- Email: [email protected]
Serotonergic receptore and alcohol dependence
s147
X07 Alcohol dependence taken as support for the assumption that PMD should be regarded as a variant of depression. However, several observations suggest that the effect of SRIs in PMD is not equivalent to the antidepressant effect, but probably mediated by other serotonergic synapses in the brain: 1. If PMD is a variant of depression, one would expect all antidepressants to be effective anti-PMD agents. In a controlled trial, we however showed that a selective serotonin reuptake inhibitor, paroxetine, was clearly superior to an antidepressant drug selectively inhibiting noradrenaline reuptake, maprotiline, for the treatment of PMD, and that maprotiline was not better than placebo (Et&son et al, 1995); subsequently, similar results have been obtained in other PMD trials comparing different antidepressants. 2. The doses required of clomipramine for the treatment of PMD are much lower (10-50 mgday) than those usually required for the treatment of depression (150 mg/day) (Eriksson, 1990; Sundblad et al, 1992; Sundblad et al, 1993). 3. The onset of action of SRIs is much shorter when they are used for PMD than when they are used for depression, panic disorder, or obsessive compulsive disorder. We have thus showed that administration of clomipmmine intermittently, during luteal phases only, effectively reduces premenstrual complaints within a few days (or hours) after the onset of drug intake (Sundblad et al, 1993); subsequently, a short onset of action of SRIs in PMD has been shown also for sertraline and fluoxetine. In a recent study we showed that intermittent administration of another selective SRI, citalopram, is in fact not only as effective as continuous treatment, but in fact more effective than continuous treatment (Wikander et al, 1998). Is the effect of SRIs in PMD due to an anti-irritability effect of these drugs? Animal experiments suggest that one of the most important functions of serotonin is to reduce irritability and anger. Aggression is thus among the most striking behavioural effects of depleting serotonin from the brain of rodents; conversely, drags facilitating brain serotonergic neurotransmission (administered systemically or in discrete areas of the brain) have been shown to reduce aggressive behaviour in rata and mice. Of particular interest in this context is our recent observation that short-term administration of a selective SRI, fluoxetine, effectively reduces cycle-related irritability/aggression in female rats studied using the resident-intruder paradigm (Ho et al, to be published). Given the fact that irritability and anger are the cardinal symptoms of PMD, it seems likely that this anti-irritability influence of serotonin is the main reason for the efficacy of the selective SRIs and clomipramine in this condition. Further supporting this assumption, the SRIs have recently been reported to reduce symptoms such as irritability and anger, hostility, and affect lability also in patients with personality disorders, schizophrenia, dementia disorders, autism, mental retardation, brain injury, or stroke (for refs, see Eriksson et al, 1995). Interestingly, several preliminary reports suggest that these effects - like the effect of SRIs in PMD - are observed shortly after the onset of treatment; moreover, similar to PMD, but in contrast to depression, many of these conditions have been reported to respond favourably to the ~-HTIA agonist buspirone. With respect to 1) the fast onset of action of SRIs, 2) the superiority of SRIs over non-serotonergic antidepressants, and 3) the efficacy of buspirone, PMD in fact appear more related to other conditions characterized by irritability or affect lability, than to major depressive disorder.
References
[ 1) [2]
[3]
[4]
[5]
Eriksson E, Lisja P, Sundblad C, Andersson K, Andersch B and Modigh K (1990) Effect of clomipramine in the premenstrual syndrome. Acta Psych Stand, 81, 87-88. Eriksson E, Hedberg A, Andersch B and Sundblad C (1995) The serotonin reuptake inhibitor pamxetine is superior to the noradrenaline reuptake inhibitor maorotiline in the treatment of oremenstrual svndrome: A olacebo-controlled &I. Neuropsychopharmacology 1995, 12, 167-176. 1 Sundblad C, Hedberg MA and Eriksson E (1993) Clomipramine administered during the luteal phase reduces the symptoms of premenstrual syndrome: a placebo-controlled trial. Neuropsychopharmacology, 9, 13345. Sundblad C, Modigh K., Andersch B and Eriksson E (1992) Clomipramine effectively reduces premenstrual irritability and dysphoria: A placebo-controlled trial. Acta Psych Stand, 85, 39-47. Wikander I, Sundblad C, Andersch B, Dagnell I, Zylberstein D, Bcngtsson and Eriksson E (1998) Citalopram in premenstrual dysphoric disorder: Is intermittent treatment more effective than continuous drug administration? J Clin Psychopharm 18, 390-398.
