial distribution of [3H] GHB binding sites (Kaupmann et al., 2003). Thus, in these GABAB knockout mice, GHB no longer produces hypothermia, an increase in striatal dopamine synthesis or EEG slow wave activity, sleep and coma. Moreover, the application of GHB to brain membrane preparations from these mice no longer elicits a GTPg [35S] response as it does in brain membranes prepared from wild type mice. Since the GTPg [35S] response in wild type mice is blocked by the GABAB antagonist CGP54626 but not by the GHB receptor antagonist NCS-382, the GTPg [35S] response may exclusively be mediated by GABAB receptors and not by high affinity GHB receptors as previously proposed. GHB’s interaction with the GABAB receptor requires further study. Despite the evidence that GABAB receptor mediates the major pharmacological effects of GHB, GHB, at best, appears to be a weak agonist at this site with a weak affinity. In Xeropus occytes, GHB can activate the GABAB receptor coexpressed with Kir 3 channels but only with an EC50 of approximately 5 mM (Lingenhoehl et al., 1999), 1000 times the physiological concentration of GHB in the brain. In rat brain membranes, GHB failed to alter high affinity GTPase activity or specific [35S] GTPgS binding in any brain region examined in sharp contrast with positive control compounds such as baclofen and GABA (Odagaki and Yamauchi, 2004) and in recombinant HEK cells, GHB failed to show any affinity for GABAB receptors (Wu et al., 2004b).

206

M. Mamelak / Progress in Neurobiology 89 (2009) 193–219

Yet other studies do show that GHB is a weak but selective agonist at the GABAB receptor with a Ki that differs according to the method used but that has been found to range between 79 and 126 mM (Bernasconi et al., 2002). In the study cited above with recombinant GABAB receptors in Xenopus oocytes, GHB was shown to be a partial agonist but even millimolar concentrations could not achieve the maximal effects observed with micromolar quantities of baclofen (Lingenhoehl et al., 1999). Baclofen, a full specific agonist, binds to the GABAB receptor with a Ki of 12–32 nM (Bernasconi et al., 2002). It has been argued that the physiological effects of GHB, such as they may be, are mediated by the high affinity GHB receptors since these receptors are sensitive to the low naturally occurring levels of this metabolite (<25 nM/g) and that the pharmacological effects of the drug can be attributed to actions at the GABAB receptors which require much higher tissue levels of GHB for their activation. Indeed, the identification of a receptor that avidly binds the low endogenous levels of GHB is often cited as part of the evidence that GHB functions naturally as a neurotransmitter or neuromodulator even though it has never been demonstrated that GHB, like other neurotransmitters, is stored in pre-synaptic vesicles that fuse with extracellular membranes in preparation for exocytosis and even though no specific nerve tracts that use GHB have been identified (Bernasconi et al., 2002). Moreover, GHB is widely distributed throughout many organ systems, often in higher concentration than in the brain (Nelson et al., 1981; Tedeschi et al., 2003). It is even found in plant cells (Allan et al., 2008). Peripheral organs do not have high affinity GHB receptors (Andriamampandry et al., 2003; Snead and Liu, 1984) and thus these receptors cannot mediate the physiological effects of endogenous GHB in these organs. The origin of GHB in all cells, plant and animal, remains to be clearly defined. It has been recognized for some time that even in the brain the transamination of alpha-ketoglutarate and GABA to form glutamate and succinic semialdehyde, the precursor of GHB, cannot be the only source of GHB (Barker et al., 1985; Lyon et al., 2007; Snead and Morley, 1981). Indeed, more recent studies, designed to inhibit the accumulation of GHB in the brain and spinal fluid of children with succinic semialdehyde dehydrogenase deficiency with the use of vigabatrin, a GABA transaminase inhibitor, have shown that this drug effects only a partial reduction in spinal fluid GHB levels (Gibson et al., 1995). There is now some evidence that GHB may be derived from the peroxidation of polyunsaturated fatty acids (Tanaka et al., 1993; Tokumura et al., 1991) and it has been proposed that in all tissues, low levels of GHB may function as a feedback inhibitor of lipid peroxidation. Tissue level of GHB in plant and animal cells rise in response to hypoxia and tissue stress (Allan et al., 2008; Kaufman, 2002) and give credence to the hypothesis that GHB acts as an endogenous tissue protective agent (Mamelak, 2007). While the intracellular sources of GHB have not yet been fully elucidated and the exact nature of its actions at receptor sites remains to be defined, many of the physiological and pharmacological effects of GHB and even its physiological effects as will be described later do appear to involve an action at the GABAB receptor that is ubiquitously distributed throughout the nervous system and peripheral tissues (Bettler et al., 2004; Bowery et al., 2002). The actual concentration of GHB at its site of action may not be as low as its measured endogenous regional brain level (Maitre et al., 2002) and the GABAB receptor may not be as insensitive to GHB in vivo as it is in the test tube. The recent development of synthetic allosteric modulators which increase the sensitivity of the GABAB receptor to its agonists raises the possibility of a similar mechanism operating endogenously (Cryan et al., 2004; Cryan and Kaupmann, 2005). For example, while pharmacological doses of GHB (>100 mg/kg i.p.) are used in most experimental studies in

the rat to elicit a loss of the righting reflex and to raise striatal dopamine levels, both of these phenomena can be elicited in this species by the intracerebroventricular administration of a little as 1.5–2.5 mg of GHB (Redgrave et al., 1982) compared to the 30 mg or more required intraperitoneally for the same effect. Both phenomena are also mediated by GABAB receptors. They can be elicited by the specific GABAB agonist baclofen and can be blocked by GABAB antagonists (Nissbrandt and Engberg, 1996; Waldmeier, 1991) and neither phenomenon can be elicited by GHB in GABAB knockout mice (Kaupmann et al., 2003). A more recent experimental paradigm utilizing scheduled controlled responding demonstrated that GHB was 276-fold more potent after intracerebroventricular administration that after intraperitoneal administration. In these studies GHB was infused intracerebroventricularly in doses between 320 and 1000 mg (Carter et al., 2006b). Electrophysiological studies (vide infra) also suggest that low concentrations of GHB may effectively activate GABAB receptors in vivo. In the rat, intraperitoneal doses of GHB of 5–50 mg/kg have not been shown to increase brain GHB levels and the metabolic and physiological effect of these doses have been attributed to actions on the GHB receptor (Bernasconi et al., 2002; Kaufman et al., 1990; Snead, 1991). But in man, low oral doses, starting at 25 mg/kg, increase slow wave sleep (Scrima et al., 1990)—an effect that can also be observed with the specific GABAB agonist, baclofen. Both GHB and baclofen produce a dose related increase in slow wave sleep and a suppression of REM sleep (Guilleminault and Flagg, 1984; Mamelak et al., 2004). Even lower oral doses of GHB (17 mg/ kg) are used clinically three times a day to reduce craving for ethanol—again, an effect which can be duplicated with baclofen (Addolorato et al., 2002; Agabio and Gessa, 2002). 9.3. GABAB: second messengers In the nervous system, GABAB receptors are coupled to Gproteins at both pre- and post-synaptic sites. In distinction to the ionotropic GABAA receptor which increases Cl conductance, the metabotropic GABAB receptor is a GPCR that addresses second messenger systems. Activation of the GABAB receptor can either inhibit or enhance the formation of cyclic AMP (Bettler et al., 2004) but it has also been shown to initiate a signaling cascade that culminates in the phosphorylation of the transcription factor cyclic-AMP response element binding protein-2 (CREB-2) (White et al., 2000). Transcription factors such as CREB mediate changes in gene expression in response to events at the cell surface and CREB phosphorylation is believed to trigger its transcriptional activity (Carlezon et al., 2005). CREB is best known for its involvement in the regulation of long term memory and synaptic plasticity (Abel and Kandel, 1998; Lonze and Ginty, 2002; Silva et al., 1998). But is also engaged in the induction of key proteins such as the brain derived neurotrophic factor (BDNF) and the glucocorticoid receptor (GR) which modulate the brain’s stress response (Shelton, 2007). CREB has also been shown to regulate the expression of cytochrome C and thus to control respiratory activity in response to extracellular signals (Gopalakrishnan and Scarpulla, 1994). In neurons, CREB is phosphorylated in response to hypoxia and oxidative stress and several pieces of evidence strongly support its role as a neuroprotective agent against ischemic and hypoxic injury and oxidative stress (Lonze and Ginty, 2002; Mabuchi et al., 2001). In the mouse, high doses of GHB, 500 mg/kg i.p., produce a rapid and long lasting increase in CREB phosphorylation. This response is mediated by GABAB receptors and antagonized by GABAB receptor blockers (Ren and Mody, 2006). GHB, it may be recalled has repeatedly been shown to antagonize ischemic and hypoxic injury and oxidative stress (Mamelak, 2007) and may owe part of its neuroprotective effects to the coupled activation of

M. Mamelak / Progress in Neurobiology 89 (2009) 193–219

GABAB receptors and the CREB signal transduction system, but the pre-synaptic inhibition of neurotransmitter release and specifically that of glutamate together with post-synaptic hyperpolarization, both mediated by GABAB receptors, may also contribute significantly to its neuroprotective potency. Pre-synaptic GABAB receptors inhibit Ca2+ influx and, thus, neurotransmitter release while post-synaptic GABAB receptors hyperpolarize the cell membrane by triggering the opening of K+ channels and the efflux of K+ (Bettler et al., 2004). The pre-synaptic GABAB receptors are subdivided into those that control GABA release (autoreceptors) and those that inhibit the release of all other neurotransmitters (heteroreceptors). In most preparations, GABAB receptors mediate their pre-synaptic effects through a voltage dependent inhibition of high voltage activated Ca2+ channels of the N type or P/Q type although effects at L and T type channels have also been demonstrated. Activation of postsynaptic GABAB receptors induces a slow inhibitory post-synaptic current (late IPSC) by opening inwardly rectifying K+ channels. The time course of the late IPSC, with a latency of 20–50 ms and a time to peak of 50–250 ms clearly differs from that of the GABAA receptor mediated fast IPSC which appears after a latency of 3– 5 ms (Bettler et al., 2004; Crunelli and Leresche, 1991). Since, as discussed earlier, GABAB receptors are not restricted to cells of neuronal origin, and, for example, have been identified on myocytes, it is noteworthy that GHB and baclofen have both been shown to activate an inwardly rectifying K+ channel in these cells (Lorente et al., 2000). 10. GABAB and the regulation of neurotransmitter release 10.1. Hypocretin GABAB receptors have been identified or have been implicated in the regulation of neurotransmitter release in noradrenergic, serotonergic, dopaminergic, histaminergic, glutamatergic, GABAergic and hypocretinergic neurons. For example, in the lateral hypothalamus, in which cells immunoreactive to both hypocretin and GABAB1 have been identified, electrophysiological studies of identified hypocretinergic neurons have revealed that the application of GABA produces an early hyperpolarization mediated by C1 and a late depolarization mediated by the efflux of HCO3 . These GABAA mediated responses can be prevented by picrotoxin and bicuculline. In the face of GABAA blockade, however, GABA consistently hyperpolarizes and reduces the firing rate of the cells. Baclofen, a specific GABAB agonist, also greatly inhibits the activity of hypocretin neurons (Xie et al., 2006; Yamanaka et al., 2003) and recently, GHB has been shown to also hyperpolarize and decrease the firing rate of these neurons (Kilduff et al., 2007). GABAB receptor activation can inhibit the pre-synaptic release of both glutamate and GABA and depress the amplitude of both excitatory post-synaptic currents (EPSCs) and inhibitory postsynaptic currents (IPSCs). GABAB receptors, therefore, appear to modulate hypocretinergic neuronal activity through both pre- and post-synaptic mechanisms (Xie et al., 2006). 10.2. Histamine The regulation of histamine release from the histaminergic tuberomamillary neurons in the posterior hypothalamus has also been shown to be mediated by both GABAA and GABAB receptors (Okakura-Mochizuki et al., 1996; Stevens et al., 1999). GABAergic neurons from the ventrolateral preoptic (VLPO) area project to and form synapses on the somata and proximal dendrites of these neurons (Sherin et al., 1998). Inhibition of these histaminergic neurons and of the other monoaminergic and hypocretinergic neurons of the brain arousal system by the GABAergic projections

207

from the VLPO is considered critical for the generation of sleep and correlates with the increased release of GABA found in the pons and posterior hypothalamus during slow wave sleep (Nitz and Siegel, 1996, 1997a,b). With the use of microdialysis, it has been demonstrated that both the GABAA agonist, muscimol and the GABAB agonist baclofen markedly decrease histamine release (Okakura-Mochizuki et al., 1996). 10.3. Dopamine Information derived from studies on the GABAergic control of dopaminergic neurons provides additional details about the role of GABAB receptors in the control of neuronal activity and, moreover, specifically provides insights into the mechanism of action of GHB on these neurons. Although the effects of GHB on histamine neurons have not been examined, a large literature exists on the effects of GHB on dopamine neuronal activity (Howard and Banerjee, 2002). Both baclofen and GHB have been shown to reduce the firing rate and burst activity of dopaminergic neurons and to regularize their firing rhythm. These effects can be reversed by GABAB blockers but not by NCS-382. A dose dependent decrease in the firing rate of nigrostriatal dopaminergic neurons was observed with intravenous doses starting as low as 12.5 mg/kg (Erhardt et al., 1998). Other studies, however, have demonstrated that low doses of GHB could also increase the firing rate of dopaminergic neurons and that this effect, too, could be blocked by GABAB antagonists (Diana et al., 1991; Engberg and Nissbrandt, 1993). These discordant observations have been difficult to reconcile. Recently, however, Cruz et al. (2004) found that the coupling efficiency of potassium channels to GABAB receptors is much lower in ventral tegmentum dopaminergic neurons than in pre-synaptic GABABergic neurons. This renders these pre-synaptic neurons, which normally exert a tonic inhibitory effect on dopaminergic neuronal activity, more sensitive to GHB. The preferential activation of pre-synaptic GABAB receptors inhibits GABA release and this in turn, disinhibits dopaminergic neuronal activity. At higher GHB doses, this effect is less prominent and the direct inhibitory effect of GHB on GABAB receptors on dopaminergic neurons becomes more evident. Higher GHB doses may also inhibit the pre-synaptic release of glutamate and other neurotransmitters which normally may stimulate neuronal activity. 10.4. Noradrenaline and serotonin The spontaneous firing rate of locus ceruleus noradrenergic neurons in the rat is reduced by both GABAA and GABAB agonists (Olpe et al., 1988) but these neurons appear to be exquisitely sensitive to the depressant effects of GHB (Szabo et al., 2004). The sustained subcutaneous administration of 40 mg/kg/day of GHB for 2- and 10-day periods decreases both the spontaneous firing rate and the evoked burst firing of these neurons by about 50% (Szabo et al., 2004). GHB withdrawal is followed by a significant 33% increase in spontaneous activity and by a robust 79% increase in burst firing in response to paw pinch. Although GABAB receptors have been identified on noradrenergic neurons (Burman et al., 2003), the exact mechanism by which GHB elicits its effects on these neurons needs to be further elucidated. It is not known whether the effects of these low doses of GHB can be blocked by either GHB receptor or GABAB receptor blockade. Many studies suggest that the noradrenergic and serotonergic neurons arising from locus ceruleus and dorsal raphe respectively operate in tandem and that noradrenergic neuronal activity maintains the tonic activity of serotonergic neurons. The systemic or local administration of a1-adrenoceptor antagonists reduces serotonin neuronal firing in vivo whereas the application of the a1adrenoceptor agonist, phenylephrine, restores tonic firing in vitro

208

M. Mamelak / Progress in Neurobiology 89 (2009) 193–219

(Baraban and Aghajanian, 1980; Vandermaelen and Aghajanian, 1983). Recent work finds that serotonergic neurons cease firing during REM sleep by disfacilitation, resulting from the cessation of noradrenergic, histaminergic and hypocretinergic neuronal discharge (Brown et al., 2002; Sakai and Crochet, 2000). It should, however, be recalled that during cataplexy in the dog, serotonergic neuronal activity persists in the absence of noradrenergic activity (Wu et al., 1999, 2004a). To date, however, no studies have specifically examined the effects of GHB on serotonergic neuronal activity. Does the GHB induced decrease in noradrenergic neuronal activity also decrease serotonergic neuronal activity and the release of serotonin? GABAB receptors have been identified on dorsal raphe serotonergic neurons (Burman et al., 2003) and it has been shown that the infusion of the GABAB agonist baclofen into the dorsal raphe of the rat can reduce the release of serotonin (Tao et al., 1996). On the other hand, under other experimental conditions, the application of baclofen may either increase or decrease the release of serotonin consistent with the action of baclofen at two different subsets of GABAB receptors located respectively on serotonergic neurons and producing a direct inhibitory effect and on GABAergic terminals or interneurons and producing an indirect excitatory effect (Abellan et al., 2000). The dual control of serotonergic neuronal activity by GABAB receptors appears to be similar to that exerted by these receptors on dopaminergic neuronal activity. 10.5. Acetycholine The role of GABAB receptors in the mediation of acetylcholine release in different regions of the brain has also been subject to experimental investigation. Acetylcholine release in the striatum of the rat appears to be regulated by GABAA receptors located on cholinergic neurons. GABAB receptors were not identified on these neurons but were identified on noncholinergic neuronal elements in the striatum (Ikarashi et al., 1999). A GABAA agonist perfused into this region inhibits acetylcholine release but so does the GABAB agonist baclofen. Noncholinergic afferents to the striatum, perhaps dopaminergic or glutamatergic, under GABAB agonist control, may tonically facilitate the activity of cholinergic neurons in this region. In the cortex, cortical perfusion with a GABAA agonist has no effect on the release of acetylcholine but the infusion of a GABAA antagonist elicits a concentration dependent increase of acetycholine release. The GABAB receptor agonist, baclofen, can also elicit, a concentration dependent increase in spontaneous acetylcholine release as well as a decrease in the spontaneous release of GABA. Both of these baclofen effects can be blocked by a GABAB antagonist (Giorgetti et al., 2000). These findings suggest that endogenous GABA tonically inhibits cortical cholinergic neuronal activity. In a sufficient dose, GHB, too, appears to inhibit cholinergic neuronal activity. Thus, in the rat hippocampus, extracellular levels of acetylcholine monitored by microdialysis are reduced in a dose dependent manner following the intraperitoneal injection of GHB in doses between 200 and 500 mg/kg. This effect could be prevented with a GABAB antagonist but not by the putative GHB receptor antagonist NCS-382 (Nava et al., 2001). 10.6. Glutamate and GABA Synaptic potentials recorded from thalamocortical neurons following the stimulation of sensory, cortical and intrathalamic afferents reveal that low doses of GHB can inhibit the release of both glutamate and GABA from these afferents (Crunelli and Leresche, 2002). For example, doses of GHB as low as 100 mM reversibly decrease the amplitude of sensory glutamatergic excitatory post-synaptic potentials evoked in the thalamocortical

