Epilepsy and migraine: The dopamine hypotheses

Medical Hypotheses (2006) 66, 466–472

http://intl.elsevierhealth.com/journals/mehy

Epilepsy and migraine: The dopamine hypotheses Shih-Cheng Chen

*

Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, No. 325, Section 2, Cheng-Kung Road, Neihu 114, Taipei, Taiwan, ROC Received 22 September 2005; accepted 27 September 2005

Summary Migraine and epilepsy are both chronic recurrent disorders with paroxysmal attacks. They also share some similar risk factors, symptoms, and preventive medications. Dopamine has long been postulated to be involved in the pathophysiology of migraine and epileptogenesis, by many supporting evidences. However, the role of dopamine is still controversial till now. A lack of a comprehensive hypothetical model may be one of the reasons. ‘‘Dopamine hypothesis’’ is not a new term, but it is proposed to explain the pathophysiology and the associated phenomena of these disorders. The hypotheses suggest that, in migraine, there is a low dopamine tone, while there is a high state of dopamine in generalized epilepsy. But the periodic attacks of headaches and seizures maybe both due to a fall in dopamine activity. Dopamine therefore plays a key role in the linkage of neuroendocrine, autonomic system and neuronal activity. Dopamine agonist is also implied in prophylaxis and neuroprotection in both disorders. c 2005 Elsevier Ltd. All rights reserved.



Introduction Migraine and epilepsy are categorized as paroxysmal disorders. They are both chronic recurrent disorders with episodic attacks. Besides the two disorders have several similarities and associations, which are listed as follows [1]: 1. They are both heterogeneous disorders with periodic nature in common. 2. The attacks of headaches and seizures tend to go through typical courses, which may include prodromal phase, aura, and postdrome. 3. There are several similar risk factors, such as stress, alcohol consumption, menstruation cycle in women, sleep deprivation or pattern changes, * Tel.: +886 2 8792 3311x16868; fax: +886 2 8792 7174. E-mail address: [email protected].



and less well-documented climatic changes. Neuroendocrine system is likely to be involved in some of the risk factors. 4. They share some preventive medications, such as valproate and topiramate, and thereby they are considered as periodic dysregulation of neuronal excitability [2]. 5. The disorders tend to progress with increasing frequency and severity of attacks. 6. The linkage of these disorders further lies on the comorbidity [3] and associated symptoms, such as post-ictal migrainous headache [4,5] and seizures following a migraine aura [6]. A case report of De Carolis showed that apomorphine, a nonselective dopamine (DA) agonist, induced both migrainous manifestations and suppression of photoparoxysmal epileptic responses [7]. Donnet et al. [8] then proposed an

0306-9877/$ - see front matter c 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2005.09.045

Epilepsy and migraine: The dopamine hypotheses intriguing hypothesis that both migraine and epilepsy could be due to a defect in dopaminergic system. Indeed, this idea could be true. The dopamine hypothesis is not a new term. It has been introduced by Grace in 1991 to explain the pathogenesis of schizophrenia [9]. Evidences and postulated hypotheses that support a major role of dopamine in the pathogenesis of migraine and epilepsy are presented.

Anatomy and physiology of dopamine neurons [10,11] The cell bodies of DA neurons are mainly located in A8 (retrorubral nucleus, RRN), A9 (substantia nigra, SN), and A10 (ventral tegmental area, VTA) areas. Besides there are also abundant dopamine neurons and receptors found in the periaqueductal gray (PAG) region [12]. There are five main DA receptor subtypes, including D1–D5 isoforms. The D1 and D2 subtypes are widely distributed in the cortical regions and also subcortical nuclei. Besides, D1 receptors are found in the thalamus and the suprachiasmatic nuclei and also in arterial walls. D2 receptors are found in the PAG, the hypothalamus, and the raphe nucleus. D2, D3, and D4 receptors are found in the area postrema, the solitary nucleus, and the dorsal motor vagal nucleus. D2 receptors are also present in the presynaptic sympathetic perivascular endings that modulate norepinephrine (NE) release. There are four major dopamine pathways found in the brain including [10]: 1. The nigrostriatal pathway from the substantia nigra to the striatum is part of the extrapyramidal pathway, which contains the largest projections. 2. The mesocortical pathway from VTA can be further divided into mesoprefrontal and mesocingulate projections. These pathways are involved in cognitive functions. 3. The mesolimbic pathway connects the midbrain tegmental area to the ventral striatum and limbic cortex. 4. The tuberoinfundibular pathway from the arcuate neucleus of hypothalamus to the anterior pituitary gland controls prolactin secretion. The release of DA is influenced by complex mechanisms that involve glutamate (Glu), c-aminobutyric acid (GABA) in midbrain region. Glutamate can tonicly excite the DA neurons in VTA through NMDA and AMPA receptors. The autoreceptors of dopamine neurons are mainly composed of D2 sub-

467 type. Different sensitivity to DA agonist is found between pre- and postsynaptic DA receptors, with higher sensitivity in presynaptic receptors [11].