S.07 Alcohol dependence -1
Serotonergic
receptors and alcohol dependence
J. De Vry, S. Maurel, R. Schreiber. CNS Research, Bayer AG, Apmther Weg 18, D-42096 Wuppertal, Germany
Introduction: Clinical studies indicate that selective serotonin reuptake inhibitors (SSRIs) may decrease alcohol intake and craving in particular subgroups of alcoholics. Also in preclinical models of alcohol dependence, such as the 2-bottle alcohol w water choice procedure in alcohol-preferring cAA rats, a genetic model of alcoholism, or an operant oral alcohol self-administration model in normal Wistar rats, SSRIs such as fluoxetine, paroxetine, citalopram or fluvoxamine induce a dose-dependent reduction of alcohol intake. The effects of SSRIs on alcohol intake, however, appear to be relatively nonselective as they coincide with reductions in ingestive behavior (food and water intake), and to be of moderate specificity (reductions in alcohol intake coincide with only weak reductions in alcohol preference). Moreover, fluoxetine and paroxetine were found to generalize to the alcohol cue, suggesting that there are similarities between the stimulus properties of SSRIs and alcohol, and that the alcohol intake-reducing effects of SSRIs may be due to drug substitution. Because SSRIs stimulate indirectly a variety of 5-HT receptor subtypes, it is to be expected that their effects on alcohol intake are due to stimulation of (particular subtypes) of 5-HT receptors. Aim of study and Methods: In an attempt to clarify which 5HT receptor subtype(s) are involved in the effects of SSRIs on alcohol intake, the behavioral profile of relatively selective agonists for various 5-HT receptor subtypes were compared with that of fluoxetine in the cAA rat model of alcoholism and in a model of operant alcohol selfadministration. In addition, it was tested to what extent the 5-HT receptor agonists were able to substitute for the alcohol cue in rats trained to discriminate alcohol (1000 mg/kg, IP) from vehicle. The compounds selected included: the ~-HT~A agonist ipsapirone, the 5-HTin agonist CP9-4,253, the ~-HT~A agonist DOI, and the mixed 5-HTzutn agonist m-CPP Involvement of particular receptors in the behavioral effects of the agonists was in some cases ascertained by antagonism tests with the following antagonists: WAY-100635 (S-HT~A), GR 127935 (5-HTtn), MDL 100,907 (~-HT~A) and SB 206,553 (5-HTzc). Results: Each 5-HT receptor agonist tested reduced alcohol intake in a dose-dependent manner in both models of alcoholism; the degree of specificity and selectivity of the effect being dependent on the compound and the model. In the cAA rat model, both ipsapirone and DOI induced a specific and selective profile; whereas CP-94,253 and m-CPP induced a (fluoxetine-like) relatively nonselective and nonspecific profile. In the operant model, DO1 induced a specific and selective effect, m-CPP induced a specific, but less selective effect; whereas ipsapirone and CP-94,253 induced a relatively nonselective disruption of behavior. In the drug discrimination procedure, both CP-94,253 and m-CPP, but not ipsapirone and DOI, generalized completely to the alcohol cue. Antagonism tests contirmed to a large degree the involvement of the suspected receptors in the effects of the 5-HT receptor agonists. Discussion and Conclusion: Because the behavioral profile of fluoxetine (and other SSRIs), closely mimicks that of the 5-HTtn receptor agonist CP-94,253 and the mixed 5-HTzc/in agonists m-CPP and TFMPP, it is hypothesized that the effects of SSRIs on alcohol intake are mainly due to activation of 5-HTta and/or 5-HTzc receptors. Reductions of alcohol intake induced by stimulation of 5-HTtn and/or 5HTzc receptors may be the result of a nonspecific inhibition of ingestive behavior and/or substitution based on similarities of stimulus properties. Because the ~-HT~Areceptor agonist ipsapirone and the ~-HT~Areceptor agonist DOI were found to induce a more selective and specific effect on alcohol intake, and because these compounds did not generalize to the alcohol cue, it is suggested that stimulation of ~-HT~A or ~-HT~A receptors results in a reduction of alcohol intake which is relatively independent of any effect on ingestive behavior and which is not based on stimulus substitution. As ~-HT~Areceptor activation has been linked to hallucinogenic effects, clinical application of this approach may be compromised. Selective ~-HTIA receptor agonists, on the other hand,