neurons by low frequency stimulation of the optic tract. Since the response of the post-synaptic GABAB receptors was blocked in these studies, inhibition of the sensory evoked excitatory postsynaptic potential was attributed to an action on pre-synaptic receptors located on sensory afferent neurons. This pre-synaptic action was blocked by a GABAB antagonist but not by NCS-382. Indeed NCS-382 appeared to act as a partial agonist and potentiated inhibitory the action of GHB on the sensory evoked excitatory post-synaptic potentials. Experimental work also demonstrated that GHB inhibited the excitatory evoked potentials elicited by stimulation of corticofugal afferents to the thalamocortical neurons. These afferents are the other major glutamatergic input to these neurons and this inhibitory effect, again, is prevented by GABAB antagonists. GHB also decreases the GABAA inhibitory post-synaptic currents elicited by stimulation of the GABAergic neurons of the thalamic retibular nucleus but only in some thalamocortical neurons. Baclofen was far more effective in this regard but, once again, the inhibitory effect of GHB on these inhibitory post-synaptic currents could be blocked by GABAB antagonists but not by the GHB receptor blocker NCS-382 which, again, could potentiate this inhibitory effect. Thus, these electrophysiological studies, in contrast to the work cited earlier (Berton et al., 1999; Brancucci et al., 2004a,b; Cammalleri et al., 2002) failed to provide any evidence for an action of GHB at a GHB receptor and these earlier findings were attributed to inadequate GABAB blockade (Gervasi et al., 2003). Indeed, Gervasi and his colleagues attributed all the actions of GHB, even at the lowest doses employed, to actions at the GABAB receptor. To strengthen this conclusion, these examiners demonstrated that NCS-356 and trans 4-hydroxy-crotonic acid, two high affinity ligands of the GHB receptor that are thought to have agonist like actions (Hechler et al., 1990, 1993) failed to produce any change in the amplitude of corticothalamic excitatory postsynaptic currents or thalamic reticular nucleus derived GABAA inhibitory post-synaptic currents in contrast to the inhibitory effect of both GHB and baclofen on these currents. 11. GHB and slow wave sleep Studies that have examined the effect of GHB on the intrinsic electrophysiological properties of the thalamocortical neurons rather than on their response to afferent stimulation have also provided important information about how this agent generates slow wave sleep and about how it differs from conventional hypnotics like the benzodiazepines. Thalamocortical neurons tonically fire single action potentials during awake attentive states when their membrane potential is maintained at levels greater than 55 mV by the release of depolarizing neurotransmitters like acetylcholine, noradrenaline, serotonin, histamine and glutamate (Crunelli et al., 2006a,b; McCormick, 1992; Steriade et al., 1993). With the reduced release of these neurotransmitters during sleep, the thalamocortical membrane potential becomes progressively more hyperpolarized during drowsiness and the early stages of sleep when spindles predominate and even more negatively polarized when delta sleep prevails (Steriade et al., 1993). GABAergic reticulo-thalamic projections set the membrane potential of the thalamocortical cells at the required level of hyperpolarization for the generation of thalamic delta oscillations and a GABAergic recurrent inhibition within the reticulo-thalamic nucleus contributes to its synchronizing actions (Huguenard and McCormick, 2007). At membrane potentials less than 65 mB, the transient opening of T type calcium channels leads to the generation of a slowly rising and falling depolarization at 0.5– 4.0 Hz that is known as the low threshold calcium spike and that is crowned by high frequency bursts of action potentials at about 300 Hz (Crunelli et al., 2006a; Destexhe and Sejnowski, 2003). This

M. Mamelak / Progress in Neurobiology 89 (2009) 193–219

is the basic rhythm of slow wave sleep even though the delta oscillations that originate from single thalamocortical neurons cannot sustain the slow delta rhythms visible in the EEG without reticular and corticothalamic input (Steriade et al., 1993). In cats and rats, GABAB receptor antagonists decrease slow wave sleep and these findings provide additional evidence that GABAB receptor activation mediates the generation of this sleep state (Gauthier et al., 1997; Juhasz et al., 1994). An elegant series of experiments demonstrated that bath application of GHB to thalamocortical neurons at concentrations as low as 100 mM hyperpolarizes these neurons into the voltage range, 65 mV to 75 mV, at which the rhythmic pacemaker oscillations of the cell membrane at 0.5–4.0 Hz occur (Crunelli and Leresche, 2002; Williams et al., 1995). Higher concentrations bring the membrane to more negative values beyond those at which these delta oscillations occur and raise the trigger threshold for all synaptically generated action potentials. The hyperpolarization produced by GHB can be blocked by GABAB antagonists but not by the GHB receptor antagonist NCS-382 which, in fact, may potentiate the hyperpolarization and thus, again, appears to act as a partial agonist. GHB’s capacity to bring the thalamocortical neuronal membrane into the region where the delta oscillations and burst activity of slow wave sleep occurs may be attributed to the increase in K+ conductance which attends GABAB receptor activation. In this regard, GHB may be distinguished from the benzodiazepines hypnotics which act as allosteric modulators of specific GABAA receptor subtypes and increase CI conductance (Kopp et al., 2004). In contrast to GHB, the benzodiazepines have been shown to reduce slow wave sleep (Kopp et al., 2004; Landolt and Gillin, 2000) and although the reasons for this have not been fully elucidated, recurrent inhibition within the reticulothalamic nucleus has not been found to be a major contributing factor to the effect of a benzodiazepine such as diazepam on the thalamic component of delta activity (Huguenard and Prince, 1994; Kopp et al., 2003; Sohal and Huguenard, 2003). Activation of the a-2GABAA receptor, located in the cortex, pons and hypothalamus and only very sparsely in the thalamus may specifically be involved in this phenomenon (Kopp et al., 2004). Another factor may be that the CI reversal potential, 70 mV, is much greater than the K+ equilibrium potential, about 100 mV (Barnett and Larkman, 2007; Benington and Heller, 1995). An increase in chloride conductance may interfere with the generation of the negative membrane potentials required for the induction of the characteristic electrophysiology of delta sleep. 12. Functions of slow wave sleep The reliable induction of slow wave sleep by GHB may confer certain unique advantages upon it. Studies in man and experimental animals have demonstrated that the duration and intensity of slow wave sleep as measured by the power in the delta band (0.5–4.0 Hz), correlate directly with the preceding period of wakefulness. An increase in both the duration and intensity of sleep following sleep deprivation compensates for the sleep time lost and suggests a restitutive function for this sleep state (Borbely and Achermann, 2005). More recent work demonstrates that the amount of new learning during wakefulness rather than the prior duration of wakefulness determine the duration and intensity of the sleep that follows. New learning during wakefulness has been proposed to lead to long term potentiation and an increase in synaptic weight that alters synaptic function (Cirelli et al., 2005). For example, in one study, in rats, in which the duration of wakefulness was kept constant, the homeostatic slow wave sleep response as well as the extent to which brain derived neurotrophic factor was induced, correlated directly with amount of exploratory

209

behaviour during wakefulness (Huber et al., 2007). Because of the synaptic potentiation which occurs with new learning, the amplitude and synchronization of cellular slow oscillations are enhanced during the sleep that follows and reflects the concomitant synaptic remodeling and downscaling that occurs at this time with benefits for energy metabolism, signal to noise ratios and performance. Studies in man provide additional support for the relationships between cortical adaptation to new learning and slow wave activity during sleep. High density EEG studies in humans show that visuomotor learning compared with a nonlearning task produces a selective increase in slow wave activity in the cortical region undergoing plastic change and that this local increase in slow activity dissipates during sleep with improved performance the next morning (Huber et al., 2004). Although the thalamic gates are closed to signals from the outside world during slow wave sleep, intracortical dialog and cortical neuronal responsiveness to callosal volleys are maintained or even increased during this sleep state and it has been proposed that slow wave sleep is a specific state in which information acquired during wakefulness is consolidated by the activation of calcium mediated intracellular cascades that facilitate signal transduction and alter gene expression (Destexhe and Sejnowski, 2003; Steriade and Timofeev, 2003). While the metabolic events that are set in motion during slow wave sleep may account for the synaptic remodeling, ion current adjustments and the reorganization of network activity in response to the day’s events, these metabolic events must also account for sleep’s remarkable capacity to generate alertness and overcome the fatigue, sleepiness, inattentiveness and cognitive decline that are the hallmarks of its deprivation. Genes whose expression are increased during sleep are involved in synaptic modeling, vesicle recycling, protein synthesis, membrane repair and specifically myelin repair (Cirelli, 2006; Tononi and Cirelli, 2003). Reserves of glycogen, the principal energy store in the brain often depleted during sleep deprivation, can be restored during sleep (Franken et al., 2006; Kong et al., 2002; Petit et al., 2002). The decrease in glucose utilization (Maquet et al., 1990) and oxygen consumption (Madsen et al., 1991) during sleep, which is most profound during slow wave sleep, may also be critical to sleep’s restorative functions. A reduction in glucose utilization and oxygen consumption may be associated with a reduction in the use and production of ATP and may correspondingly conserve energy. The inhibition of many neuronal neurotransmitter systems during NREM sleep, a prerequisite for the induction of this sleep state and of slow wave delta sleep in particular, likely also facilitates the recovery of these systems and their coupled receptors after the sustained demands of wakefulness. Although the effects of GHB on synaptic plasticity have never been examined, the slow wave sleep induced by this agent has been found to have many features in common with the naturally occurring state. Thus, in distinction to other hypnotic agents, GHB is able to bring brain cell membrane potentials into the region required for the induction of delta pacemaker activity, the fundamental rhythm of slow wave sleep (Crunelli and Leresche, 2002). This property follows from its capacity to activate GABAB receptors. Both naturally occurring slow wave sleep and GHB induced sleep can be prevented by GABAB antagonists. An increase in cerebral glycogen reserves occurs in response to GHB as it does with sleep (MacMillan, 1978; Taberner et al., 1972; Taberner, 1973). Animal work demonstrates that GHB can also produce a dose related decrease in glucose utilization (Haller et al., 1990; Kuschinsky et al., 1985; Wolfson et al., 1977). Curiously, in the cat, the one species in which this matter has been examined, this decrease is not accompanied by the expected decrease in oxygen consumption (Haller et al., 1990). GHB’s metabolic transformation to succinate, a citric acid cycle substrate and thus

210

M. Mamelak / Progress in Neurobiology 89 (2009) 193–219

an energy source, may account for this phenomenon. Intracellular ATP levels may remain unchanged with GHB hypnosis and, indeed, GHB has been shown to spare energy utilization and maintain normal cellular levels of glycogen and ATP even in the face of hypoxia (MacMillan, 1978). And although much work remains to be done, the evidence to date suggests that the neuronal arousal systems that depolarize the thalamocortical and other cerebral neurons during wakefulness are shut down by GHB much as they are during slow wave sleep. Thus, as described earlier, GHB inhibits glutamate release (Banerjee and Snead, 1995; Bernasconi et al., 2002; Crunelli and Leresche, 2002; Ferraro et al., 2001). It also inhibits noradrenergic neuronal activity in very low doses (Szabo et al., 2004) and since noradrenergic and serotonergic-neurons appear to operate in tandem (Baraban and Aghajanian, 1980; Brown et al., 2002; Sakai and Crochet, 2000; Vandermaelen and Aghajanian, 1983) it likely also decreases serotonergic neuronal activity. GHB has been shown to decrease the release of acetycholine (Giorgetti et al., 2000; Ikarashi et al., 1999; Nava et al., 2001) and its inhibitory effects on dopaminergic activity and dopamine release have been very amply documented (Howard and Banerjee, 2002). Only a subset of dopaminergic neurons, those emanating from the periaqueductal grey matter, reduce their activity level during slow wave sleep and thus the global reduction in dopaminergic neuronal activity with GHB is unique to this agent and not naturally occurring during slow wave sleep. The actions of GHB on the histaminergic arousal system have never been examined but as described earlier, GHB can also inhibit the activity of hypocretin neurons and, therefore, dampen the activation of the entire arousal system (Kilduff et al., 2007). Agents such as glucose which provide energy to the cell also inhibit the activity of hypocretin neurons (Burdakov and Alexopoulos, 2005; Yamanaka et al., 2003) and GHB may also do so for this reason. 13. Neurotransmitter circuits in sleep and wakefulness The glutamatergic, monoaminergic and cholinergic neuromodulator arousal systems that are active during wakefulness and the GABA and galanin containing inhibitory neurons arising from the ventrolateral preoptic (VLPO) area that are active during sleep are mutually inhibitory. The VLPO has been shown to send inhibitory outputs to all of the major cell groups in the hypothalamus and brain stem that are components of the arousal system. These inhibitory neurons have been shown to be particularly active during deep stages of sleep when slow wave activity is most intense (Szymusiak et al., 1998). The VLPO receives afferents from each of the major monoaminergic systems and both noradrenaline and serotonin inhibit VLPO neurons (Chou et al., 2002; Saper, 2006; Saper et al., 2001). These neurons do not have histamine receptors but tuberomamillary histamine neurons also contain GABA which is inhibitory to VLPO neurons. Dopaminergic and cholinergic neurons only sparsely innervate the VLPO and although the VLPO has no receptors for hypocretin, increased hypocretin neuronal activity may inhibit the VLPO by activating its monoaminergic inputs. Thus, the VLPO can be inhibited by the very arousal system that it inhibits during sleep. A circuit containing mutually inhibitory elements, i.e., a flipflop circuit, is self-reinforcing in that if either side gains the advantage it shuts off the other side and disinhibits its own activity (Saper et al., 2001; Saper, 2006). This type of relationship creates sharp boundaries between the two states and may account for the rapid transition that normally occurs between wakefulness and sleep and for the distinct nature of each of these states. An increase in the frequency of state transitions can be predicted following a malfunction of either side of such a circuit. To some extent this has been shown to hold true for the biological circuit formed between

the mutually inhibitory VLPO and hypocretin neurons but not exactly. In this naturally occurring circuit, damage to each side has unique and distinguishing effects. Animals with lesions of the VLPO have normal circadian sleep rhythms but wake up more often during the sleep cycle and fall asleep more often during the wake cycle (Lu et al., 2000). In this respect they fulfill the expectations of damage to a flip-flop circuit. But lesions that destroy the majority of neurons in the VLPO reduce the total sleep time by more than 50% with the result that these animals are chronically sleep deprived and sleepy but are not able to stay asleep (Lu et al., 2000; Saper, 2006). On the other side of the circuit, damage to the hypocretin neurons may also increase the numbers of transitions between sleep and wakefulness but in contrast to damage to the VLPO, it does not reduce the total sleep time. Moreover, damage to hypocretin neurons causes an overall breakdown in the organization of sleep with transitions between wakefulness and REM sleep and even the appearance of cataplexy (Sakurai, 2007; Sutcliff and de Lecea, 2002). This is not observed following lesions of the VLPO (Lu et al., 2000). Nor are transition between wakefulness and REM sleep or episodes of motor atonia observed following damage to components of the arousal circuit such as to the noradrenergic neurones emanating from the locus ceruleus (Blanco-Centurion et al., 2004) or to the histaminergic neurons arising from the tuberomamillary nucleus (Parmentier et al., 2002). It is the loss of hypocretinergic innervation, uniquely, which produces the specific biological state identified as narcolepsy–cataplexy in which the components of sleep become ‘‘unglued’’. REM sleep and its motor atonic component dissociate from each other and from the other components of sleep and are prematurely expressed. Under normal circumstances, the release of hypocretin inhibits the sleep inducing neurons in the VLPO and facilitates the actions of the neuronal systems that maintain arousal. Failure to fully inhibit the VLPO may lead to the interruptions of wakefulness by drowsiness and periods of sleep but loss of the trophic influence of hypocretin on the arousal system specifically leads to an imbalance in central neurotransmission that appears to be a prerequisite for REM sleep dissociation and the uncoupling its motor atonic component. 14. Neurotransmitter disequilibrium in cataplexy Monoaminergic insufficiency and cholinergic supersensitivity may broadly describe this new and altered central equilibrium whose distinct properties have been experimentally described (Nishino and Mignot, 1997; Nishino, 2007). For example, in the absence of hypocretin, reduced noradrenergic neuronal activity may account for the elevated number of a-2 adrenoreceptors in the locus coerulus (Fruhstorfer et al., 1989) as well as for the unusual response to prazocin, an a-1 noradrenergic antagonist which induces cataplexy in man and in the dog with narcolepsy but not in normal members of either species (Guilleminault et al., 1988; Mignot et al., 1989). The increased D2/D3 receptor density in canine narcolepsy likely develops in response to reduced dopaminergic neuronal activity and dopamine release (Bowersox et al., 1987; Mefford et al., 1983; Nishino et al., 1991; Reid et al., 1996). In the dog with narcolepsy, but not in normal members of this species, quinpirole, a dopamine agonist which further inhibits dopamine release, elicits cataplexy. Similarly, in the absence of hypocretin, reduced cholinergic neural activity likely accounts for the development of muscarinic-M2-cholinergic supersensitivity. Indeed, an increase in the number of muscarinic-M2-cholinergic receptors has been demonstrated in canine narcolepsy (Boehme et al., 1984; Kilduff et al., 1986). Low doses of muscarinic cholinergic agonists can easily elicit cataplexy in the dog with narcolepsy but not in a normal dog (Nishino et al., 1995). Noradrenergic neuronal activity normally inhibits REM sleep and cataplexy and serves to maintain muscle tone. The anti-