S148
S.07 Alcohol dependence
with their additional anxiolytic and antidepressive properties, may offer a more attractive pharmaceutical approach for the treatment of alcohol dependence, especially in view of the high comorbodity of this disorder with anxiety and affective disorders. References
PI Maurel, S., De Vry, J. and Schreiber, R. (1999a) 5-HTz* and 5-HT&-HTla receptors are differentially involved in alcohol preference and consummatory behavior in cAA rats. Pharmacol. Biochem. Behav., 62, 89-96. PI Maurel, S., De Vry, J. and Scbreiber, R. (1999b) Serotonin receptor ligands differentially affect operant oral self-administration of ethanol in the rat. Eur. J. Pharmacol. in prwa. [31Maorel, S., De Vry, J. and Schreiber, R. (1999~) Comparison of the effects of the selective serotonin reoptake inhibitors fluoxetine, paroxetine, citalopram and fluvoxamine in alcohol-preferring cAA rats. Alcohol in press. and [41Maurel, S., Schreiber, R. and De Vry, J. (1998) Role of 5a-HTz~ 5-HT2c receptors in the generalization of 5-HT receptor agonists to the ethanol cue in the rat. Behav. Pharmacol., 9, 337-343. r51Maurel. S.. Schreibex R. and De Vrv. 1. (19991 Lack of ootentiation of the anti-alcohol effects of fluoxetine by pindolol in alcohol-preferring cAA rats. Prog. Neuro-Psychopharmacol. Biol. Psych&. 22, 1361-1378. ~I
-1
~
I
PET and SPECT studies in alcohol dependence
A. Lingford-Hughes. MRC Cyclotrwn Unit, Hammersmith Hospital, Imperial College School of Medicine, Du Cane Rd., London, W12 OhN, UK Functional imaging techniques such as PET and SPET are increasingly used to explore the neural networks and neuropharmacology of alcohol dependence. Such techniques can be used to assess the activity of a region of the brain by measuring blood flow or metabolism, or distribution and levels of neurotransmitter receptor sites. These can then be related to neuropsychological function, clinical indices, or subjective states such as ‘craving’. This paper will review published and ongoing studies and describe the potential of these techniques. Many PET and SPET studies have shown that alcohol dependence is associated with reduced cerebral activity, particularly in the frontal and parietal lobes. In many of these studies, despite subjects being neurologically healthy, their structural scans revealed atrophic changes. The functional consequences of hypometabolism, particularly in the frontal lobe, have been assessed in a number of studies using different neuropsychological tasks. Correlations have been found between task performance and hypometabolism, but not consistently. Generally, greater cerebral activity is correlated with better performance. It is important to note that current published studies do not involve paradigms where activity is assessed during task performance. Craving is receiving much attention currently and is perceived as critical to addictive behaviour. Craving is problematic to define but is a subjective state reflecting a person’s desire or compulsion to take alcohol. Many studies have been conducted exploring the neural networks of craving in cocaine addiction, however our experience is that inducing craving for alcohol whilst undergoing a PET or SPET scan is by comparison, difficult. There is only one study in alcohol dependence showing that increases in desire and craving were associated with increased perfusion in the right caudate nucleus. Dysfunction in this region has been implicated in obsessive-compulsive disorder. Craving is likely to become an intense field of research since not only is it commonly cited as the cause of relapse from abstinence, but also new pharmacotherapies (acamprosate, nahmxone) reputedly reduce craving in alcoholism. Concerning the neurophannacology of alcohol dependence, PET and SPET studies have concentrated on the GABA-benzodiazepine (GABABDZ) receptor and dopaminergic system. Animal models have provided much evidence that many central effects of alcohol are mediated through the GABA-BDZ receptor and alcohol shares many of the pharmacological actions of benzodiazepines. The GABA-BDZ receptor has been studied in alcohol dependency using l’C-flumazenil and PET or lz31iomazenil and SPET. A number of studies have now shown that alcohol dependence is associated with reductions in the level of GABA-BDZ
receptors, predominantly in the frontal lobe. These lower levels are seen in the absence of detectable atrophy in some studies. In patients with alcoholic cerebellar degeneration (ACD), reductions in the level of GABA-BDZ receptor are seen in the cerebellar vermis. However, interestingly, compared to patients without ACD, the level of GABABDZ receptors in the frontal cortex is the same. These studies support the hypothesis of differing regional sensitivity to alcohol. There is evidence from animal studies that the subunit profile of the GABA-BDZ receptor critically confers sensitivity to alcohol, but it is unknown whether such process occurs in man. Recent results suggest gender differences in the effects of alcohol on the brain. It has been thought that alcohol caused greater morbidity in females than males at lower levels of consumption. A recent study revealed no hypometabolism in female ALD subjects compared to males. However, the female group had consumed less alcohol than the male group. There is preliminary evidence that the cerebellum may be more sensitive in female ALD than males, with reductions in GABA-BDZ receptor levels present only in the female group. The converse is seen in the frontal cortex with little reduction seen in female ALD. Lower levels of GABA-BDZ receptors may be a trait rather state marker in alcohol dependence. Support for the hypothesis that the GABA-benzodiazepine receptor is different in alcohol dependency comes from studies assessing the metabolic response to lorazepam. Subjects with a family history of alcoholism but not themselves alcohol dependent, as opposed to those without such a family history, have a blunted cetebellar metabolic response to loraxepam. We are currently investigating the function of the GABA-BDZ receptor in alcohol dependence by assessing displacement of “C-flumazenil by midaxolam and its effects on EEG and saccadic eye movements. The dopaminergic mesolimbic system is key in mediating reward and hence is hypothesised to be crucially involved in the addictive process. Specifically, release of dopamine in the nucleus accumbens, lying in the ventral striattun, is associated with reward seeking behaviour. Of note current PET and SPET technology, at best, only allows definition of the ventral striatum, and the studies of the post-synaptic dopamine D2 receptor and pre-synaptic dopamine transporter have assessed the whole striatum. A PET study revealed reductions in striatal dopamine D2 receptors, but no ditlbrences in the level of dopamine reuptake sites. Another study used SPET and B-CIT to assess the level of striatal dopamine reuptake sites in violent and non-violent alcohol dependent subjects. Compared to control subjects, violent alcoholics had slightly higher levels of the dopamine reuptake site and non-violent alcoholics had markedly lower levels. This study is significant in relation to the subclassification of alcoholism into type 1 and type 2, and suggests they have different abnormalities in their dopaminergic system. Use of SPET and PET to detine the neural networks and neuropharmacology of alcohol dependence will undoubtedly increase. The application and exploitation of these techniques, for example by assessing the msponsivity of cerebral metabolism or a neurochemical system to a pharmacological, psychological or behavioural challenge are only in their infancy. The results will provide crucial information about the vulnerability to and the consequences of alcohol dependence, thus improving prevention and treatment.