M. Mamelak / Progress in Neurobiology 89 (2009) 193–219

depressant drugs as described earlier, suppress REM sleep and cataplexy by blocking the reuptake of noradrenaline and by raising its level in the synapse. Reduced release of noradrenaline in narcolepsy may predispose to the premature activation of REM sleep and to REM dissociation especially in the face of heightened muscarinic-M2-cholinergic sensitivity. It may now be possible to better understand how GHB induces REM sleep and cataplexy in patients with narcolepsy. In a brain primed by the absence of hypocretin, GHB, like quinpirole, may further reduce the release of dopamine and induce cataplexy. Or by further reducing the release of noradrenaline and serotonin, GHB may block the inhibitory effects which these neurotransmitters exert on REM sleep as well as their facilitatory effects on motor tone. A reduced REM sleep latency or even sleep paralysis and cataplexy may follow. It appears unlikely that GHB either induces or prevents cataplexy by acting peripherally at the level of the spinal monosynpatic reflex arc even though this arc is inhibited by GHB (Mamelak and Sowden, 1983) as it is during cataplexy (Guilleminault, 1976). GHB has been shown to have a pre-synaptic site of action in the spinal cord (Mamelak and Sowden, 1983; Osorio and Davidoff, 1979) and likely acts on the GABAB receptors concentrated in the dorsal horn on primary afferent terminals (Price et al., 1987). GHB has been shown to hyperpolarize these afferent terminals (Osorio and Davidoff, 1979). The analgesic effects of baclofen have been attributed to its agonistic actions on these dorsal horn GABAB receptors (Bowery et al., 2002; Enna et al., 1998) and this may help account as well for GHB’s pain relieving properties now being explored for the treatment of fibromyalgia (Scharf et al., 1998, 2003; Russel et al., 2005, 2009). However in normal subjects, GHB does not induce cataplexy or REM sleep (Metcalf et al., 1966; Yamada et al., 1967) even though it abolishes the H-reflex, i.e. the spinal monosynaptic reflex arc whether or not the dose is high enough to induce sleep (Mamelak and Sowden, 1983). Thus, GHB appears to induce cataplexy by acting centrally rather than peripherally. As described earlier, in narcolepsy, this central alteration consists of a change in the balance between monoaminergic and cholinergic neurotransmission. In the absence of the trophic influence of hypocretin, monoaminergic and cholinergic neurotransmission are reduced and cholinergic supersensitivity develops. The normal reciprocal relationship between these two systems is altered (McCarley, 2007). Antidepressants promote transmission through the monaminergic ‘‘REM off’’ neurons and correspondingly inhibit transmission through cholinergic ‘‘REM on’’ neurons. Upon antidepressant withdrawal, the rebound increase in REM sleep and reduced REM sleep latency have been attributed to the development of cholinergic receptor supersensitivity with the use of these drugs (Wilson and Argyropoulos, 2005). In rare cases, the withdrawal of antidepressants even leads to cataplexy (Nissen et al., 2005). GHB will even further reduce the short REM sleep latency in patients with narcolepsy (Mamelak et al., 2004) and may produce motor atonia or sleep paralysis in patients with narcolepsy or a history of depression (Mamelak et al., 1977; Price et al., 1981). Thus, the altered equilibrium between monoaminergic and cholinergic transmission, more than the absence of hypocretin, appears to be the essential neurochemical substrate for narcolepsy–cataplexy (Nishino et al., 1995; Nishino, 2007). 15. GHB and the neurochemistry of cataplexy Nevertheless, clinical work, as described earlier, demonstrates that the repeated use of GHB at night reintegrates sleep and improves daytime measures of wakefulness without necessarily increasing the total sleep time at night (Mamelak et al., 2004). The latency to REM sleep following sleep onset recedes to normal

211

values and cataplexy becomes uncommon or even rare after 4–6 weeks of nightly treatment. The repeated nocturnal use of GHB at night may effect these clinical improvements and restore the normal organization of sleep by reestablishing the normal balance between monoaminergic and cholinergic tone. Indeed, it has been demonstrated in rats that the repeated use of a congener of GHB, butyrolactone, for 3 weeks produces a significant decrease in the number of 3H-quinuclidinyl benzilate (3H-QNB) bindings sites (Giorgi and Rubio, 1981). 3H-QNB binds to muscarinic receptors. Reduced muscarinic sensitivity following treatment with butyrolactone has been attributed to the inhibition of dopaminergic neurotransmission by butyrolactone which in turn releases cholinergic neurons from tonic inhibition by dopaminergic neuronal activity (Giorgi and Rubio, 1981). This study bears repeating but GHB may also help restore central neurotransmitter equilibrium specifically through its actions on noradrenergic neurotransmission. Thus, the inhibitory effect of nocturnal GHB on noradrenergic neuronal activity followed by an increase in noradrenergic activity during the day when GHB is withdrawn would restore the normal diurnal rhythm of noradrengic and serotonergic neuronal activity especially, if as has been discussed earlier, these two monoaminergic systems operate in tandem (Szabo et al., 2004). Improved noradrenergic and serotonergic tone during the day would improve motor tone and inhibit the dissociated activation of REM sleep. This process would be abetted by the gradual dissipation cholinergic supersensitivity as cholinergic neuronal activity returns to normal in response to the return of normal circadian noradrenergic and serotonergic activity. Nocturnal GHB may also lead to rebound increase in histamine and dopamine release during the day with salutary effects on wakefulness. The effects of GHB on histaminergic neuronal activity, a powerful promoter of wakefulness, have not been examined but the inhibition of histamine release with baclofen, a specific GABAB antagonist (Okakura-Mochizuki et al., 1996) suggests that GHB would have a similar effect. Directed studies are required to determine if a rebound in histamine neuronal activity during the day follows its putative inhibition at night by GHB. A rebound increase in the availability and release of dopamine, the neurotransmitter which mediates the alerting effects of the stimulant drugs in common use, i.e., d-amphetamine, methylphenidate and modafinil, has also not been definitively demonstrated following the withdrawal of GHB but appears likely. Dopamine accumulates in dopaminergic neurons in response to their inactivation by GHB (Howard and Banerjee, 2002). GHB, given alone at night, improves the subjective sense of alertness during the day as well as modafinil (Black and Houghton, 2006). These observations suggest that withdrawal of GHB after its overnight use is followed by the release of the increased synaptic stores of dopamine and there is some experimental work to support of this idea (Cheramy et al., 1977; Hechler et al., 1991; Redgrave et al., 1982). GHB’s neuroprotective effect, its antioxidant properties and its ability to spare ATP utilization may also promote alertness– much like modafinil (Gerrard and Malcolm, 2007; Mamelak, 2007). The brain may wake from GHB induced sleep cleansed of oxidants and optimally able to produce energy in the form of ATP. Of note, nocturnal GHB also improves daytime alertness in patients with Parkinson’s disease (Ondo et al., 2007). Thus, GHB may owe its effectiveness in narcolepsy to its ability to substitute for inhibitory effects of VLPO neuronal activity. The nocturnal application of GHB turns off monoaminergic and cholinergic neurotransmission as required for NREM sleep but allows these systems to function during the day. GHB has been shown to produce a rebound increase in the activity of noradrenergic neurons and future studies may reveal that it does so for other neurotransmitter systems as well. Like the VLPO, GHB promotes slow wave sleep but it is not known if GHB engages the

212

M. Mamelak / Progress in Neurobiology 89 (2009) 193–219

sleep inducing neurons of the VLPO. Nor is it known whether the slow wave activity induced by GHB promotes synaptic remodeling and whether the nightly use of GHB would improve learning and adaptation to the day’s events. Why is baclofen not effective in the treatment of narcolepsy? Baclofen may be too powerful a GABAB agonist. Its repeated application causes an apparent desensitization of GABAB receptor mediated function (Bowery et al., 2002; Lehmann et al., 2003) which is revealed by the reduced responsiveness to applied baclofen over time of both pre- and post-synaptic GABAB receptors. As a result, baclofen’s capacity to depress synaptic responses is markedly reduced and post-synaptic membrane hyperpolarization can no longer be detected (Malcangio et al., 1995). Tolerance to baclofen’s sedative and antinociceptive effects develops rapidly (Enna et al., 1998; Sands et al., 2003). Although persistently high levels of GHB also desensitize GABAB receptors (Buzzi et al., 2006), in clinical practice the response of GABAB receptors to repeated low doses of this weak agonist appears to be maintained and tolerance fails to develop to GHB’s sedative effects (Mamelak et al., 1986; US Xyrem Multicenter Study Group, 2003). Given its short duration of action, the nocturnal application of GHB in clinically recommended doses may only weakly desensitize its receptors which, in turn, may be able to fully recover by the time GHB is given again on the following night. The absence of a withdrawal reaction may account for the absence of GHB abuse and addiction in patients who use the drug to treat narcolepsy. Moreover, the GABAB mechanisms mediating the behavioural effects of GHB may differ from those mediating the effects baclofen (Carter et al., 2004, 2009; Koek et al., 2005, 2007). GHB and baclofen have been shown to differ in their capacity to depress Nmethly-D-aspartate (NMDA) and alpha-amino-3 hydroxy-5methyl-4-isoxazole propionic acid (AMPA) mediated excitatory post-synaptic currents in layers II/III pyramidal cells (Li et al., 2007). At clinically relevant concentrations, GHB and baclofen have also been shown to have opposite effects on the activation of ventral tegmental dopamine neurons (Cruz et al., 2004). GHB may also have unique and advantageous effects on cell energy metabolism and on the cell redox state that may be important for sleep. Unlike baclofen, GHB may act as a substrate for cell energy metabolism and maintain cellular levels of ATP. GHB metabolism also generates NADPH, an essential cofactor for reductive detoxification and biosynthesis. No other hypnotic or anaesthetic agent possesses these properties (Mamelak and Hyndman, 2002; Mamelak, 2007). 16. GHB and the neurochemistry of depression GHB may be useful for the treatment of major depression—a possibility which first our raised interest in this compound. An imbalance between monoaminergic and cholinergic neurotransmission has been described in depression as it has been in narcolepsy. In both conditions, there are signs pointing to a deficiency in monoaminergic neurotransmission and an increased sensitivity to muscarinic-M2-cholinergic agonists (Belmaker and Agam, 2008; Dilsaver, 1986; Janowsky et al., 1972; Shiromani et al., 1987). Increased a-2 noradrenergic receptor sensitivity, a result of noradrenergic insufficiency, is also found in both conditions (Ordway et al., 2003). Polysomnographic studies reveal short latency sleep onset REM sleep periods at night in both conditions (Benson, 2006; Benca et al., 1992; Peterson and Benca, 2006; Shaffery et al., 2003) and the dissociated REM sleep events identified clinically as the auxiliary features of narcolepsy, i.e., cataplexy, sleep paralysis and hypnagogic hallucinations, are found with surprising frequency in patients with depression (Szklo-Coxe et al., 2007). Indeed, it is noteworthy that GHB can induce sleep onset REM periods and sleep paralysis in depressed

patients (Mamelak et al., 1977) much as its initial application in patients with narcolepsy further reduces REM sleep latency (Mamelak et al., 2004) and induces cataplexy (Price et al., 1981). Antidepressant drugs, which improve monoaminergic transmission (Belmaker and Agam, 2008) and suppress REM sleep (Wilson and Argyropoulos, 2005) are also anticataplectic drugs and function to restore the normal balance between noradrenergic and cholinergic transmission. The repeated use of GHB at night in patients with depression may be equally effective in shifting this equilibrium back to normal. Animal studies cited earlier provide some evidence in favour of this thesis (Giorgi and Rubio, 1981). Current work suggest that antidepressants owe their clinical efficacy not only to their effects on neurotransmission but perhaps even more so to the activation after 2–6 weeks of continued use of transcription factors such as CREB or trophic factors such as BDNF and GR (Belmaker and Agam, 2008; Malberg and Blendy, 2005; Pariante, 2006). Indeed, CREB activation mediates the formation of both BDNF and GR (Chen et al., 2001; Shelton, 2007). GR, in particular, has been shown to play a major role in the resistance to stress and the development of depression (Pariante, 2006). GR functions as a transcription factor and regulates the expression of other genes, specifically exerting an inhibitory effect on corticotrophin releasing hormone (Malkoski and Dorin, 1999). Brain BDNF levels and GR function are reduced in depression (Karege et al., 2005; Pariante, 2006) but are increased and upregulated by antidepressants and electroconvulsive therapy (Chen et al., 2001; Karege et al., 2005; Pariante, 2006). GHB has been shown to activate CREB (Ren and Mody, 2006) and future studies may clarify whether this translates into an increase in BDNF formation and GR levels, an increased resistance to stress and, correspondingly, an antidepressant response. The induction of slow wave activity with GHB, often deficient in patients with depression (Shaffery et al., 2003), and the restoration of a full night’s sleep night after night without the development of tolerance may be GHB’s paramount antidepressant property. A voluminous literature describes the intimate relationship between the deterioration of sleep and the affective disorders. Insomnia appears to play a causal role in the onset of these disorders; it is present in the acute stages and all too often predicts the relapse of patients in remission (Harvey, 2008; Ohayon, 2007; Plante and Winkelman, 2008). A recent case study corroborates the long term mood stabilizing actions of sleep induced with GHB (Berner, 2008). Severe or melancholic forms of depression have been viewed as sustained stress responses. Although prolonged stress may lead to noradrenergic insufficiency in time, acute stress seems to be characterized more by both noradrenergic and corticosteroid overdrive (Koob, 1999; Wong et al., 2000). Significantly higher levels of both CSF noradrenaline and plasma cortisol are found throughout the day and night in this condition and it has been proposed that acute severe stress is mediated by a mutually reinforcing directional link between a central hyperadrenergic state and a hyperfunctioning corticotrophin releasing hormone pathway that are each driven and sustained by hypercortisolism. Investigators has suggested that the potential efficacy of an a-noradrenergic blocker be examined for the treatment of these acute and severe stress states. Given the exquisite sensitivity of noradrenergic neurons to the inhibitory effects of GHB, could the use of this agent be used to interrupt the self-sustaining momentum of the brain’s stress system in melancholic depression? Could GHB be the agent Harry Stack Sullivan was looking for? Disclosure I have been a consultant to Orphan Medical Inc. I have received speaker’s honoraria from Orphan Medical Inc, Jazz Pharmaceuticals Inc and from Valeant Canada Inc. I own patents on new

M. Mamelak / Progress in Neurobiology 89 (2009) 193–219

chemical entities related to gammahydroxybutyrate. I have received funding from Orphan Medical Inc and Jazz Pharmaceuticals Inc to conduce clinical trials of gammahydroxybutyrate in narcolepsy. Valeant Canada Inc provides funding for work on the basic pharmacology of gammahydroxybutyrate. I have not received any funding or encouragements from any source for this review paper. I have no conflict of interest. Acknowledgement I thank Susy O’Neill for her expert help with this manuscript. References American Sleep Disorders Association, 1997. International Classification of Sleep Disorders, Revised: Diagnostic and Coding Manual. American Sleep Disorders Association, Rochester, Minnesota. American Academy of Sleep Medicine, 2005. International Classification of Sleep Disorders. Diagnostic and Coding Manual, 2nd ed., vol. 2. American Academy of Sleep Medicine, Westchest, Illinois. Abel, T., Kandel, E., 1998. Positive and negative regulatory mechanisms that mediate long-term memory storage. Brain Res. Brain Res. Rev. 26, 360–378. Abellan, M.T., Jolas, T., Aghajanian, G.K., Artigas, F., 2000. Dual control of dorsal raphe serotonergic neurons by GABA(B) receptors. Electrophysiological and microdialysis studies. Synapse 36, 21–34. Addolorato, G., Caputo, F., Capristo, E., Domenicali, M., Bernardi, M., Janiri, L., Agabio, R., Colombo, G., Gessa, G.L., Gasbarrini, G., 2002. Baclofen efficacy in reducing alcohol craving and intake: a preliminary double-blind randomized controlled study. Alcohol Alcohol 37, 504–508. Agabio, R., Gessa, G., 2002. Therapeutic uses of g-hydroxybutyrate. In: Tunnicliff, G., Cash, C. (Eds.), Gammahydroxybutryate: Molecular, Functional and Clinical Aspects. Taylor and Francis, London and New York, pp. 169–187. Akimoto, H., Honda, Y., Takahashi, Y., 1960. Pharmacotherapy in narcolepsy. Dis. Nerv. Syst. 21, 704–706. Alam, M.N., Kumar, S., Bashir, T., Suntsova, N., Methippara, M.M., Szymusiak, R., McGinty, D., 2005. GABA-mediated control of hypocretin- but not melaninconcentrating hormone-immunoreactive neurones during sleep in rats. J. Physiol. 563, 569–582. Allan, W.L., Simpson, J.P., Clark, S.M., Shelp, B.J., 2008. Gamma-hydroxybutyrate accumulation in Arabidopsis and tobacco plants is a general response to abiotic stress: putative regulation by redox balance and glyoxylate reductase isoforms. J. Exp. Bot. 59, 2555–2564. American Narcolepsy Association, 1992. Stimulant Medication Survey. The Eye Opener. , pp. 1–3. Andriamampandry, C., Taleb, O., Viry, S., Muller, C., Humbert, J.P., Gobaille, S., Aunis, D., Maitre, M., 2003. Cloning and characterization of a rat brain receptor that binds the endogenous neuromodulator gamma-hydroxybutyrate (GHB). FASEB J. 17, 1691–1693. Andriamampandry, C., Taleb, O., Kemmel, V., Humbert, J.P., Aunis, D., Maitre, M., 2007. Cloning and functional characterization of a gamma-hydroxybutyrate receptor identified in the human brain. FASEB J. 21, 885–895. Argyropoulos, S.V., Wilson, S.J., 2005. Sleep disturbances in depression and the effects of antidepressants. Int. Rev. Psychiatry 17, 237–245. Aston-Jones, G., Bloom, F.E., 1981. Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle. J. Neurosci. 1, 876–886. Banerjee, D., Vitiello, M.V., Grunstein, R.R., 2004. Pharmacotherapy for excessive daytime sleepiness. Sleep Med. Rev. 8, 339–354. Banerjee, P.K., Snead III, O.C., 1995. Presynaptic gamma-hydroxybutyric acid (GHB) and gamma-aminobutyric acid B (GABAB) receptor-mediated release of GABA and glutamate (GLU) in rat thalamic ventrobasal nucleus (VB): a possible mechanism for the generation of absence-like seizures induced by GHB. J. Pharmacol. Exp. Ther. 273, 1534–1543. Baraban, J.M., Aghajanian, G.K., 1980. Suppression of firing activity of 5-HT neurons in the dorsal raphe by alpha-adrenoceptor antagonists. Neuropharmacology 19, 355–363. Barker, S.A., Snead, O.C., Poldrugo, F., Liu, C.C., Fish, F.P., Settine, R.L., 1985. Identification and quantitation of 1,4-butanediol in mammalian tissues: an alternative biosynthetic pathway for gamma-hydroxybutyric acid. Biochem. Pharmacol. 34, 1849–1852. Barnett, M.W., Larkman, P.M., 2007. The action potential. Pract. Neurol. 7, 192–197. Baumann, C.R., Stocker, R., Imhof, H.G., Trentz, O., Hersberger, M., Mignot, E., Bassetti, C.L., 2005. Hypocretin-1 (orexin A) deficiency in acute traumatic brain injury. Neurology 65, 147–149. Baumann, C.R., Bassetti, C.L., 2005. Hypocretins (orexins): clinical impact of the discovery of a neurotransmitter. Sleep Med. Rev. 9, 253–268. Bayer, L., Eggermann, E., Serafin, M., Saint-Mleux, B., Machard, D., Jones, B., Muhlethaler, M., 2001. Orexins (hypocretins) directly excite tuberomammillary neurons. Eur. J. Neurosci. 14, 1571–1575. Bayer, L., Eggermann, E., Saint-Mleux, B., Machard, D., Jones, B.E., Muhlethaler, M., Serafin, M., 2002. Selective action of orexin (hypocretin) on nonspecific thalamocortical projection neurons. J. Neurosci. 22, 7835–7839.