-1
Controversial issues In the assessment of craving and Its role in clinlcal trials
H. de Wit. Department of Psychiatry, The University of Chicago, Chicago, IL, USA Subjective feelings of craving are virtually defining symptoms of drug and alcohol dependence. They are unpleasant and intrusive experiences for the drug user attempting to abstain from drug use, and they are thought to increase the risk of relapse. Yet, our understanding of the concept of “craving” is poor. Craving has been defined differently by many different investigators, and as a result there is no single agreed-upon measure of craving. In studies with laboratory animals, craving is often inferred from overt drug-seeking behavior and drug selfadministration, and thus it is often considered to be synonymous with
X07 Alcohol dependence taken as support for the assumption that PMD should be regarded as a variant of depression. However, several observations suggest that the effect of SRIs in PMD is not equivalent to the antidepressant effect, but probably mediated by other serotonergic synapses in the brain: 1. If PMD is a variant of depression, one would expect all antidepressants to be effective anti-PMD agents. In a controlled trial, we however showed that a selective serotonin reuptake inhibitor, paroxetine, was clearly superior to an antidepressant drug selectively inhibiting noradrenaline reuptake, maprotiline, for the treatment of PMD, and that maprotiline was not better than placebo (Et&son et al, 1995); subsequently, similar results have been obtained in other PMD trials comparing different antidepressants. 2. The doses required of clomipramine for the treatment of PMD are much lower (10-50 mgday) than those usually required for the treatment of depression (150 mg/day) (Eriksson, 1990; Sundblad et al, 1992; Sundblad et al, 1993). 3. The onset of action of SRIs is much shorter when they are used for PMD than when they are used for depression, panic disorder, or obsessive compulsive disorder. We have thus showed that administration of clomipmmine intermittently, during luteal phases only, effectively reduces premenstrual complaints within a few days (or hours) after the onset of drug intake (Sundblad et al, 1993); subsequently, a short onset of action of SRIs in PMD has been shown also for sertraline and fluoxetine. In a recent study we showed that intermittent administration of another selective SRI, citalopram, is in fact not only as effective as continuous treatment, but in fact more effective than continuous treatment (Wikander et al, 1998). Is the effect of SRIs in PMD due to an anti-irritability effect of these drugs? Animal experiments suggest that one of the most important functions of serotonin is to reduce irritability and anger. Aggression is thus among the most striking behavioural effects of depleting serotonin from the brain of rodents; conversely, drags facilitating brain serotonergic neurotransmission (administered systemically or in discrete areas of the brain) have been shown to reduce aggressive behaviour in rata and mice. Of particular interest in this context is our recent observation that short-term administration of a selective SRI, fluoxetine, effectively reduces cycle-related irritability/aggression in female rats studied using the resident-intruder paradigm (Ho et al, to be published). Given the fact that irritability and anger are the cardinal symptoms of PMD, it seems likely that this anti-irritability influence of serotonin is the main reason for the efficacy of the selective SRIs and clomipramine in this condition. Further supporting this assumption, the SRIs have recently been reported to reduce symptoms such as irritability and anger, hostility, and affect lability also in patients with personality disorders, schizophrenia, dementia disorders, autism, mental retardation, brain injury, or stroke (for refs, see Eriksson et al, 1995). Interestingly, several preliminary reports suggest that these effects - like the effect of SRIs in PMD - are observed shortly after the onset of treatment; moreover, similar to PMD, but in contrast to depression, many of these conditions have been reported to respond favourably to the ~-HTIA agonist buspirone. With respect to 1) the fast onset of action of SRIs, 2) the superiority of SRIs over non-serotonergic antidepressants, and 3) the efficacy of buspirone, PMD in fact appear more related to other conditions characterized by irritability or affect lability, than to major depressive disorder.
References
[ 1) [2]
[3]
[4]
[5]
Eriksson E, Lisja P, Sundblad C, Andersson K, Andersch B and Modigh K (1990) Effect of clomipramine in the premenstrual syndrome. Acta Psych Stand, 81, 87-88. Eriksson E, Hedberg A, Andersch B and Sundblad C (1995) The serotonin reuptake inhibitor pamxetine is superior to the noradrenaline reuptake inhibitor maorotiline in the treatment of oremenstrual svndrome: A olacebo-controlled &I. Neuropsychopharmacology 1995, 12, 167-176. 1 Sundblad C, Hedberg MA and Eriksson E (1993) Clomipramine administered during the luteal phase reduces the symptoms of premenstrual syndrome: a placebo-controlled trial. Neuropsychopharmacology, 9, 13345. Sundblad C, Modigh K., Andersch B and Eriksson E (1992) Clomipramine effectively reduces premenstrual irritability and dysphoria: A placebo-controlled trial. Acta Psych Stand, 85, 39-47. Wikander I, Sundblad C, Andersch B, Dagnell I, Zylberstein D, Bcngtsson and Eriksson E (1998) Citalopram in premenstrual dysphoric disorder: Is intermittent treatment more effective than continuous drug administration? J Clin Psychopharm 18, 390-398.