213

Belmaker, R., Agam, G., 2008. Mechanisms of disease: major depressive disorder. N. Engl. J. Med. 358, 55–68. Benavides, J., Rumigny, J.F., Bourguignon, J.J., Cash, C., Wermuth, C.G., Mandel, P., Vincendon, G., Maitre, M., 1982. High affinity binding sites for gamma-hydroxybutyric acid in rat brain. Life Sci. 30, 953–961. Benca, R.M., Obermeyer, W.H., Thisted, R.A., Gillin, J.C., 1992. Sleep and psychiatric disorders. A meta-analysis. Arch. Gen. Psychiatry 49, 651–668. Benington, J.H., Heller, H.C., 1995. Restoration of brain energy metabolism as the function of sleep. Prog. Neurobiol. 45, 347–360. Benson, K.L., 2006. Sleep in schizophrenia: impairments, correlates, and treatment. Psychiatr. Clin. North Am. 29, 1033–1045. Bernasconi, R., Mathivet, P., Otten, U., Bettler, B., Bischoff, S., Marescaux, C., 2002. Part of the pharmacological actions of g-hydroxybutyrate are mediated by GABAB receptors. In: Tunnicliff, G., Cash, C. (Eds.), Gammahydroxybutyrate: Molecular, Functional and Clinical Aspects. Taylor and Francis, London and New York, pp. 28–63. Berner, J.E., 2008. A case of sodium oxybate treatment of tardive dyskinesia and bipolar disorder. J. Clin. Psychiatry 69, 862. Berridge, C.W., O’Neil, J., Wifler, K., 1999. Amphetamine acts within the medial basal forebrain to initiate and maintain alert waking. Neuroscience 93, 885–896. Berridge, C.W., Isaac, S.O., Espana, R.A., 2003. Additive wake-promoting actions of medial basal forebrain noradrenergic alpha1- and beta-receptor stimulation. Behav. Neurosci. 117, 350–359. Berton, F., Brancucci, A., Beghe, F., Cammalleri, M., Demuro, A., Francesconi, W., Gessa, G.L., 1999. Gamma-hydroxybutyrate inhibits excitatory postsynaptic potentials in rat hippocampal slices. Eur. J. Pharmacol. 380, 109–116. Bettler, B., Kaupmann, K., Mosbacher, J., Gassmann, M., 2004. Molecular structure and physiological functions of GABA(B) receptors. Physiol. Rev. 84, 835–867. Beuckmann, C.T., Sinton, C.M., Williams, S.C., Richardson, J.A., Hammer, R.E., Sakurai, T., Yanagisawa, M., 2004. Expression of a poly-glutamine-ataxin-3 transgene in orexin neurons induces narcolepsy–cataplexy in the rat. J. Neurosci. 24, 4469– 4477. Beusterien, K.M., Rogers, A.E., Walsleben, J.A., Emsellem, H.A., Reblando, J.A., Wang, L., Goswami, M., Steinwald, B., 1999. Health-related quality of life effects of modafinil for treatment of narcolepsy. Sleep 22, 757–765. Billiard, M., 2008. Narcolepsy: current treatment options and future approaches. Neuropsychiatr. Dis. Treat. 4, 557–566. Black, J., Houghton, W.C., 2006. Sodium oxybate improves excessive daytime sleepiness in narcolepsy. Sleep 29, 939–946. Blanco-Centurion, C., Gerashchenko, D., Salin-Pascual, R.J., Shiromani, P.J., 2004. Effects of hypocretin2-saporin and antidopamine-beta-hydroxylase-saporin neurotoxic lesions of the dorsolateral pons on sleep and muscle tone. Eur. J. Neurosci. 19, 2741–2752. Boehme, R.E., Baker, T.L., Mefford, I.N., Barchas, J.D., Dement, W.C., Ciaranello, R.D., 1984. Narcolepsy: cholinergic receptor changes in an animal model. Life Sci. 34, 1825–1828. Borbely, A., Achermann, P., 2005. Sleep homeostasis and models of sleep regulation. In: Kryger, M., Roth, T., Dement, W.C. (Eds.), Principles and Practice of Sleep Medicine. Elsevier, Philadelphia, pp. 405–417. Boutrel, B., Koob, G.F., 2004. What keeps us awake: the neuropharmacology of stimulants and wakefulness-promoting medications. Sleep 27, 1181–1194. Bowersox, S.S., Kilduff, T.S., Faull, K.F., Zeller-DeAmicis, L., Dement, W.C., Ciaranello, R.D., 1987. Brain dopamine receptor levels elevated in canine narcolepsy. Brain Res. 402, 44–48. Bowery, N., Bettler, B., Froestl, W., Gallagher, J., Raiteri, M., Bonner, T., Enna, S., 2002. Mammalian g-aminobutyric acidB receptors. Pharmacol. Rev. 54, 247–264. Brancucci, A., Berretta, N., Mercuri, N.B., Francesconi, W., 2004a. Presynaptic modulation of spontaneous inhibitory postsynaptic currents by gamma-hydroxybutyrate in the substantia nigra pars compacta. Neuropsychopharmacology 29, 537–543. Brancucci, A., Berretta, N., Mercuri, N.B., Francesconi, W., 2004b. Gamma-hydroxybutyrate and ethanol depress spontaneous excitatory postsynaptic currents in dopaminergic neurons of the substantia nigra. Brain Res. 997, 62–66. Brisbare-Roch, C., Dingemanse, J., Koberstein, R., Hoever, P., Aissaoui, H., Flores, S., Mueller, C., Nayler, O., van, G.J., de Haas, S.L., Hess, P., Qiu, C., Buchmann, S., Scherz, M., Weller, T., Fischli, W., Clozel, M., Jenck, F., 2007. Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nat. Med. 13, 150–155. Broughton, R., Ghanem, Q., 1976. The impact of compound narcolepsy on the life of the patient. In: Guilleminault, C., Dement, W.C., Passouant, P. (Eds.), Narcolepsy. Advances in Sleep Research. Spectrum, New York, pp. 201–220. Broughton, R., Mamelak, M., 1976. Gammahydroxybutyrate in the treatment of narcolepsy: a preliminary report. In: Guilleminault, C., Dement, W.C., Passouant, P. (Eds.), Narcolepsy. Advances in Sleep Research. Spectrum, New York, pp. 659–667. Broughton, R., Mamelak, M., 1979. The treatment of narcolepsy–cataplexy with nocturnal gamma-hydroxybutyrate. Can. J. Neurol. Sci. 6, 1–6. Broughton, R., Mamelak, M., 1980. Effects of nocturnal gamma-hydroxybutyrate on sleep/waking patterns in narcolepsy–cataplexy. Can. J. Neurol. Sci. 7, 23–31. Broughton, R.J., Guberman, A., Roberts, J., 1984. Comparison of the psychosocial effects of epilepsy and narcolepsy/cataplexy: a controlled study. Epilepsia 25, 423–433. Brown, R.E., Sergeeva, O.A., Eriksson, K.S., Haas, H.L., 2002. Convergent excitation of dorsal raphe serotonin neurons by multiple arousal systems (orexin/hypocretin, histamine and noradrenaline). J. Neurosci. 22, 8850–8859. Burdakov, D., Alexopoulos, H., 2005. Metabolic state signalling through central hypocretin/orexin neurons. J. Cell Mol. Med. 9, 795–803.

214

M. Mamelak / Progress in Neurobiology 89 (2009) 193–219

Burlet, S., Tyler, C.J., Leonard, C.S., 2002. Direct and indirect excitation of laterodorsal tegmental neurons by hypocretin/orexin peptides: implications for wakefulness and narcolepsy. J. Neurosci. 22, 2862–2872. Burman, K.J., Ige, A.O., White, J.H., Marshall, F.H., Pangalos, M.N., Emson, P.C., Minson, J.B., Llewellyn-Smith, I.J., 2003. GABAB receptor subunits, R1 and R2, in brainstem catecholamine and serotonin neurons. Brain Res. 970, 35–46. Buzzi, A., Wu, Y., Frantseva, M.V., Perez Velazquez, J.L., Cortez, M.A., Liu, C.C., Shen, L.Q., Gibson, K.M., Snead III, O.C., 2006. Succinic semialdehyde dehydrogenase deficiency: GABAB receptor-mediated function. Brain Res. 1090, 15–22. Cammalleri, M., Brancucci, A., Berton, F., Loche, A., Gessa, G.L., Francesconi, W., 2002. Gamma-hydroxybutyrate reduces GABA(A)-mediated inhibitory postsynaptic potentials in the CA1 region of hippocampus. Neuropsychopharmacology 27, 960–969. Carai, M.A., Colombo, G., Brunetti, G., Melis, S., Serra, S., Vacca, G., Mastinu, S., Pistuddi, A.M., Solinas, C., Cignarella, G., Minardi, G., Gessa, G.L., 2001. Role of GABA(B) receptors in the sedative/hypnotic effect of gamma-hydroxybutyric acid. Eur. J. Pharmacol. 428, 315–321. Carlezon Jr., W.A., Duman, R.S., Nestler, E.J., 2005. The many faces of CREB. Trends Neurosci. 28, 436–445. Carskadon, M.A., Dement, W.C., 1980. Distribution of REM sleep on a 90 min sleep– wake schedule. Sleep 2, 309–317. Carter, L.P., Flores, L.R., Wu, H., Chen, W., Unzeitig, A.W., Coop, A., France, C.P., 2003. The role of GABAB receptors in the discriminative stimulus effects of gammahydroxybutyrate in rats: time course and antagonism studies. J. Pharmacol. Exp. Ther. 305, 668–674. Carter, L.P., Wu, H., Chen, W., Cruz, C.M., Lamb, R.J., Koek, W., Coop, A., France, C.P., 2004. Effects of gamma-hydroxybutyrate (GHB) on schedule-controlled responding in rats: role of GHB and GABAB receptors. J. Pharmacol. Exp. Ther. 308, 182–188. Carter, L.P., Wu, H., Chen, W., Matthews, M.M., Mehta, A.K., Hernandez, R.J., Thomson, J.A., Ticku, M.K., Coop, A., Koek, W., France, C.P., 2005a. Novel gamma-hydroxybutyric acid (GHB) analogs share some, but not all, of the behavioral effects of GHB and GABAB receptor agonists. J. Pharmacol. Exp. Ther. 313, 1314–1323. Carter, L.P., Chen, W., Wu, H., Mehta, A.K., Hernandez, R.J., Ticku, M.K., Coop, A., Koek, W., France, C.P., 2005b. Comparison of the behavioral effects of gamma-hydroxybutyric acid (GHB) and its 4-methyl-substituted analog, gamma-hydroxyvaleric acid (GHV). Drug Alcohol Depend. 78, 91–99. Carter, L.P., Richards, B.D., Mintzer, M.Z., Griffiths, R.R., 2006a. Relative abuse liability of GHB in humans: a comparison of psychomotor, subjective, and cognitive effects of supratherapeutic doses of triazolam, pentobarbital, and GHB. Neuropsychopharmacology 31, 2537–2551. Carter, L.P., Koek, W., France, C.P., 2006b. Lack of effects of GHB precursors GBL and 1,4-BD following i.c.v. administration in rats. Eur. J. Neurosci. 24, 2595–2600. Carter, L.P., Koek, W., France, C.P., 2009. Behavioral analyses of GHB: receptor mechanisms. Pharmacol. Ther. 121, 100–114. Castelli, M.P., Mocci, I., Langlois, X., Gommerendagger, W., Luyten, W.H., Leysen, J.E., Gessa, G.L., 2000. Quantitative autoradiographic distribution of gamma-hydroxybutyric acid binding sites in human and monkey brain. Brain Res. Mol. Brain Res. 78, 91–99. Castelli, M.P., Ferraro, L., Mocci, I., Carta, F., Carai, M.A., Antonelli, T., Tanganelli, S., Cignarella, G., Gessa, G.L., 2003. Selective gamma-hydroxybutyric acid receptor ligands increase extracellular glutamate in the hippocampus, but fail to activate G protein and to produce the sedative/hypnotic effect of gamma-hydroxybutyric acid. J. Neurochem. 87, 722–732. Castelli, M.P., Pibiri, F., Carboni, G., Piras, A.P., 2004. A review of pharmacology of NCS-382, a putative antagonist of gamma-hydroxybutyric acid (GHB) receptor. CNS Drug Rev. 10, 243–260. Castelli, M.P., 2008. Multi-faceted aspects of gamma-hydroxybutyric acid: a neurotransmitter, therapeutic agent and drug of abuse. Mini Rev. Med. Chem. 8, 1188–1202. Chemelli, R.M., Willie, J.T., Sinton, C.M., Elmquist, J.K., Scammell, T., Lee, C., Richardson, J.A., Williams, S.C., Xiong, Y., Kisanuki, Y., Fitch, T.E., Nakazato, M., Hammer, R.E., Saper, C.B., Yanagisawa, M., 1999. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98, 437–451. Chen, B., Dowlatshahi, D., MacQueen, G.M., Wang, J.F., Young, L.T., 2001. Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol. Psychiatry 50, 260–265. Chen, C.N., 1979. Sleep, depression and antidepressants. Br. J. Psychiatry 135, 385– 402. Cheramy, A., Nieoullon, A., Glowinski, J., 1977. Stimulating effects of gammahydroxybutyrate on dopamine release from the caudate nucleus and the substantia nigra of the cat. J. Pharmacol. Exp. Ther. 203, 283–293. Chou, T.C., Bjorkum, A.A., Gaus, S.E., Lu, J., Scammell, T.E., Saper, C.B., 2002. Afferents to the ventrolateral preoptic nucleus. J. Neurosci. 22, 977–990. Cirelli, C., Huber, R., Gopalakrishnan, A., Southard, T.L., Tononi, G., 2005. Locus ceruleus control of slow-wave homeostasis. J. Neurosci. 25, 4503–4511. Cirelli, C., 2006. Cellular consequences of sleep deprivation in the brain. Sleep Med. Rev. 10, 307–321. Cornil, C.A., Balthazart, J., Motte, P., Massotte, L., Seutin, V., 2002. Dopamine activates noradrenergic receptors in the preoptic area. J. Neurosci. 22, 9320–9330. Crochet, S., Sakai, K., 2003. Dopaminergic modulation of behavioral states in mesopontine tegmentum: a reverse microdialysis study in freely moving cats. Sleep 26, 801–806. Crunelli, V., Leresche, N., 1991. A role for GABAB receptors in excitation and inhibition of thalamocortical cells. Trends Neurosci. 14, 16–21.