S.07 Alcohol dependence -1
Serotonergic
receptors and alcohol dependence
J. De Vry, S. Maurel, R. Schreiber. CNS Research, Bayer AG, Apmther Weg 18, D-42096 Wuppertal, Germany
Introduction: Clinical studies indicate that selective serotonin reuptake inhibitors (SSRIs) may decrease alcohol intake and craving in particular subgroups of alcoholics. Also in preclinical models of alcohol dependence, such as the 2-bottle alcohol w water choice procedure in alcohol-preferring cAA rats, a genetic model of alcoholism, or an operant oral alcohol self-administration model in normal Wistar rats, SSRIs such as fluoxetine, paroxetine, citalopram or fluvoxamine induce a dose-dependent reduction of alcohol intake. The effects of SSRIs on alcohol intake, however, appear to be relatively nonselective as they coincide with reductions in ingestive behavior (food and water intake), and to be of moderate specificity (reductions in alcohol intake coincide with only weak reductions in alcohol preference). Moreover, fluoxetine and paroxetine were found to generalize to the alcohol cue, suggesting that there are similarities between the stimulus properties of SSRIs and alcohol, and that the alcohol intake-reducing effects of SSRIs may be due to drug substitution. Because SSRIs stimulate indirectly a variety of 5-HT receptor subtypes, it is to be expected that their effects on alcohol intake are due to stimulation of (particular subtypes) of 5-HT receptors. Aim of study and Methods: In an attempt to clarify which 5HT receptor subtype(s) are involved in the effects of SSRIs on alcohol intake, the behavioral profile of relatively selective agonists for various 5-HT receptor subtypes were compared with that of fluoxetine in the cAA rat model of alcoholism and in a model of operant alcohol selfadministration. In addition, it was tested to what extent the 5-HT receptor agonists were able to substitute for the alcohol cue in rats trained to discriminate alcohol (1000 mg/kg, IP) from vehicle. The compounds selected included: the ~-HT~A agonist ipsapirone, the 5-HTin agonist CP9-4,253, the ~-HT~A agonist DOI, and the mixed 5-HTzutn agonist m-CPP Involvement of particular receptors in the behavioral effects of the agonists was in some cases ascertained by antagonism tests with the following antagonists: WAY-100635 (S-HT~A), GR 127935 (5-HTtn), MDL 100,907 (~-HT~A) and SB 206,553 (5-HTzc). Results: Each 5-HT receptor agonist tested reduced alcohol intake in a dose-dependent manner in both models of alcoholism; the degree of specificity and selectivity of the effect being dependent on the compound and the model. In the cAA rat model, both ipsapirone and DOI induced a specific and selective profile; whereas CP-94,253 and m-CPP induced a (fluoxetine-like) relatively nonselective and nonspecific profile. In the operant model, DO1 induced a specific and selective effect, m-CPP induced a specific, but less selective effect; whereas ipsapirone and CP-94,253 induced a relatively nonselective disruption of behavior. In the drug discrimination procedure, both CP-94,253 and m-CPP, but not ipsapirone and DOI, generalized completely to the alcohol cue. Antagonism tests contirmed to a large degree the involvement of the suspected receptors in the effects of the 5-HT receptor agonists. Discussion and Conclusion: Because the behavioral profile of fluoxetine (and other SSRIs), closely mimicks that of the 5-HTtn receptor agonist CP-94,253 and the mixed 5-HTzc/in agonists m-CPP and TFMPP, it is hypothesized that the effects of SSRIs on alcohol intake are mainly due to activation of 5-HTta and/or 5-HTzc receptors. Reductions of alcohol intake induced by stimulation of 5-HTtn and/or 5HTzc receptors may be the result of a nonspecific inhibition of ingestive behavior and/or substitution based on similarities of stimulus properties. Because the ~-HT~Areceptor agonist ipsapirone and the ~-HT~Areceptor agonist DOI were found to induce a more selective and specific effect on alcohol intake, and because these compounds did not generalize to the alcohol cue, it is suggested that stimulation of ~-HT~A or ~-HT~A receptors results in a reduction of alcohol intake which is relatively independent of any effect on ingestive behavior and which is not based on stimulus substitution. As ~-HT~Areceptor activation has been linked to hallucinogenic effects, clinical application of this approach may be compromised. Selective ~-HTIA receptor agonists, on the other hand,
S148
S.07 Alcohol dependence
with their additional anxiolytic and antidepressive properties, may offer a more attractive pharmaceutical approach for the treatment of alcohol dependence, especially in view of the high comorbodity of this disorder with anxiety and affective disorders. References
PI Maurel, S., De Vry, J. and Schreiber, R. (1999a) 5-HTz* and 5-HT&-HTla receptors are differentially involved in alcohol preference and consummatory behavior in cAA rats. Pharmacol. Biochem. Behav., 62, 89-96. PI Maurel, S., De Vry, J. and Scbreiber, R. (1999b) Serotonin receptor ligands differentially affect operant oral self-administration of ethanol in the rat. Eur. J. Pharmacol. in prwa. [31Maorel, S., De Vry, J. and Schreiber, R. (1999~) Comparison of the effects of the selective serotonin reoptake inhibitors fluoxetine, paroxetine, citalopram and fluvoxamine in alcohol-preferring cAA rats. Alcohol in press. and [41Maurel, S., Schreiber, R. and De Vry, J. (1998) Role of 5a-HTz~ 5-HT2c receptors in the generalization of 5-HT receptor agonists to the ethanol cue in the rat. Behav. Pharmacol., 9, 337-343. r51Maurel. S.. Schreibex R. and De Vrv. 1. (19991 Lack of ootentiation of the anti-alcohol effects of fluoxetine by pindolol in alcohol-preferring cAA rats. Prog. Neuro-Psychopharmacol. Biol. Psych&. 22, 1361-1378. ~I
-1
~
I
PET and SPECT studies in alcohol dependence
A. Lingford-Hughes. MRC Cyclotrwn Unit, Hammersmith Hospital, Imperial College School of Medicine, Du Cane Rd., London, W12 OhN, UK Functional imaging techniques such as PET and SPET are increasingly used to explore the neural networks and neuropharmacology of alcohol dependence. Such techniques can be used to assess the activity of a region of the brain by measuring blood flow or metabolism, or distribution and levels of neurotransmitter receptor sites. These can then be related to neuropsychological function, clinical indices, or subjective states such as ‘craving’. This paper will review published and ongoing studies and describe the potential of these techniques. Many PET and SPET studies have shown that alcohol dependence is associated with reduced cerebral activity, particularly in the frontal and parietal lobes. In many of these studies, despite subjects being neurologically healthy, their structural scans revealed atrophic changes. The functional consequences of hypometabolism, particularly in the frontal lobe, have been assessed in a number of studies using different neuropsychological tasks. Correlations have been found between task performance and hypometabolism, but not consistently. Generally, greater cerebral activity is correlated with better performance. It is important to note that current published studies do not involve paradigms where activity is assessed during task performance. Craving is receiving much attention currently and is perceived as critical to addictive behaviour. Craving is problematic to define but is a subjective state reflecting a person’s desire or compulsion to take alcohol. Many studies have been conducted exploring the neural networks of craving in cocaine addiction, however our experience is that inducing craving for alcohol whilst undergoing a PET or SPET scan is by comparison, difficult. There is only one study in alcohol dependence showing that increases in desire and craving were associated with increased perfusion in the right caudate nucleus. Dysfunction in this region has been implicated in obsessive-compulsive disorder. Craving is likely to become an intense field of research since not only is it commonly cited as the cause of relapse from abstinence, but also new pharmacotherapies (acamprosate, nahmxone) reputedly reduce craving in alcoholism. Concerning the neurophannacology of alcohol dependence, PET and SPET studies have concentrated on the GABA-benzodiazepine (GABABDZ) receptor and dopaminergic system. Animal models have provided much evidence that many central effects of alcohol are mediated through the GABA-BDZ receptor and alcohol shares many of the pharmacological actions of benzodiazepines. The GABA-BDZ receptor has been studied in alcohol dependency using l’C-flumazenil and PET or lz31iomazenil and SPET. A number of studies have now shown that alcohol dependence is associated with reductions in the level of GABA-BDZ