Crunelli, V., Leresche, N., 2002. Action of g-hydroxybutyrate on neuronal excitability and underlying membrance conductances. In: Tunnicliff, G., Cash, C. (Eds.), Gammahydroxybutyrate: Molecular, Functional and Clinical Aspects. Taylor and Francis, London and New York, pp. 75–110. Crunelli, V., Cope, D.W., Hughes, S.W., 2006a. Thalamic T-type Ca2+ channels and NREM sleep. Cell Calcium 40, 175–190. Crunelli, V., Emri, Z., Leresche, N., 2006b. Unravelling the brain targets of gammahydroxybutyric acid. Curr. Opin. Pharmacol. 6, 44–52. Cruz, H.G., Ivanova, T., Lunn, M.L., Stoffel, M., Slesinger, P.A., Luscher, C., 2004. Bidirectional effects of GABA(B) receptor agonists on the mesolimbic dopamine system. Nat. Neurosci. 7, 153–159. Cryan, J.F., O’Leary, O.F., Jin, S.H., Friedland, J.C., Ouyang, M., Hirsch, B.R., Page, M.E., Dalvi, A., Thomas, S.A., Lucki, I., 2004. Norepinephrine-deficient mice lack responses to antidepressant drugs, including selective serotonin reuptake inhibitors. Proc. Natl. Acad. Sci. U.S.A. 101, 8186–8191. Cryan, J.F., Kaupmann, K., 2005. Don’t worry ‘B’ happy!: a role for GABA(B) receptors in anxiety and depression Trends Pharmacol. Sci. 26, 36–43. Czeisler, C.A., Walsh, J.K., Roth, T., Hughes, R.J., Wright, K.P., Kingsbury, L., Arora, S., Schwartz, J.R., Niebler, G.E., Dinges, D.F., 2005. Modafinil for excessive sleepiness associated with shift-work sleep disorder. N. Engl. J. Med. 353, 476–486. Daniels, E., King, M.A., Smith, I.E., Shneerson, J.M., 2001. Health-related quality of life in narcolepsy. J. Sleep Res. 10, 75–81. Daniels, L., 1934. Narcolepsy Med. 13, 1–122. de Saint Hilaire, Z., Orosco, M., Rouch, C., Blanc, G., Nicolaidis, S., 2001. Variations in extracellular monoamines in the prefrontal cortex and medial hypothalamus after modafinil administration: a microdialysis study in rats. Neuroreport 12, 3533–3537. de Lecea, L., Kilduff, T.S., Peyron, C., Gao, X., Foye, P.E., Danielson, P.E., Fukuhara, C., Battenberg, E.L., Gautvik, V.T., Bartlett, F.S., Frankel, W.N., van den Pol, A.N., Bloom, F.E., Gautvik, K.M., Sutcliffe, J.G., 1998. The hypocretins: hypothalamusspecific peptides with neuroexcitatory activity. Proc. Natl. Acad. Sci. U.S.A. 95, 322–327. Destexhe, A., Sejnowski, T.J., 2003. Interactions between membrane conductances underlying thalamocortical slow-wave oscillations. Physiol. Rev. 83, 1401– 1453. Diana, M., Mereu, G., Mura, A., Fadda, F., Passino, N., Gessa, G., 1991. Low doses of gamma-hydroxybutyric acid stimulate the firing rate of dopaminergic neurons in unanesthetized rats. Brain Res. 566, 208–211. Dilsaver, S.C., 1986. Pathophysiology of ‘‘cholinoceptor supersensitivity’’ in affective disorders. Biol. Psychiatry 21, 813–829. Duteil, J., Rambert, F.A., Pessonnier, J., Hermant, J.F., Gombert, R., Assous, E., 1990. Central alpha 1-adrenergic stimulation in relation to the behaviour stimulating effect of modafinil; studies with experimental animals. Eur. J. Pharmacol. 180, 49–58. Eggermann, E., Serafin, M., Bayer, L., Machard, D., Saint-Mleux, B., Jones, B.E., Muhlethaler, M., 2001. Orexins/hypocretins excite basal forebrain cholinergic neurones. Neuroscience 108, 177–181. Eggermann, E., Bayer, L., Serafin, M., Saint-Mleux, B., Bernheim, L., Machard, D., Jones, B.E., Muhlethaler, M., 2003. The wake-promoting hypocretin–orexin neurons are in an intrinsic state of membrane depolarization. J. Neurosci. 23, 1557–1562. Eisensehr, I., Linke, R., Tatsch, K., von, L.H., Kharraz, B., Gildehaus, F.J., Eberle, R., Pollmacher, T., Schuld, A., Noachtar, S., 2003. Alteration of the striatal dopaminergic system in human narcolepsy. Neurology 60, 1817–1819. Engberg, G., Nissbrandt, H., 1993. gamma-Hydroxybutyric acid (GHBA) induces pacemaker activity and inhibition of substantia nigra dopamine neurons by activating GABAB-receptors. Naunyn Schmiedebergs Arch. Pharmacol. 348, 491–497. Enna, S.J., Harstad, E.B., McCarson, K.E., 1998. Regulation of neurokinin-1 receptor expression by GABA(B) receptor agonists. Life Sci 62, 1525–1530. Erhardt, S., Andersson, B., Nissbrandt, H., Engberg, G., 1998. Inhibition of firing rate and changes in the firing pattern of nigral dopamine neurons by gammahydroxybutyric acid (GHBA) are specifically induced by activation of GABA(B) receptors. Naunyn Schmiedebergs Arch. Pharmacol. 357, 611–619. Ervik, S., Abdelnoor, M., Heier, M.S., Ramberg, M., Strand, G., 2006. Health-related quality of life in narcolepsy. Acta Neurol. Scand. 114, 198–204. Estabrooke, I.V., McCarthy, M.T., Ko, E., Chou, T.C., Chemelli, R.M., Yanagisawa, M., Saper, C.B., Scammell, T.E., 2001. Fos expression in orexin neurons varies with behavioral state. J. Neurosci. 21, 1656–1662. Ferraro, L., Antonelli, T., O’Connor, W.T., Tanganelli, S., Rambert, F.A., Fuxe, K., 1998. The effects of modafinil on striatal, pallidal and nigral GABA and glutamate release in the conscious rat: evidence for a preferential inhibition of striatopallidal GABA transmission. Neurosci. Lett. 253, 135–138. Ferraro, L., Tanganelli, S., O’Connor, W.T., Francesconi, W., Loche, A., Gessa, G.L., Antonelli, T., 2001. gamma-Hydroxybutyrate modulation of glutamate levels in the hippocampus: an in vivo and in vitro study. J. Neurochem. 78, 929–939. Fleckenstein, A.E., Volz, T.J., Riddle, E.L., Gibb, J.W., Hanson, G.R., 2007. New insights into the mechanism of action of amphetamines. Annu. Rev. Pharmacol. Toxicol. 47, 681–698. Follwell, M.J., Ferguson, A.V., 2002. Cellular mechanisms of orexin actions on paraventricular nucleus neurones in rat hypothalamus. J. Physiol. 545, 855– 867. Franken, P., Gip, P., Hagiwara, G., Ruby, N.F., Heller, H.C., 2006. Glycogen content in the cerebral cortex increases with sleep loss in C57BL/6J mice. Neurosci. Lett. 402, 176–179.

M. Mamelak / Progress in Neurobiology 89 (2009) 193–219 Fredholm, B.B., Battig, K., Holmen, J., Nehlig, A., Zvartau, E.E., 1999. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol. Rev. 51, 83–133. Fruhstorfer, B., Mignot, E., Bowersox, S., Nishino, S., Dement, W.C., Guilleminault, C., 1989. Canine narcolepsy is associated with an elevated number of alpha 2-receptors in the locus coeruleus. Brain Res. 500, 209–214. Fujiki, N., Yoshida, Y., Ripley, B., Honda, K., Mignot, E., Nishino, S., 2001. Changes in CSF hypocretin-1 (orexin A) levels in rats across 24 h and in response to food deprivation. Neuroreport 12, 993–997. Fujiki, N., Yoshida, Y., Ripley, B., Mignot, E., Nishino, S., 2003. Effects of IV and ICV hypocretin-1 (orexin A) in hypocretin receptor-2 gene mutated narcoleptic dogs and IV hypocretin-1 replacement therapy in a hypocretin-ligand-deficient narcoleptic dog. Sleep 26, 953–959. Fukui, R., Svenningsson, P., Matsuishi, T., Higashi, H., Nairn, A.C., Greengard, P., Nishi, A., 2003. Effect of methylphenidate on dopamine/DARPP signalling in adult, but not young, mice. J. Neurochem. 87, 1391–1401. Gallopin, T., Luppi, P.H., Rambert, F.A., Frydman, A., Fort, P., 2004. Effect of the wakepromoting agent modafinil on sleep-promoting neurons from the ventrolateral preoptic nucleus: an in vitro pharmacologic study. Sleep 27, 19–25. Gaus, S.E., Strecker, R.E., Tate, B.A., Parker, R.A., Saper, C.B., 2002. Ventrolateral preoptic nucleus contains sleep-active, galaninergic neurons in multiple mammalian species. Neuroscience 115, 285–294. Gauthier, P., Arnaud, C., Gandolfo, G., Gottesmann, C., 1997. Influence of a GABA(B) receptor antagonist on the sleep-waking cycle in the rat. Brain Res. 773, 8–14. Gerrard, P., Malcolm, R., 2007. Mechanisms of modafinil: a review of current research. Neuropsychiatr. Dis. Treat. 3, 349–364. Gervasi, N., Monnier, Z., Vincent, P., Paupardin-Tritsch, D., Hughes, S.W., Crunelli, V., Leresche, N., 2003. Pathway-specific action of gamma-hydroxybutyric acid in sensory thalamus and its relevance to absence seizures. J. Neurosci. 23, 11469– 11478. Gibson, K.M., Jakobs, C., Ogier, H., Hagenfeldt, L., Eeg-Olofsson, K.E., Eeg-Olofsson, O., Aksu, F., Weber, H.P., Rossier, E., Vollmer, B., 1995. Vigabatrin therapy in six patients with succinic semialdehyde dehydrogenase deficiency. J. Inherit. Metab. Dis. 18, 143–146. Giorgetti, M., Bacciottini, L., Giovannini, M.G., Colivicchi, M.A., Goldfarb, J., Blandina, P., 2000. Local GABAergic modulation of acetylcholine release from the cortex of freely moving rats. Eur. J. Neurosci. 12, 1941–1948. Giorgi, O., Rubio, M.C., 1981. Decreased 3H-L-quinuclidinyl benzilate binding and muscarinic receptor subsensitivity after chronic gamma-butyrolactone treatment. Naunyn Schmiedebergs Arch. Pharmacol. 318, 14–18. Godbout, R., Montplaisir, J., 2002. Effects of g-hydroxybutyrate on sleep. In: Tunnicliff, G., Cash, C.D. (Eds.), Gammahydroxybutyrate: Molecular, Functional and Clinical Aspects. Taylor and Francis, London and New York, pp. 120–132. Gopalakrishnan, L., Scarpulla, R.C., 1994. Differential regulation of respiratory chain subunits by a CREB-dependent signal transduction pathway. Role of cyclic AMP in cytochrome c and COXIV gene expression. J. Biol. Chem. 269, 105–113. Gross, M.D., 1969. A note on cataplexy treated with protriptyline. Dis. Nerv. Syst. 30, 418. Guilleminault, C., 1976. Cataplexy. Adv. Sleep Res. 3, 125–143. Guilleminault, C., Raynal, D., Takahashi, S., Carskadon, M., Dement, W., 1976. Evaluation of short-term and long-term treatment of the narcolepsy syndrome with clomipramine hydrochloride. Acta Neurol. Scand. 54, 71–87. Guilleminault, C., Flagg, W., 1984. Effect of baclofen on sleep-related periodic leg movements. Ann. Neurol. 15, 234–239. Guilleminault, C., Mignot, E., Aldrich, M., Quera-Salva, M.A., Tiberge, M., Partinen, M., 1988. Prazosin contraindicated in patients with narcolepsy. Lancet 2, 511. Hagan, J.J., Leslie, R.A., Patel, S., Evans, M.L., Wattam, T.A., Holmes, S., Benham, C.D., Taylor, S.G., Routledge, C., Hemmati, P., Munton, R.P., Ashmeade, T.E., Shah, A.S., Hatcher, J.P., Hatcher, P.D., Jones, D.N., Smith, M.I., Piper, D.C., Hunter, A.J., Porter, R.A., Upton, N., 1999. Orexin A activates locus coeruleus cell firing and increases arousal in the rat. Proc. Natl. Acad. Sci. U.S.A. 96, 10911–10916. Haller, C., Mende, M., Schuier, F., Schuh, R., Schrock, H., Kuschinsky, W., 1990. Effect of gamma-hydroxybutyrate on local and global glucose metabolism in the anesthetized cat brain. J. Cereb. Blood Flow Metab. 10, 493–498. Harsh, J.R., Hayduk, R., Rosenberg, R., Wesnes, K.A., Walsh, J.K., Arora, S., Niebler, G.E., Roth, T., 2006. The efficacy and safety of armodafinil as treatment for adults with excessive sleepiness associated with narcolepsy. Curr. Med. Res. Opin. 22, 761–774. Harvey, A.G., 2008. Sleep and circadian rhythms in bipolar disorder: seeking synchrony, harmony, and regulation. Am. J. Psychiatry 165, 820–829. Hechler, V., Gobaille, S., Maitre, M., 1989. Localization studies of gamma-hydroxybutyrate receptors in rat striatum and hippocampus. Brain Res. Bull. 23, 129– 135. Hechler, V., Schmitt, M., Bourguignon, J.J., Maitre, M., 1990. Trans-gamma-hydroxycrotonic acid binding sites in brain: evidence for a subpopulation of gammahydroxybutyrate sites. Neurosci. Lett. 110, 204–209. Hechler, V., Gobaille, S., Bourguignon, J.J., Maitre, M., 1991. Extracellular events induced by gamma-hydroxybutyrate in striatum: a microdialysis study. J. Neurochem. 56, 938–944. Hechler, V., Gobaille, S., Maitre, M., 1992. Selective distribution pattern of gammahydroxybutyrate receptors in the rat forebrain and midbrain as revealed by quantitative autoradiography. Brain Res. 572, 345–348. Hechler, V., Peter, P., Gobaille, S., Bourguignon, J.J., Schmitt, M., Ehrhardt, J.D., Mark, J., Maitre, M., 1993. gamma-Hydroxybutyrate ligands possess antidopaminergic and neuroleptic-like activities. J. Pharmacol. Exp. Ther. 264, 1406–1414.

215

Hishikawa, Y., Ida, H., Nakai, K., Kaneko, Z., 1966. Treatment of narcolepsy with imipramine (tofranil) and desmethylimipramine (pertofran). J. Neurol. Sci. 3, 453–461. Hoffman, B., Lefkowitz, R., 1996. Catecholamines, sympathomimetic drugs and adrenergic receptor antagonists. In: Hardman, J., Goodman Gilman, A., Limbud, L. (Eds.), The Pharmacological Basis of Therapeutics. pp. 199–248. Honda, Y., 1988. Clinical features of narcolepsy: Japanese experience. In: Honda, T., Juji, T. (Eds.), HLA in Narcolepsy. Springer-Verlag, Berlin, pp. 24–57. Horvath, T.L., Peyron, C., Diano, S., Ivanov, A., ston-Jones, G., Kilduff, T.S., van den Pol, A.N., 1999. Hypocretin (orexin) activation and synaptic innervation of the locus coeruleus noradrenergic system. J. Comp. Neurol. 415, 145–159. Howard, S., Banerjee, P., 2002. Regulation of central dopamine by g-hydroxybutyrate. In: Tunnicliff, G., Cash, C. (Eds.), Gammahydroxybutyrate: Molecular, Functional and Clinical Aspects. Taylor and Francis, London and New York, pp. 111–119. Huang, Z.L., Qu, W.M., Li, W.D., Mochizuki, T., Eguchi, N., Watanabe, T., Urade, Y., Hayaishi, O., 2001. Arousal effect of orexin A depends on activation of the histaminergic system. Proc. Natl. Acad. Sci. U.S.A. 98, 9965–9970. Huber, R., Ghilardi, M.F., Massimini, M., Tononi, G., 2004. Local sleep and learning. Nature 430, 78–81. Huber, R., Tononi, G., Cirelli, C., 2007. Exploratory behavior, cortical BDNF expression, and sleep homeostasis. Sleep 30, 129–139. Hublin, C., Partinen, M., Heinonen, E.H., Puukka, P., Salmi, T., 1994. Selegiline in the treatment of narcolepsy. Neurology 44, 2095–2101. Huguenard, J.R., McCormick, D.A., 2007. Thalamic synchrony and dynamic regulation of global forebrain oscillations. Trends Neurosci. 30, 350–356. Huguenard, J.R., Prince, D.A., 1994. Clonazepam suppresses GABAB-mediated inhibition in thalamic relay neurons through effects in nucleus reticularis. J. Neurophysiol. 71, 2576–2581. Ikarashi, Y., Yuzurihara, M., Takahashi, A., Hirohisa, I., Shiobara, T., Maruyama, Y., 1999. Modulation of acetylcholine release via GABAA and GABAB receptors in rat striatum. Brain Res. 816, 238–240. Isaac, S.O., Berridge, C.W., 2003. Wake-promoting actions of dopamine D1 and D2 receptor stimulation. J. Pharmacol. Exp. Ther. 307, 386–394. Ishizuka, T., Sakamoto, Y., Sakurai, T., Yamatodani, A., 2003. Modafinil increases histamine release in the anterior hypothalamus of rats. Neurosci. Lett. 339, 143–146. Janowsky, D.S., el-Yousef, M.K., Davis, J.M., Sekerke, H.J., 1972. A cholinergic– adrenergic hypothesis of mania and depression. Lancet 2, 632–635. John, J., Wu, M.F., Siegel, J.M., 2000. Systemic administration of hypocretin-1 reduces cataplexy and normalizes sleep and waking durations in narcoleptic dogs. Sleep Res. Online 3, 23–28. Jones, B.E., Harper, S.T., Halaris, A.E., 1977. Effects of locus coeruleus lesions upon cerebral monoamine content, sleep–wakefulness states and the response to amphetamine in the cat. Brain Res. 124, 473–496. Jones, B.E., 2004. Activity, modulation and role of basal forebrain cholinergic neurons innervating the cerebral cortex. Prog. Brain Res. 145, 157–169. Jones, K.A., Borowsky, B., Tamm, J.A., Craig, D.A., Durkin, M.M., Dai, M., Yao, W.J., Johnson, M., Gunwaldsen, C., Huang, L.Y., Tang, C., Shen, Q., Salon, J.A., Morse, K., Laz, T., Smith, K.E., Nagarathnam, D., Noble, S.A., Branchek, T.A., Gerald, C., 1998. GABA(B) receptors function as a heteromeric assembly of the subunits GABA(B)R1 and GABA(B)R2. Nature 396, 674–679. Jouvet, M., Delorme, F., 1965. Locus coeruleus et sommeil paradoxal. C. R. Soc. Biol. 159, 895–899. Juhasz, G., Emri, Z., Kekesi, K.A., Salfay, O., Crunelli, V., 1994. Blockade of thalamic GABAB receptors decreases EEG synchronization. Neurosci. Lett. 172, 155–158. Kanbayashi, T., Honda, K., Kodama, T., Mignot, E., Nishino, S., 2000. Implication of dopaminergic mechanisms in the wake-promoting effects of amphetamine: a study of D- and L-derivatives in canine narcolepsy. Neuroscience 99, 651–659. Karege, F., Vaudan, G., Schwald, M., Perroud, N., La, H.R., 2005. Neurotrophin levels in postmortem brains of suicide victims and the effects of antemortem diagnosis and psychotropic drugs. Brain Res. Mol. Brain Res. 136, 29–37. Kastin, A.J., Akerstrom, V., 1999. Orexin A but not orexin B rapidly enters brain from blood by simple diffusion. J. Pharmacol. Exp. Ther. 289, 219–223. Kaufman, E.E., Porrino, L.J., Nelson, T., 1990. Pyretic action of low doses of gammahydroxybutyrate in rats. Biochem. Pharmacol. 40, 2637–2640. Kaufman, E.E., 2002. Metabolism and distribution of g-hydroxybutyrate in the brain. In: Tunnicliff, G., Cash, C. (Eds.), Gammahydroxybutyrate: Molecular, Functional and Clinical Aspects. Taylor and Francis, London and New York, pp. 1–16. Kaupmann, K., Malitschek, B., Schuler, V., Heid, J., Froestl, W., Beck, P., Mosbacher, J., Bischoff, S., Kulik, A., Shigemoto, R., Karschin, A., Bettler, B., 1998. GABA(B)receptor subtypes assemble into functional heteromeric complexes. Nature 396, 683–687. Kaupmann, K., Cryan, J.F., Wellendorph, P., Mombereau, C., Sansig, G., Klebs, K., Schmutz, M., Froestl, W., Van der, P.H., Mosbacher, J., Brauner-Osborne, H., Waldmeier, P., Bettler, B., 2003. Specific gamma-hydroxybutyrate-binding sites but loss of pharmacological effects of gamma-hydroxybutyrate in GABA(B)(1)deficient mice. Eur. J. Neurosci. 18, 2722–2730. Keating, G.M., Raffin, M.J., 2005. Modafinil: a review of its use in excessive sleepiness associated with obstructive sleep apnoea/hypopnoea syndrome and shift work sleep disorder. CNS Drugs 19, 785–803. Kemmel, V., Taleb, O., Perard, A., Andriamampandry, C., Siffert, J.C., Mark, J., Maitre, M., 1998. Neurochemical and electrophysiological evidence for the existence of a functional gamma-hydroxybutyrate system in NCB-20 neurons. Neuroscience 86, 989–1000.