receptors, predominantly in the frontal lobe. These lower levels are seen in the absence of detectable atrophy in some studies. In patients with alcoholic cerebellar degeneration (ACD), reductions in the level of GABA-BDZ receptor are seen in the cerebellar vermis. However, interestingly, compared to patients without ACD, the level of GABABDZ receptors in the frontal cortex is the same. These studies support the hypothesis of differing regional sensitivity to alcohol. There is evidence from animal studies that the subunit profile of the GABA-BDZ receptor critically confers sensitivity to alcohol, but it is unknown whether such process occurs in man. Recent results suggest gender differences in the effects of alcohol on the brain. It has been thought that alcohol caused greater morbidity in females than males at lower levels of consumption. A recent study revealed no hypometabolism in female ALD subjects compared to males. However, the female group had consumed less alcohol than the male group. There is preliminary evidence that the cerebellum may be more sensitive in female ALD than males, with reductions in GABA-BDZ receptor levels present only in the female group. The converse is seen in the frontal cortex with little reduction seen in female ALD. Lower levels of GABA-BDZ receptors may be a trait rather state marker in alcohol dependence. Support for the hypothesis that the GABA-benzodiazepine receptor is different in alcohol dependency comes from studies assessing the metabolic response to lorazepam. Subjects with a family history of alcoholism but not themselves alcohol dependent, as opposed to those without such a family history, have a blunted cetebellar metabolic response to loraxepam. We are currently investigating the function of the GABA-BDZ receptor in alcohol dependence by assessing displacement of “C-flumazenil by midaxolam and its effects on EEG and saccadic eye movements. The dopaminergic mesolimbic system is key in mediating reward and hence is hypothesised to be crucially involved in the addictive process. Specifically, release of dopamine in the nucleus accumbens, lying in the ventral striattun, is associated with reward seeking behaviour. Of note current PET and SPET technology, at best, only allows definition of the ventral striatum, and the studies of the post-synaptic dopamine D2 receptor and pre-synaptic dopamine transporter have assessed the whole striatum. A PET study revealed reductions in striatal dopamine D2 receptors, but no ditlbrences in the level of dopamine reuptake sites. Another study used SPET and B-CIT to assess the level of striatal dopamine reuptake sites in violent and non-violent alcohol dependent subjects. Compared to control subjects, violent alcoholics had slightly higher levels of the dopamine reuptake site and non-violent alcoholics had markedly lower levels. This study is significant in relation to the subclassification of alcoholism into type 1 and type 2, and suggests they have different abnormalities in their dopaminergic system. Use of SPET and PET to detine the neural networks and neuropharmacology of alcohol dependence will undoubtedly increase. The application and exploitation of these techniques, for example by assessing the msponsivity of cerebral metabolism or a neurochemical system to a pharmacological, psychological or behavioural challenge are only in their infancy. The results will provide crucial information about the vulnerability to and the consequences of alcohol dependence, thus improving prevention and treatment.
-1
Controversial issues In the assessment of craving and Its role in clinlcal trials
H. de Wit. Department of Psychiatry, The University of Chicago, Chicago, IL, USA Subjective feelings of craving are virtually defining symptoms of drug and alcohol dependence. They are unpleasant and intrusive experiences for the drug user attempting to abstain from drug use, and they are thought to increase the risk of relapse. Yet, our understanding of the concept of “craving” is poor. Craving has been defined differently by many different investigators, and as a result there is no single agreed-upon measure of craving. In studies with laboratory animals, craving is often inferred from overt drug-seeking behavior and drug selfadministration, and thus it is often considered to be synonymous with