216

M. Mamelak / Progress in Neurobiology 89 (2009) 193–219

Kemmel, V., Taleb, O., Andriamampandry, C., Aunis, D., Maitre, M., 2003. Gammahydroxybutyrate receptor function determined by stimulation of rubidium and calcium movements from NCB-20 neurons. Neuroscience 116, 1021–1031. Kemmel, V., Miehe, M., Roussel, G., Taleb, O., Nail-Boucherie, K., Marchand, C., Stutz, C., Andriamampandry, C., Aunis, D., Maitre, M., 2006. Immunohistochemical localization of a GHB receptor-like protein isolated from rat brain. J. Comp.Neurol. 498, 508–524. Kilduff, T., Morairty, S., Steininger, T., Xie, X., 2007. Hypocretin, GABAB receptors and sleep. Lung Biol. Health Dis. 220, 375–385. Kilduff, T.S., Bowersox, S.S., Kaitin, K.I., Baker, T.L., Ciaranello, R.D., Dement, W.C., 1986. Muscarinic cholinergic receptors and the canine model of narcolepsy. Sleep 9, 102–106. Kish, S.J., Mamelak, M., Slimovitch, C., Dixon, L.M., Lewis, A., Shannak, K., DiStefano, L., Chang, L.J., Hornykiewicz, O., 1992. Brain neurotransmitter changes in human narcolepsy. Neurology 42, 229–234. Kiyashchenko, L.I., Mileykovskiy, B.Y., Maidment, N., Lam, H.A., Wu, M.F., John, J., Peever, J., Siegel, J.M., 2002. Release of hypocretin (orexin) during waking and sleep states. J. Neurosci. 22, 5282–5286. Kodama, T., Lai, Y.Y., Siegel, J.M., 2003. Changes in inhibitory amino acid release linked to pontine-induced atonia: an in vivo microdialysis study. J. Neurosci. 23, 1548–1554. Koek, W., Carter, L.P., Lamb, R.J., Chen, W., Wu, H., Coop, A., France, C.P., 2005. Discriminative stimulus effects of gamma-hydroxybutyrate (GHB) in rats discriminating GHB from baclofen and diazepam. J. Pharmacol. Exp. Ther. 314, 170–179. Koek, W., Mercer, S.L., Coop, A., 2007. Cataleptic effects of gamma-hydroxybutyrate (GHB), its precursor gamma-butyrolactone (GBL), and GABAB receptor agonists in mice: differential antagonism by the GABAB receptor antagonist CGP35348. Psychopharmacology (Berlin) 192, 407–414. Kong, J., Shepel, P.N., Holden, C.P., Mackiewicz, M., Pack, A.I., Geiger, J.D., 2002. Brain glycogen decreases with increased periods of wakefulness: implications for homeostatic drive to sleep. J. Neurosci. 22, 5581–5587. Koob, G.F., 1999. Corticotropin-releasing factor, norepinephrine, and stress. Biol. Psychiatry 46, 1167–1180. Kopp, C., Rudolph, U., Keist, R., Tobler, I., 2003. Diazepam-induced changes on sleep and the EEG spectrum in mice: role of the alpha3-GABA(A) receptor subtype. Eur. J. Neurosci. 17, 2226–2230. Kopp, C., Rudolph, V., Low, K., Tobler, I., 2004. Modulation of rhythmic brain activity by diazepam: GABAA receptor subtype and state specifically. PNAS 100, 3674– 3679. Korotkova, T.M., Sergeeva, O.A., Eriksson, K.S., Haas, H.L., Brown, R.E., 2003. Excitation of ventral tegmental area dopaminergic and nondopaminergic neurons by orexins/hypocretins. J. Neurosci. 23, 7–11. Kumar, R., 2008. Approved and investigational uses of modafinil: an evidence-based review. Drugs 68, 1803–1839. Kupfer, D.J., Gillin, J.C., Coble, P.A., Spiker, D.G., Shaw, D., Holzer, B., 1981. REM sleep, naps, and depression. Psychiatry Res. 5, 195–203. Kuschinsky, W., Suda, S., Sokoloff, L., 1985. Influence of gamma-hydroxybutyrate on the relationship between local cerebral glucose utilization and local cerebral blood flow in the rat brain. J. Cereb. Blood Flow Metab. 5, 58–64. Laborit, H.-M., 1964. Sodium–4-hydroxybutyrate. Int. J. Neuropharmacol. 3, 433– 452. Lai, Y.Y., Kodama, T., Siegel, J.M., 2001. Changes in monoamine release in the ventral horn and hypoglossal nucleus linked to pontine inhibition of muscle tone: an in vivo microdialysis study. J. Neurosci. 21, 7384–7391. Lammers, G.J., Arends, J., Declerck, A.C., Ferrari, M.D., Schouwink, G., Troost, J., 1993. Gammahydroxybutyrate and narcolepsy: a double-blind placebo-controlled study. Sleep 16, 216–220. Landolt, H., Gillin, J., 2000. CNS Drugs 13, 185–199. Lapierre, O., Montplaisir, J., Lamarre, M., Bedard, M.A., 1990. The effect of gammahydroxybutyrate on nocturnal and diurnal sleep of normal subjects: further considerations on REM sleep-triggering mechanisms. Sleep 13, 24–30. Lee, M.G., Hassani, O.K., Jones, B.E., 2005. Discharge of identified orexin/hypocretin neurons across the sleep-waking cycle. J. Neurosci. 25, 6716–6720. Lehmann, A., Mattson, J., Edlund, A., Johansson, T., Ekstrand, A., 2003. Effects of repeated administration of baclofen to rats on GABAB receptor binding sites and subunit expression in the brain. Neurochem. Res. 28, 387–393. Li, Q., Kuhn, C.M., Wilson, W.A., Lewis, D.V., 2007. Effects of gamma hydroxybutyric acid on inhibition and excitation in rat neocortex. Neuroscience 150, 82–92. Lin, J.S., Roussel, B., Akaoka, H., Fort, P., Debilly, G., Jouvet, M., 1992. Role of catecholamines in the modafinil and amphetamine induced wakefulness, a comparative pharmacological study in the cat. Brain Res. 591, 319–326. Lin, L., Faraco, J., Li, R., Kadotani, H., Rogers, W., Lin, X., Qiu, X., de Jong, P.J., Nishino, S., Mignot, E., 1999. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98, 365–376. Lingenhoehl, K., Brom, R., Heid, J., Beck, P., Froestl, W., Kaupmann, K., Bettler, B., Mosbacher, J., 1999. Gamma-hydroxybutyrate is a weak agonist at recombinant GABA(B) receptors. Neuropharmacology 38, 1667–1673. Linnoila, M., Simpson, D., Skinner, T., 1980. Characteristics of therapeutic response to imipramine in cataplectic men. Am. J. Psychiatry 137, 237–238. Liu, R.J., van den Pol, A.N., Aghajanian, G.K., 2002. Hypocretins (orexins) regulate serotonin neurons in the dorsal raphe nucleus by excitatory direct and inhibitory indirect actions. J. Neurosci. 22, 9453–9464. Lodi, R., Tonon, C., Vignatelli, L., Iotti, S., Montagna, P., Barbiroli, B., Plazzi, G., 2004. In vivo evidence of neuronal loss in the hypothalamus of narcoleptic patients. Neurology 63, 1513–1515.

Lonze, B.E., Ginty, D.D., 2002. Function and regulation of CREB family transcription factors in the nervous system. Neuron 35, 605–623. Lorente, P., Lacampagne, A., Pouzeratte, Y., Richards, S., Malitschek, B., Kuhn, R., Bettler, B., Vassort, G., 2000. gamma-aminobutyric acid type B receptors are expressed and functional in mammalian cardiomyocytes. Proc. Natl. Acad. Sci. U.S.A. 97, 8664–8669. Lu, J., Greco, M.A., Shiromani, P., Saper, C.B., 2000. Effect of lesions of the ventrolateral preoptic nucleus on NREM and REM sleep. J. Neurosci. 20, 3830–3842. Lu, J., Jhou, T.C., Saper, C.B., 2006. Identification of wake-active dopaminergic neurons in the ventral periaqueductal gray matter. J. Neurosci. 26, 193–202. Luppi, P.H., Gervasoni, D., Boissard, R., Verret, L., Goutagny, R., Peyron, C., Salvert, D., Leger, L., Barbagli, B., Fort, P., 2004. Brainstem structures responsible for paradoxical sleep onset and maintenance. Arch. Ital. Biol. 142, 397–411. Lyon, R.C., Johnston, S.M., Watson, D.G., McGarvie, G., Ellis, E.M., 2007. Synthesis and catabolism of gamma-hydroxybutyrate in SH-SY5Y human neuroblastoma cells: role of the aldo-keto reductase AKR7A2. J. Biol. Chem. 282, 25986–25992. Mabuchi, T., Kitagawa, K., Kuwabara, K., Takasawa, K., Ohtsuki, T., Xia, Z., Storm, D., Yanagihara, T., Hori, M., Matsumoto, M., 2001. Phosphorylation of cAMP response element-binding protein in hippocampal neurons as a protective response after exposure to glutamate in vitro and ischemia in vivo. J. Neurosci. 21, 9204–9213. MacFarlane, J.G., List, S.J., Moldofsky, H., Firnau, G., Chen, J.J., Szechtman, H., Garnett, S., Nahmias, C., 1997. Dopamine D2 receptors quantified in vivo in human narcolepsy. Biol. Psychiatry 41, 305–310. MacMillan, V., 1978. The effects of gamma-hydroxybutyrate and gamma-butyrolactone upon the energy metabolism of the normoxic and hypoxic rat brain. Brain Res. 146, 177–187. Madsen, P.L., Schmidt, J.F., Wildschiodtz, G., Friberg, L., Holm, S., Vorstrup, S., Lassen, N.A., 1991. Cerebral O2 metabolism and cerebral blood flow in humans during deep and rapid-eye-movement sleep. J. Appl. Physiol. 70, 2597–2601. Maitre, M., Rumigny, J.F., Cash, C., Mandel, P., 1983. Subcellular distribution of gamma-hydroxybutyrate binding sites in rat brain principal localization in the synaptosomal fraction. Biochem. Biophys. Res. Commun. 110, 262–265. Maitre, M., Kemmel, V., Andriamampandry, C., Gobaille, S., Aunis, D., 2002. The role of g-hydroxybutyrate in brain function. In: Tunnicliff, G., Cash, C. (Eds.), Gammahydroxybutyrate: Molecular, Funcitonal and Clinical Aspects. Taylor and Francis, London and New York, pp. 236–247. Maitre, M., 1997. The gamma-hydroxybutyrate signalling system in brain: organization and functional implications. Prog. Neurobiol. 51, 337–361. Malberg, J.E., Blendy, J.A., 2005. Antidepressant action: to the nucleus and beyond. Trends Pharmacol. Sci. 26, 631–638. Malcangio, M., Libri, V., Teoh, H., Constanti, A., Bowery, N.G., 1995. Chronic ( )baclofen or CGP 36742 alters GABAB receptor sensitivity in rat brain and spinal cord. Neuroreport 6, 399–403. Malenka, R.C., Nicoll, R.A., 1986. Dopamine decreases the calcium-activated afterhyperpolarization in hippocampal CA1 pyramidal cells. Brain Res. 379, 210–215. Malkoski, S.P., Dorin, R.I., 1999. Composite glucocorticoid regulation at a functionally defined negative glucocorticoid response element of the human corticotropin-releasing hormone gene. Mol. Endocrinol. 13, 1629–1644. Mamelak, M., Escriu, J.M., Stokan, O., 1973. Sleep-inducing effects of gammahydroxybutyrate. Lancet 2, 328–329. Mamelak, M., Escriu, J.M., Stokan, O., 1977. The effects of gamma-hydroxybutyrate on sleep. Biol. Psychiatry 12, 273–288. Mamelak, M., Sowden, K., 1983. The effect of gammahydroxybutyrate on the Hreflex: pilot study. Neurology 33, 1497–1500. Mamelak, M., Scharf, M.B., Woods, M., 1986. Treatment of narcolepsy with gammahydroxybutyrate. A review of clinical and sleep laboratory findings. Sleep 9, 285–289. Mamelak, M., Hyndman, D., 2002. g-Hydroxybutyrate and oxidative stress. In: Tunnicliff, G., Cash, C. (Eds.), Gammahydroxybutryate: Molecular, Functional and Clinical Aspects. Taylor and Francis, London and New York, pp. 218–235. Mamelak, M., Black, J., Montplaisir, J., Ristanovic, R., 2004. A pilot study on the effects of sodium oxybate on sleep architecture and daytime alertness in narcolepsy. Sleep 27, 1327–1334. Mamelak, M., 2007. Alzheimer’ s disease, oxidative stress and gammahydroxybutyrate. Neurobiol. Aging 28, 1340–1360. Maquet, P., Dive, D., Salmon, E., Sadzot, B., Franco, G., Poirrier, R., von, F.R., Franck, G., 1990. Cerebral glucose utilization during sleep–wake4 cycle in man determined by positron emission tomography and [18F]2-fluoro-2-deoxy-D-glucose method. Brain Res. 513, 136–143. Marcus, J.N., Aschkenasi, C.J., Lee, C.E., Chemelli, R.M., Saper, C.B., Yanagisawa, M., Elmquist, J.K., 2001. Differential expression of orexin receptors 1 and 2 in the rat brain. J. Comp. Neurol. 435, 6–25. Martinez-Rodriguez, J., Iranzo, A., Santamaria, J., Genis, D., Molins, A., Silva, Y., Melendez, R., 2002. Status cataplecticus induced by abrupt withdrawal of clomipramine. Neurologia 17, 113–116. Mayer, G., Ewert, M.K., Hephata, K., 1995. Selegeline hydrochloride treatment in narcolepsy. A double-blind, placebo-controlled study. Clin. Neuropharmacol. 18, 306–319. Mayers, A.G., Baldwin, D.S., 2005. Antidepressants and their effect on sleep. Hum. Psychopharmacol. 20, 533–559. McCarley, R.W., 2007. Neurobiology of REM and NREM sleep. Sleep Med. 8, 302– 330. McCormick, D.A., 1992. Neurotransmitter actions in the thalamus and cerebral cortex and their role in neuromodulation of thalamocortical activity. Prog. Neurobiol. 39, 337–388.

M. Mamelak / Progress in Neurobiology 89 (2009) 193–219 Mefford, I.N., Baker, T.L., Boehme, R., Foutz, A.S., Ciaranello, R.D., Barchas, J.D., Dement, W.C., 1983. Narcolepsy: biogenic amine deficits in an animal model. Science 220, 629–632. Mehta, A.K., Gould, G.G., Gupta, M., Carter, L.P., Gibson, K.M., Ticku, M.K., 2006. Succinate semialdehyde dehydrogenase deficiency does not down-regulate gamma-hydroxybutyric acid binding sites in the mouse brain. Mol. Genet. Metab. 88, 86–89. Metcalf, D.R., Emde, R.N., Stripe, J.T., 1966. An EEG-behavioral study of sodium hydroxybutyrate in humans. Electroencephalogr. Clin. Neurophysiol. 20, 506– 512. Mieda, M., Willie, J.T., Hara, J., Sinton, C.M., Sakurai, T., Yanagisawa, M., 2004. Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice. Proc. Natl. Acad. Sci. U.S.A. 101, 4649–4654. Mignot, E., Guilleminault, C., Bowersox, S., Frusthofer, B., Nishino, S., Maddaluno, J., Ciaranello, R., Dement, W.C., 1989. Central alpha 1 adrenoceptor subtypes in narcolepsy–cataplexy: a disorder of REM sleep. Brain Res. 490, 186–191. Mignot, E., Renaud, A., Nishino, S., Arrigoni, J., Guilleminault, C., Dement, W.C., 1993. Canine cataplexy is preferentially controlled by adrenergic mechanisms: evidence using monoamine selective uptake inhibitors and release enhancers. Psychopharmacology (Berlin) 113, 76–82. Mignot, E., Nishino, S., Guilleminault, C., Dement, W.C., 1994. Modafinil binds to the dopamine uptake carrier site with low affinity. Sleep 17, 436–437. Mignot, E., 1998. Genetic and familial aspects of narcolepsy. Neurology 50, S16–S22. Mignot, E., Lin, L., Rogers, W., Honda, Y., Qiu, X., Lin, X., Okun, M., Hohjoh, H., Miki, T., Hsu, S., Leffell, M., Grumet, F., Fernandez-Vina, M., Honda, M., Risch, N., 2001. Complex HLA-DR and -DQ interactions confer risk of narcolepsy–cataplexy in three ethnic groups. Am. J. Hum. Genet. 68, 686–699. Mignot, E., Lammers, G.J., Ripley, B., Okun, M., Nevsimalova, S., Overeem, S., Vankova, J., Black, J., Harsh, J., Bassetti, C., Schrader, H., Nishino, S., 2002. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch. Neurol. 59, 1553–1562. Mignot, E., Nishino, S., 2005. Emerging therapies in narcolepsy–cataplexy. Sleep 28, 754–763. Mignot, E., Lin, L., Finn, L., Lopes, C., Pluff, K., Sundstrom, M.L., Young, T., 2006. Correlates of sleep-onset REM periods during the Multiple Sleep Latency Test in community adults. Brain 129, 1609–1623. Mitler, M.M., Erman, M., Hajdukovic, R., 1993. The treatment of excessive somnolence with stimulant drugs. Sleep 16, 203–206. Mitler, M.M., Aldrich, M.S., Koob, G.F., Zarcone, V.P., 1994. Narcolepsy and its treatment with stimulants. ASDA standards of practice. Sleep 17, 352–371. Mitler, M.M., Harsh, J., Hirshkowitz, M., Guilleminault, C., 2000. Long-term efficacy and safety of modafinil (PROVIGIL((R))) for the treatment of excessive daytime sleepiness associated with narcolepsy. Sleep Med. 1, 231–243. Monaca, C., Boutrel, B., Hen, R., Hamon, M., Adrien, J., 2003. 5-HT 1A/1B receptormediated effects of the selective serotonin reuptake inhibitor, citalopram, on sleep: studies in 5-HT 1A and 5-HT 1B knockout mice. Neuropsychopharmacology 28, 850–856. Morgenthaler, T.I., Kapur, V.K., Brown, T., Swick, T.J., Alessi, C., Aurora, N., Boehlecke, B., Chesson Jr., A.L., Friedman, L., Maganti, R., Owens, J., Pancer, J., Zak, R., 2007. Standards of Practice Committee of the AASM. Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin. Sleep 30, 1705–1711. Muyard, J., Laborit, H.-M., 1977. Gammahydroxybutyrate psychotherapeutic drugs: Part II. In: Eds, E., Usdin, J., Forrest, (Eds.), Applications: Psychopharmacology. Marcel-Dekker, New York, pp. 1339–1375. Nakamura, T., Uramura, K., Nambu, T., Yada, T., Goto, K., Yanagisawa, M., Sakurai, T., 2000. Orexin-induced hyperlocomotion and stereotypy are mediated by the dopaminergic system. Brain Res. 873, 181–187. Nambu, T., Sakurai, T., Mizukami, K., Hosoya, Y., Yanagisawa, M., Goto, K., 1999. Distribution of orexin neurons in the adult rat brain. Brain Res. 827, 243–260. Nava, F., Carta, G., Bortolato, M., Gessa, G.L., 2001. gamma-Hydroxybutyric acid and baclofen decrease extracellular acetylcholine levels in the hippocampus via GABA(B) receptors. Eur. J. Pharmacol. 430, 261–263. Nelson, T., Kaufman, E., Kline, J., Sokoloff, L., 1981. The extraneural distribution of gamma-hydroxybutyrate. J. Neurochem. 37, 1345–1348. Nicolaidis, S., Danguir, J., 1984. Metabolic determinants of feeding and sleep. The ischymetric hypothesis. Exp. Brain Res. 54, 173–187. Nishino, S., Arrigoni, J., Valtier, D., Miller, J.D., Guilleminault, C., Dement, W.C., Mignot, E., 1991. Dopamine D2 mechanisms in canine narcolepsy. J. Neurosci. 11, 2666–2671. Nishino, S., Arrigoni, J., Shelton, J., Dement, W.C., Mignot, E., 1993. Desmethyl metabolites of serotonergic uptake inhibitors are more potent for suppressing canine cataplexy than their parent compounds. Sleep 16, 706–712. Nishino, S., Tafti, M., Reid, M.S., Shelton, J., Siegel, J.M., Dement, W.C., Mignot, E., 1995. Muscle atonia is triggered by cholinergic stimulation of the basal forebrain: implication for the pathophysiology of canine narcolepsy. J. Neurosci. 15, 4806–4814. Nishino, S., Mignot, E., 1997. Pharmacological aspects of human and canine narcolepsy. Prog. Neurobiol. 52, 27–78. Nishino, S., Mao, J., Sampathkumaran, R., Shelton, J., 1998. Increased dopaminergic transmission mediates the wake-promoting effects of CNS stimulants. Sleep Res. Online 1, 49–61. Nishino, S., Ripley, B., Overeem, S., Nevsimalova, S., Lammers, G.J., Vankova, J., Okun, M., Rogers, W., Brooks, S., Mignot, E., 2001. Low cerebrospinal fluid hypocretin (Orexin) and altered energy homeostasis in human narcolepsy. Ann. Neurol. 50, 381–388.

217

Nishino, S., Kanbayashi, T., Fujiki, N., Uchino, M., Ripley, B., Watanabe, M., Lammers, G.J., Ishiguro, H., Shoji, S., Nishida, Y., Overeem, S., Toyoshima, I., Yoshida, Y., Shimizu, T., Taheri, S., Mignot, E., 2003. CSF hypocretin levels in Guillain– Barre syndrome and other inflammatory neuropathies. Neurology 61, 823–825. Nishino, S., Kanbayashi, T., 2005. Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/orexin system. Sleep Med. Rev. 9, 269–310. Nishino, S., 2007. Clinical and neurobiological aspects of narcolepsy. Sleep Med. 8, 373–399. Nishino, S., Mignot, E., 2007. Pharmacology of CNS stimulants. In: Bassetti, C., Billiard, M., Mignot, E. (Eds.), Narcolepsy and Hypersomnia. Informa Health Care USA Inc, pp. 513–530. Nissbrandt, H., Engberg, G., 1996. The GABAB-receptor antagonist, CGP 35348, antagonises gamma-hydroxybutyrate- and baclofen-induced alterations in locomotor activity and forebrain dopamine levels in mice. J. Neural Transm. 103, 1255–1263. Nissen, C., Feige, B., Nofzinger, E., Riemann, D., Berger, M., Voderholzer, U., 2005. Transient narcolepsy–cataplexy syndrome after discontinuation of the antidepressant venlafaxine. J. Sleep Res. 14, 207–208. Nitz, D., Siegel, J.M., 1996. GABA release in posterior hypothalamus across sleep– wake cycle. Am. J. Physiol. 271, R1707–R1712. Nitz, D., Siegel, J.M., 1997a. GABA release in the dorsal raphe nucleus: role in the control of REM sleep. Am. J. Physiol. 273, R451–R455. Nitz, D., Siegel, J.M., 1997b. GABA release in the locus coeruleus as a function of sleep/wake state. Neuroscience 78, 795–801. Nofzinger, E.A., Thase, M.E., Reynolds III, C.F., Himmelhoch, J.M., Mallinger, A., Houck, P., Kupfer, D.J., 1991. Hypersomnia in bipolar depression: a comparison with narcolepsy using the multiple sleep latency test. Am. J. Psychiatry 148, 1177–1181. Odagaki, Y., Yamauchi, T., 2004. Gamma-hydroxybutyric acid, unlike gammaaminobutyric acid, does not stimulate Gi/Go proteins in rat brain membranes. Basic Clin. Pharmacol. Toxicol. 94, 89–98. Ohayon, M.M., 2007. Insomnia: a ticking clock for depression? J. Psychiatr. Res. 41, 893–894. Okakura-Mochizuki, K., Mochizuki, T., Yamamoto, Y., Horii, A., Yamatodani, A., 1996. Endogenous GABA modulates histamine release from the anterior hypothalamus of the rat. J. Neurochem. 67, 171–176. Olpe, H.R., Steinmann, M.W., Hall, R.G., Brugger, F., Pozza, M.F., 1988. GABAA and GABAB receptors in locus coeruleus: effects of blockers. Eur. J. Pharmacol. 149, 183–185. Ondo, W., Perkins, A., Swick, T., Hull Jr., K., Jiminez, J., Pardi, D., 2007. Sodium oxybate for excessive sleepiness in Parkinson’s disease. Sleep 30, A287. Ordway, G.A., Schenk, J., Stockmeier, C.A., May, W., Klimek, V., 2003. Elevated agonist binding to alpha2-adrenoceptors in the locus coeruleus in major depression. Biol. Psychiatry 53, 315–323. Osorio, I., Davidoff, R.A., 1979. Gamma-Hydroxybutyric acid is not a GABA-mimetic agent in the spinal cord. Ann. Neurol. 6, 111–116. Oswald, I., 1970. Effects on sleep of amphertamine and its derivatives. In: Costa, E., Garratini, S. (Eds.), Amphetamines and Related Compounds. Raven Press, New York, pp. 865–871. Pardi, D., Black, J., 2006. gamma-Hydroxybutyrate/sodium oxybate: neurobiology, and impact on sleep and wakefulness. CNS Drugs 20, 993–1018. Pariante, C.M., 2006. The glucocorticoid receptor: part of the solution or part of the problem? J. Psychopharmacol. 20, 79–84. Parkes, J.D., Schachter, M., 1979. Clomipramine and clonazepam in cataplexy. Lancet 2, 1085–1086. Parkes, J., 1976. Amphetamines and alertness. In: Guilleminault, C., Dement, W.C., Passouant, P. (Eds.), Narcolepsy. Advances in Sleep Research. Spectrum, New York, pp. 643–658. Parmentier, R., Ohtsu, H., Djebbara-Hannas, Z., Valatx, J.L., Watanabe, T., Lin, J.S., 2002. Anatomical, physiological, and pharmacological characteristics of histidine decarboxylase knock-out mice: evidence for the role of brain histamine in behavioral and sleep–wake control. J. Neurosci. 22, 7695–7711. Peever, J.H., Lai, Y.Y., Siegel, J.M., 2003. Excitatory effects of hypocretin-1 (orexin-A) in the trigeminal motor nucleus are reversed by NMDA antagonism. J. Neurophysiol. 89, 2591–2600. Peterson, M.J., Benca, R.M., 2006. Sleep in mood disorders. Psychiatr. Clin. North Am. 29, 1009–1032. Petit, J.M., Tobler, I., Allaman, I., Borbely, A.A., Magistretti, P.J., 2002. Sleep deprivation modulates brain mRNAs encoding genes of glycogen metabolism. Eur. J. Neurosci. 16, 1163–1167. Peyron, C., Tighe, D.K., van den Pol, A.N., de, L.L., Heller, H.C., Sutcliffe, J.G., Kilduff, T.S., 1998. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J. Neurosci. 18, 9996–10015. Peyron, C., Faraco, J., Rogers, W., Ripley, B., Overeem, S., Charnay, Y., Nevsimalova, S., Aldrich, M., Reynolds, D., Albin, R., Li, R., Hungs, M., Pedrazzoli, M., Padigaru, M., Kucherlapati, M., Fan, J., Maki, R., Lammers, G.J., Bouras, C., Kucherlapati, R., Nishino, S., Mignot, E., 2000. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat. Med. 6, 991–997. Plante, D.T., Winkelman, J.W., 2008. Sleep disturbance in bipolar disorder: therapeutic implications. Am. J. Psychiatry 165, 830–843. Pompeiano, O., 1967. The neurophysiological mechanisms of the postural and motor events during desynchronized sleep. Res. Publ. Assoc. Res. Nerv. Ment. Dis. 45, 351–423.

218

M. Mamelak / Progress in Neurobiology 89 (2009) 193–219

Price, G.W., Kelly, J.S., Bowery, N.G., 1987. The location of GABAB receptor binding sites in mammalian spinal cord. Synapse 1, 530–538. Price, P.A., Schachter, M., Smith, S.J., Baxter, R.C., Parkes, J.D., 1981. gamma-Hydroxybutyrate in narcolepsy. Ann. Neurol. 9, 198. Prinzmetal, M., Bloomberg, W., 1935. The use of benzedrine for treatment of narcolepsy. JAMA 105, 2051–2054. Prosser, H.M., Gill, C.H., Hirst, W.D., Grau, E., Robbins, M., Calver, A., Soffin, E.M., Farmer, C.E., Lanneau, C., Gray, J., Schenck, E., Warmerdam, B.S., Clapham, C., Reavill, C., Rogers, D.C., Stean, T., Upton, N., Humphreys, K., Randall, A., Geppert, M., Davies, C.H., Pangalos, M.N., 2001. Epileptogenesis and enhanced prepulse inhibition in GABA(B1)-deficient mice. Mol. Cell Neurosci. 17, 1059–1070. Queva, C., Bremner-Danielsen, M., Edlund, A., Ekstrand, A.J., Elg, S., Erickson, S., Johansson, T., Lehmann, A., Mattsson, J.P., 2003. Effects of GABA agonists on body temperature regulation in GABA(B(1))-/- mice. Br. J. Pharmacol. 140, 315– 322. Ratomponirina, C., Hode, Y., Hechler, V., Maitre, M., 1995. gamma-Hydroxybutyrate receptor binding in rat brain is inhibited by guanyl nucleotides and pertussis toxin. Neurosci. Lett. 189, 51–53. Redgrave, P., Taha, E.B., White, L., Dean, P., 1982. Increased food intake following the manipulation of intracerebral dopamine levels with gamma-hydroxybutyrate. Psychopharmacology (Berlin) 76, 273–277. Reid, M.S., Tafti, M., Nishino, S., Sampathkumaran, R., Siegel, J.M., Mignot, E., 1996. Local administration of dopaminergic drugs into the ventral tegmental area modulates cataplexy in the narcoleptic canine. Brain Res. 733, 83–100. Ren, X., Mody, I., 2006. gamma-Hydroxybutyrate induces cyclic AMP-responsive element-binding protein phosphorylation in mouse hippocampus: an involvement of GABA(B) receptors and cAMP-dependent protein kinase activation. Neuroscience 141, 269–275. Rinne, J.O., Hublin, C., Partinen, M., Ruottinen, H., Ruotsalainen, U., Nagren, K., Lehikoinen, P., Laihinen, A., 1995. Positron emission tomography study of human narcolepsy: no increase in striatal dopamine D2 receptors. Neurology 45, 1735–1738. Robertson, S.D., Matthies, H.J., Galli, A., 2009. A closer look at amphetamine-induced reverse transport and trafficking of the dopamine and norepinephrine transporters. Mol. Neurobiol. 39, 73–80. Robinson, D.M., Keating, G.M., 2007. Sodium oxybate: a review of its use in the management of narcolepsy. CNS Drugs 21, 337–354. Roehrs, T., Zorick, F., Wittig, R., Paxton, C., Sicklesteel, J., Roth, T., 1986. Alerting effects of naps in patients with narcolepsy. Sleep 9, 194–199. Roselaar, S.E., Langdon, N., Lock, C.B., Jenner, P., Parkes, J.D., 1987. Selegiline in narcolepsy. Sleep 10, 491–495. Roth, R.H., Giarman, N.J., 1969. Conversion in vivo of gamma-aminobutyric to gamma-hydroxybutyric acid in the rat. Biochem. Pharmacol. 18, 247–250. Russel, I., Bennett, R., Michalek, J., Oxybate for FMS Study Group, 2005. Sodium oxybate relieves pain and improves sleep in fibromyalgia syndrome [FMS]: a randomized double blind, placebo-controlles, multicenter clinical trial. In: Proceeding of the American College of Rheumatology Annual Scientific Meeting, San Diego, USA, p. L30. Russel, I., Perkins, A., Michalek, J., The Oxybate SXB-26 Fibromyalgia Syndrome Study Group, 2009. Sodium oxybate relieves pain and improves function in fibromyalgia syndrome: a randomized, double blind, placebo controlled multicenter clinical trial. Arthritis Rheum. 60, 299–309. Sakai, K., Crochet, S., 2000. Serotonergic dorsal raphe neurons cease firing by disfacilitation during paradoxical sleep. Neuroreport 11, 3237–3241. Sakurai, T., 2007. The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat. Rev. Neurosci. 8, 171–181. Sakurai, T., Amemiya, A., Ishii, M., Matsuzaki, I., Chemelli, R.M., Tanaka, H., Williams, S.C., Richardson, J.A., Kozlowski, G.P., Wilson, S., Arch, J.R., Buckingham, R.E., Haynes, A.C., Carr, S.A., Annan, R.S., McNulty, D.E., Liu, W.S., Terrett, J.A., Elshourbagy, N.A., Bergsma, D.J., Yanagisawa, M., 1998. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92, 573–585. Sakurai, T., 2005. Roles of orexin/hypocretin in regulation of sleep/wakefulness and energy homeostasis. Sleep Med. Rev. 9, 231–241. Salomon, R.M., Ripley, B., Kennedy, J.S., Johnson, B., Schmidt, D., Zeitzer, J.M., Nishino, S., Mignot, E., 2003. Diurnal variation of cerebrospinal fluid hypocretin-1 (orexin-A) levels in control and depressed subjects. Biol. Psychiatry 54, 96–104. Sands, S.A., McCarson, K.E., Enna, S.J., 2003. Differential regulation of GABA B receptor subunit expression and function. J. Pharmacol. Exp. Ther. 305, 191–196. Saper, C.B., Chou, T.C., Scammell, T.E., 2001. The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci. 24, 726–731. Saper, C.B., 2006. Staying awake for dinner: hypothalamic integration of sleep, feeding, and circadian rhythms. Prog. Brain Res. 153, 243–252. Scammell, T.E., Estabrooke, I.V., McCarthy, M.T., Chemelli, R.M., Yanagisawa, M., Miller, M.S., Saper, C.B., 2000. Hypothalamic arousal regions are activated during modafinil-induced wakefulness. J. Neurosci. 20, 8620–8628. Scharf, M.B., Brown, D., Woods, M., Brown, L., Hirschowitz, J., 1985. The effects and effectiveness of gamma-hydroxybutyrate in patients with narcolepsy. J. Clin. Psychiatry 46, 222–225. Scharf, M.B., Hauck, M., Stover, R., McDannold, M., Berkowitz, D., 1998. Effect of gamma-hydroxybutyrate on pain, fatigue, and the alpha sleep anomaly in patients with fibromyalgia. Preliminary report. J. Rheumatol. 25, 1986–1990. Scharf, M.B., Baumann, M., Berkowitz, D.V., 2003. The effects of sodium oxybate on clinical symptoms and sleep patterns in patients with fibromyalgia. J. Rheumatol. 30, 1070–1074.

Scharf, M.B., 2006. Sodium oxybate for narcolepsy. Expert. Rev. Neurother. 6, 1139– 1146. Schuler, V., Luscher, C., Blanchet, C., Klix, N., Sansig, G., Klebs, K., Schmutz, M., Heid, J., Gentry, C., Urban, L., Fox, A., Spooren, W., Jaton, A.L., Vigouret, J., Pozza, M., Kelly, P.H., Mosbacher, J., Froestl, W., Kaslin, E., Korn, R., Bischoff, S., Kaupmann, K., Van der, P.H., Bettler, B., 2001. Epilepsy, hyperalgesia, impaired memory, and loss of pre- and postsynaptic GABA(B) responses in mice lacking GABA(B(1)). Neuron 31, 47–58. Scrima, L., Hartman, P.G., Johnson Jr., F.H., Hiller, F.C., 1989. Efficacy of gammahydroxybutyrate versus placebo in treating narcolepsy–cataplexy: doubleblind subjective measures. Biol. Psychiatry 26, 331–343. Scrima, L., Hartman, P.G., Johnson Jr., F.H., Thomas, E.E., Hiller, F.C., 1990. The effects of gamma-hydroxybutyrate on the sleep of narcolepsy patients: a double-blind study. Sleep 13, 479–490. Shaffery, J., Hoffmann, R., Armitage, R., 2003. The neurobiology of depression: perspectives from animal and human sleep studies. Neuroscientist 9, 82–98. Shelton, R.C., 2007. The molecular neurobiology of depression. Psychitr. Clin. North Am. 30, 1–11. Sherin, J.E., Elmquist, J.K., Torrealba, F., Saper, C.B., 1998. Innervation of histaminergic tuberomammillary neurons by GABAergic and galaninergic neurons in the ventrolateral preoptic nucleus of the rat. J. Neurosci. 18, 4705–4721. Shiromani, P.J., Gillin, J.C., Henriksen, S.J., 1987. Acetylcholine and the regulation of REM sleep: basic mechanisms and clinical implications for affective illness and narcolepsy. Annu. Rev. Pharmacol. Toxicol. 27, 137–156. Siegel, J.M., 2000. Brain stem mechanisms generating REM sleep. In: Kryger, M., Roth, T., Dement, W.C. (Eds.), Principles and Practice of Sleep Medicine. Saunders, Philadelphia, pp. 112–133. Siegel, J.M., 2004. Hypocretin (orexin): role in normal behavior and neuropathology. Annu. Rev. Psychol. 55, 125–148. Silber, M., Black, J., Krahn, L., Fredrickson, P., 2007. Autoimmune studies in narcolepsy. In: Bassetti, C., Billiard, M., Mignot, E. (Eds.), Narcolepsy and Hypersomnia. Informa Health Care USA, Inc., pp. 451–458. Silva, A.J., Kogan, J.H., Frankland, P.W., Kida, S., 1998. CREB and memory. Annu. Rev. Neurosci. 21, 127–148. Singh, M., Drake, C.L., Roth, T., 2006. The prevalence of multiple sleep-onset REM periods in a population-based sample. Sleep 29, 890–895. Snead III, O.C., Morley, B.J., 1981. Ontogeny of gamma-hydroxybutyric acid. I. Regional concentration in developing rat, monkey and human brain. Brain Res. 227, 579–589. Snead III, O.C., Liu, C.C., 1984. Gamma-hydroxybutyric acid binding sites in rat and human brain synaptosomal membranes. Biochem. Pharmacol. 33, 2587– 2590. Snead III, O.C., 1991. The gamma-hydroxybutyrate model of absence seizures: correlation of regional brain levels of gamma-hydroxybutyric acid and gamma-butyrolactone with spike wave discharges. Neuropharmacology 30, 161–167. Snead III, O.C., 1992. Evidence for G protein modulation of experimental-generalized absence seizures in rat. Neurosci. Lett. 148, 15–18. Snead III, O.C., 2000. Evidence for a G protein-coupled gamma-hydroxybutyric acid receptor. J. Neurochem. 75, 1986–1996. Snead III, O.C., Gibson, K.M., 2005. Gamma-hydroxybutyric acid. N. Engl. J. Med. 352, 2721–2732. Sohal, V.S., Huguenard, J.R., 2003. Inhibitory connections control burst pattern and emergent network synchrony in reticular thalamus. J. Neurosci. 23, 8978–8988. Staedt, J., Stoppe, G., Kogler, A., Riemann, H., Hajak, G., Rodenbeck, A., Mayer, G., Steinhoff, B.J., Munz, D.L., Emrich, D., Ruther, E., 1996. [123I]IBZM SPET analysis of dopamine D2 receptor occupancy in narcoleptic patients in the course of treatment. Biol. Psychiatry 39, 107–111. Steriade, M., McCormick, D.A., Sejnowski, T.J., 1993. Thalamocortical oscillations in the sleeping and aroused brain. Science 262, 679–685. Steriade, M., Timofeev, I., 2003. Neuronal plasticity in thalamocortical networks during sleep and waking oscillations. Neuron 37, 563–576. Stevens, D.R., Kuramasu, A., Haas, H.L., 1999. GABAB-receptor-mediated control of GABAergic inhibition in rat histaminergic neurons in vitro. Eur. J. Neurosci. 11, 1148–1154. Sullivan, H.S., 1965. Personal Psychopathology. W.W. Norton and Company, New York. Sutcliff, J.G., de Lecea, L., 2002. The hypocretins: setting the arousal threshold. Nat. Rev. Neurosci. 3, 339–349. Szabo, S.T., Gold, M.S., Goldberger, B.A., Blier, P., 2004. Effects of sustained gammahydroxybutyrate treatments on spontaneous and evoked firing activity of locus coeruleus norepinephrine neurons. Biol. Psychiatry 55, 934–939. Szklo-Coxe, M., Young, T., Finn, L., Mignot, E., 2007. Depression: relationships to sleep paralysis and other sleep disturbances in a community sample. J. Sleep Res. 16, 297–312. Szymusiak, R., Alam, N., Steininger, T.L., McGinty, D., 1998. Sleep-waking discharge patterns of ventrolateral preoptic/anterior hypothalamic neurons in rats. Brain Res. 803, 178–188. Taberner, P.V., Rick, J.T., Kerkut, G.A., 1972. The action of gamma-hydroxybutyric acid on cerebral glucose metabolism. J. Neurochem. 19, 245–254. Taberner, P.V., 1973. Effects of gamma-hydroxybutyric acid and other hypnotics on glucose uptake in vivo and in vitro. J. Neurochem. 20, 669–680. Taheri, S., Zeitzer, J.M., Mignot, E., 2002. The role of hypocretins (orexins) in sleep regulation and narcolepsy. Annu. Rev. Neurosci. 25, 283–313. Takakusaki, K., Takahashi, K., Saitoh, K., Harada, H., Okumura, T., Kayama, Y., Koyama, Y., 2005. Orexinergic projections to the cat midbrain mediate

M. Mamelak / Progress in Neurobiology 89 (2009) 193–219 alternation of emotional behavioural states from locomotion to cataplexy. J. Physiol. 568, 1003–1020. Tanaka, T., Minamino, H., Unezaki, S., Tsukatani, H., Tokumura, A., 1993. Formation of platelet-activating factor-like phospholipids by Fe2+/ascorbate/EDTAinduced lipid peroxidation. Biochim. Biophys. Acta 1166, 264–274. Tanganelli, S., Perez de la, M.M., Ferraro, L., Mendez-Franco, J., Beani, L., Rambert, F.A., Fuxe, K., 1995. Modafinil and cortical gamma-aminobutyric acid outflow. Modulation by 5-hydroxytryptamine neurotoxins. Eur. J. Pharmacol. 273, 63–71. Tao, R., Ma, Z., Auerbach, S.B., 1996. Differential regulation of 5-hydroxytryptamine release by GABAA and GABAB receptors in midbrain raphe nuclei and forebrain of rats. Br. J. Pharmacol. 119, 1375–1384. Tarabar, A.F., Nelson, L.S., 2004. The gamma-hydroxybutyrate withdrawal syndrome. Toxicol. Rev. 23, 45–49. Tecce, J.J., Cole, J.O., 1974. Amphetamine effects in man: paradoxical drowsiness and lowered electrical brain activity (CNV). Science 185, 451–453. Tedeschi, L., Carai, M.A., Frison, G., Favretto, D., Colombo, G., Ferrara, S.D., Gessa, G.L., 2003. Endogenous gamma-hydroxybutyric acid is in the rat, mouse and human gastrointestinal tract. Life Sci. 72, 2481–2488. Thakkar, M.M., Ramesh, V., Cape, E.G., Winston, S., Strecker, R.E., McCarley, R.W., 1999. REM sleep enhancement and behavioral cataplexy following orexin (hypocretin)-II receptor antisense perfusion in the pontine reticular formation. Sleep Res. Online 2, 112–120. Thannickal, T.C., Moore, R.Y., Nienhuis, R., Ramanathan, L., Gulyani, S., Aldrich, M., Cornford, M., Siegel, J.M., 2000. Reduced number of hypocretin neurons in human narcolepsy. Neuron 27, 469–474. Thannickal, T.C., Siegel, J.M., Nienhuis, R., Moore, R.Y., 2003. Pattern of hypocretin (orexin) soma and axon loss, and gliosis, in human narcolepsy. Brain Pathol. 13, 340–351. Tokumura, A., Tanaka, T., Yotsumoto, T., Tsukatani, H., 1991. Identification of sn-2omega-hydroxycarboxylate-containing phospholipids in a lipid extract from bovine brain. Biochem. Biophys. Res. Commun. 177, 466–473. Tononi, G., Cirelli, C., 2003. Sleep and synaptic homeostasis: a hypothesis. Brain Res. Bull. 62, 143–150. Torterolo, P., Yamuy, J., Sampogna, S., Morales, F., Chase, M., 2001. Hypothalamic neurons that contain hypocretin (orexin) express C-fos during active wakefulness and carbachol induced active sleep. Sleep Res. Online 4, 25–32. Trivedi, P., Yu, H., MacNeil, D.J., Van der Ploeg, L.H., Guan, X.M., 1998. Distribution of orexin receptor mRNA in the rat brain. FEBS Lett. 438, 71–75. US Xyrem Multicenter Study Group, 2002. A randomized double blind, placebo controlled multicenter trial comparing the effects of three doses of orally administered sodium oxybate with placebo for the treatment of narcolepsy. Sleep 25, 42–49. US Xyrem Multicenter Study Group, 2003. A 12 month, open label, multicenter extension trial of orally administered sodium oxybate for the treatment of narcolepsy. Sleep 26, 31–35. US Xyrem Multicenter Study Group, 2004. Sodium oxybate demonstrates long term efficacy for the treatment of cataplexy in patients with narcolepsy. Sleep Med. 5, 119–123. van den Pol, A.N., Gao, X.B., Obrietan, K., Kilduff, T.S., Belousov, A.B., 1998. Presynaptic and postsynaptic actions and modulation of neuroendocrine neurons by a new hypothalamic peptide, hypocretin/orexin. J. Neurosci. 18, 7962–7971. Vandermaelen, C.P., Aghajanian, G.K., 1983. Electrophysiological and pharmacological characterization of serotonergic dorsal raphe neurons recorded extracellularly and intracellularly in rat brain slices. Brain Res. 289, 109–119. Vayer, P., Ehrhardt, J., Gobaille, S., Mandel, P., Maitre, M., 1988. g-Hydroxybutyrate distribution and turnover rates in discrete brain regions of the rat. Neurochem. Int. 12, 53–59. Vickers, M.D., 1969. Gammahydroxybutyric acid. Int. Anesthesiol. Clin. 7, 75–89. Vignatelli, L., D’Alessandro, R., Mosconi, P., Ferini-Strambi, L., Guidolin, L., De, V.A., Plazzi, G., 2004. Health-related quality of life in Italian patients with narcolepsy: the SF-36 health survey. Sleep Med. 5, 467–475. Waldmeier, P.C., 1991. The GABAB antagonist, CGP 35348, antagonizes the effects of baclofen, gamma-butyrolactone and HA 966 on rat striatal dopamine synthesis. Naunyn Schmiedebergs Arch. Pharmacol. 343, 173–178. Weaver, T.E., Cuellar, N., 2006. A randomized trial evaluating the effectiveness of sodium oxybate therapy on quality of life in narcolepsy. Sleep 29, 1189–1194. Weerts, E.M., Goodwin, A.K., Griffiths, R.R., Brown, P.R., Froestl, W., Jakobs, C., Gibson, K.M., 2005. Spontaneous and precipitated withdrawal after chronic intragastric administration of gamma-hydroxybutyrate (GHB) in baboons. Psychopharmacology (Berlin) 179, 678–687. Wellendorf, P., Hog, S., Greenwood, J., de Lichtenberg, A., Nielsen, B., Frolund, B., Brehm, L., Clausen, R.P., Brauner-Osborne, H., 2005. Novel cyclic (gamma)hydroxybutyrate (GHB) analogues with high affinity and stereoselectivity of binding to GHB sites in rat brain. J. Pharmacol. Exp. Ther. 315, 346–351. Wesenstein, N., Beleenky, G., Kautz, M., Thorne, D., Reichart, R., Balkin, T., 2002. Maintaining alertness and performance during sleep deprivation: modafinil versus caffeine. Psychopharmacology (Berlin) 59, 238–247. White, J.H., McIllhinney, R.A., Wise, A., Ciruela, F., Chan, W.Y., Emson, P.C., Billinton, A., Marshall, F.H., 2000. The GABAB receptor interacts directly with the related transcription factors CREB2 and ATFx. Proc. Natl. Acad. Sci. U.S.A. 97, 13967– 13972.

219

Williams, S., Turner, J., Crunelli, V., 1995. Gammahydroxybutyrate promotes oscillatory activity of rat and cat thalamocortical neurones by a tonic GABAB receptor-mediated hyperpolarization. Neuroscience 66, 131–141. Willie, J.T., Chemelli, R.M., Sinton, C.M., Yanagisawa, M., 2001. To eat or to sleep? Orexin in the regulation of feeding and wakefulness. Annu. Rev. Neurosci. 24, 429–458. Willie, J.T., Renthal, W., Chemelli, R.M., Miller, M.S., Scammell, T.E., Yanagisawa, M., Sinton, C.M., 2005. Modafinil more effectively induces wakefulness in orexinnull mice than in wild-type littermates. Neuroscience 130, 983–995. Wilson, S., Argyropoulos, S., 2005. Antidepressnats and sleep: a qualitative review of the literature. Drugs 65, 927–947. Wise, M.S., Arand, D.L., Auger, R.R., Brooks, S.N., Watson, N.F., 2007. Treatment of narcolepsy and other hypersomnias of central origin. Sleep 30, 1712–1727. Wisor, J.P., Nishino, S., Sora, I., Uhl, G.H., Mignot, E., Edgar, D.M., 2001. Dopaminergic role in stimulant-induced wakefulness. J. Neurosci. 21, 1787–1794. Wisor, J.P., Eriksson, K.S., 2005. Dopaminergic-adrenergic interactions in the wake promoting mechanism of modafinil. Neuroscience 132, 1027–1034. Wolfson, L.I., Sakurada, O., Sokoloff, L., 1977. Effects of gamma-butyrolactone on local cerebral glucose utilization in the rat. J. Neurochem. 29, 777–783. Wong, M.L., Kling, M.A., Munson, P.J., Listwak, S., Licinio, J., Prolo, P., Karp, B., McCutcheon, I.E., Geracioti Jr., T.D., DeBellis, M.D., Rice, K.C., Goldstein, D.S., Veldhuis, J.D., Chrousos, G.P., Oldfield, E.H., McCann, S.M., Gold, P.W., 2000. Pronounced and sustained central hypernoradrenergic function in major depression with melancholic features: relation to hypercortisolism and corticotropin-releasing hormone. Proc. Natl. Acad. Sci. U.S.A. 97, 325–330. Wong, C.G., Chan, K.F., Gibson, K.M., Snead, O.C., 2004. Gamma-hydroxybutyric acid: neurobiology and toxicology of a recreational drug. Toxicol. Rev. 23, 3–20. Wu, H., Zink, N., Carter, L.P., Mehta, A.K., Hernandez, R.J., Ticku, M.K., Lamb, R., France, C.P., Coop, A., 2003. A tertiary alcohol analog of gamma-hydroxybutyric acid as a specific gamma-hydroxybutyric acid receptor ligand. J. Pharmacol. Exp. Ther. 305, 675–679. Wu, M.F., Gulyani, S.A., Yau, E., Mignot, E., Phan, B., Siegel, J.M., 1999. Locus coeruleus neurons: cessation of activity during cataplexy. Neuroscience 91, 1389–1399. Wu, M.F., John, J., Boehmer, L.N., Yau, D., Nguyen, G.B., Siegel, J.M., 2004a. Activity of dorsal raphe cells across the sleep-waking cycle and during cataplexy in narcoleptic dogs. J. Physiol. 554, 202–215. Wu, Y., Ali, S., Ahmadian, G., Liu, C.C., Wang, Y.T., Gibson, K.M., Calver, A.R., Francis, J., Pangalos, M.N., Carter III, S.O., 2004b. Gamma-hydroxybutyric acid (GHB) and gamma-aminobutyric acidB receptor (GABABR) binding sites are distinctive from one another: molecular evidence. Neuropharmacology 47, 1146–1156. Wyatt, R.J., Fram, D.H., Buchbinder, R., Snyder, F., 1971. Treatment of intractable narcolepsy with a monoamine oxidase inhibitor. N. Engl. J. Med. 285, 987–991. Xie, X., Crowder, T.L., Yamanaka, A., Morairty, S.R., Lewinter, R.D., Sakurai, T., Kilduff, T.S., 2006. GABA(B) receptor-mediated modulation of hypocretin/orexin neurones in mouse hypothalamus. J. Physiol. 574, 399–414. Xyrem International Study Group, 2005a. Further evidence supporting the use of sodium oxybate for the treatment of cataplexy: a double blind placebo-controlled study in 228 patients. Sleep Med. 6, 415–421. Xyrem International Study Group, 2005b. A double blind, placebo controlled study demonstrates sodium oxybate is effective for the treatment of excessive daytime sleepiness in narcolepsy. J. Clin. Sleep Med. 1, 391–397. Yamada, Y., Yamamoto, J., Fujiki, A., Hishikawa, Y., Kaneko, Z., 1967. Effect of butyrolactone and gamma-hydroxybutyrate on the EEG and sleep cycle in man. Electroencephalogr. Clin. Neurophysiol. 22, 558–562. Yamanaka, A., Tsujino, N., Funahashi, H., Honda, K., Guan, J.L., Wang, Q.P., Tominaga, M., Goto, K., Shioda, S., Sakurai, T., 2002. Orexins activate histaminergic neurons via the orexin 2 receptor. Biochem. Biophys. Res. Commun. 290, 1237–1245. Yamanaka, A., Beuckmann, C.T., Willie, J.T., Hara, J., Tsujino, N., Mieda, M., Tominaga, M., Yagami, K., Sugiyama, F., Goto, K., Yanagisawa, M., Sakurai, T., 2003. Hypothalamic orexin neurons regulate arousal according to energy balance in mice. Neuron 38, 701–713. Yamuy, J., Fung, S.J., Sampogna, S., Morales, F., Chase, M.H., 2000. Orexin (hypocretin)-A and orexin type-1 receptor immunoreactivity in ventral horn of cat spinal cord. Soc. Neurosci. Abstr. 26, 761–762. Yamuy, J., Fung, S.J., Xi, M., Chase, M.H., 2004. Hypocretinergic control of spinal cord motoneurons. J. Neurosci. 24, 5336–5345. Yoshida, Y., Fujiki, N., Nakajima, T., Ripley, B., Matsumura, H., Yoneda, H., Mignot, E., Nishino, S., 2001. Fluctuation of extracellular hypocretin-1 (orexin A) levels in the rat in relation to the light-dark cycle and sleep–wake activities. Eur. J. Neurosci. 14, 1075–1081. Yoss, R.E., Daly, D., 1959. Treatment of narcolepsy with ritalin. Neurology 9, 171– 173. Zeitzer, J.M., Buckmaster, C.L., Parker, K.J., Hauck, C.M., Lyons, D.M., Mignot, E., 2003. Circadian and homeostatic regulation of hypocretin in a primate model: implications for the consolidation of wakefulness. J. Neurosci. 23, 3555–3560. Zeitzer, J.M., Nishino, S., Mignot, E., 2006. The neurobiology of hypocretins (orexins), narcolepsy and related therapeutic interventions. Trends Pharmacol. Sci. 27, 368–374. Zhang, W.P., Ouyang, M., Thomas, S.A., 2004. Potency of catecholamines and other L-tyrosine derivatives at the cloned mouse adrenergic receptors. Neuropharmacology 47, 438–449.