Migraine Migraine is a chronic headache with periodic attack. Although there is the so-called paroxysm, the attack of migraine is not chaotic, and moreover, it is often predictable. A typical migraine episode follows an incremental–decremental course. The prodromal and postdromal phases of migraine each last for 12–24 h, and such duration is compatible with a period for up- and down-regulation of receptors. The role of dopamine in the pathogenesis of migraine has been proposed for a long time [13]. The evidences that indicate the DA involvement are summarized as follows [13–15]: 1. The DA receptor hypersensitivity in migrainers. 2. DA antagonists are effective in reducing migraine headache and its associated (dopaminergic) symptoms. 3. The efficacy of DA agonist, especially with continuous use, in prophylactic migraine treatment. 4. The ability of DA receptors to regulate nociception, vasoregulation and autonomic responses. 5. The genetic data on the correlation between DRD2, DRD4 genes and migraine. Besides, one study found an improvement or remission of migraine in some patients after onset of Parkinson’s disease (PD), and that PD might somehow shorten the clinical course of migraine [16]. However, there is no yet convincing evidence to prove a direct or unequivocal role of dopamine in the pathogenesis of migraine, according to the review by Mascia et al. [13]. The reason for the controversial conclusion may be due to a more complex interaction between different neurotransmitters (e.g., serotonin, dopamine and norepinephrine) or a lack of a comprehensive model of migraine that includes the role of dopamine. Brain stem dysfunction was proved in the pathogenesis of migraine through results of a positive emission tomography (PET) study [17]. In several case reports, brain stem lesions could give rise to a newly onset migraine disorder, even migraine with aura. The lesions in those cases were mainly located in PAG and dorsal raphe nucleus (DRN) regions [18–22]. There are more evidences about the role of serotonin (5HT) in migraine pathogenesis in brain stem, and one may suggest that the hypoactivity of

468 dopamine in migrainers is due to a low central 5HT turnover, because serotonin can facilitate dopamine release in brain stem and in forebrain [23–25]. However, there is also growing evidence that dopamine, in turn, can excite the 5HT neurons in DRN, especially through D2 and 5-HT1A receptors [26,27]. Recent data indicated that dopaminergic fibers innervate neocortical sites that were previously thought to be devoid of dopamine input such as the visual and association cortices [11]. A recent in vivo study showed that serotonergic fibers could increase extracellular dopamine in noradrenalinerich isocortical (i.e., occipital and parietal corteces) area, depending on 5-HT1A receptors rather than noradrenergic innervation [28]. Although there are much fewer DA receptors in occipital cortex than in frontal lobe, dopamine, in combination with 5HT, may still have considerable actions on modulation of neuronal activity. Interestingly, one study revealed a correlation between migraine and REM sleep, a period that 5HT activity is turned to a lowest level [29]. REM sleep is associated with generation of ponto-geniculo-occipital spikes (PGOs) through activation of thalamic nuclei, which are disinhibited by raphe nuclei. The PGOs were suggested to induce cortical spreading depression (CSD) by the author [29]. This phenomenon gives another possibility that the serotonergic projection modulate the cortical excitability, especially in occipital lobe. CSD has been considered a key role in migraine pathogenesis [30,31]. Pietrobon [30] reviewed the genetics and neurobiology of familial hemiplegic migraine 1 and 2, in which calcium channelopathy and mutations in a subunit of Na, K-ATPase, respectively, could lead to susceptibility to CSD, a trigger of migraine attack. Activation of some monoaminergic receptors modulate neuronal excitability through working on G protein-coupled ion channels, and those receptors with inhibitory function open the G protein-activated inwardly rectifying K+ (GIRK) channels to make membrane hyperpolarization, such as D2, 5HT1, and a2 adrenergic receptors [32,33]. There is yet little evidence that opening GIRK channels (e.g., activation of 5-HT1A receptor) can cease or attenuate CSD [34]. But since CSD is thought to be ignited by abnormal firing in regional neurons, keeping membrane hyperpolarization can theoretically decrease the susceptibility to CSD.

The dopamine hypothesis of migraine My hypothesis of migraine pathogenesis is divided into two comparable models, an anatomical model

Chen PRC/IC

CSD

Thalamus Visual cortex HT PAG

DRN TGV

AP

Figure 1 Proposed pathophysiological mechanism of migraine generation with anatomical correlation. Hypothalamic dysfunction is also implied in this mechanism. Blue arrow: serotonergic projection; green arrow: dopaminergic projection; orange arrow: excitatory transmission using glutamate. AP, area postrema; CSD, cortical spreading depression; DRN, dorsal raphe nucleus; HT, hypothalamus; IC, insular cortex; PAG, periaqueductal gray; PRC, peri-rolandic cortex; TGV, trigeminovascular system. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Serotonin (5HT1A?) CSD

?

Glu

Dopamine (D2)

DA receptor hypersensitivity DA agent

DA

Dopaminergic symptoms/ Headache

D2 antagonist

-? 5-HT1B

Figure 2 Schematic view of a neurochemical model in migraine generation. Fluctuation of dopamine activity is proposed to play an important role. CSD, cortical spreading depression; DA, dopamine; Glu, glutamate.

(Fig. 1), and a dynamic neurochemical model (Fig. 2). In the anatomical model, the serotonergic projection arising from DRN may have an inhibitory modulation on occipital cortical neurons (possibly through 5-HT1A activation). The serotonergic innervation can act both directly and indirectly through the thalamic nuclei. The main hypothesis is that activation of D2 and 5-HT1A receptors could reduce neuronal excitability by opening GIRK channels, and therefore delay or attenuate the occurrence of CSD. DRN is supported by certain innervation from PAG, which is supposed to be composed of DA neurons. The hypothalamus is also implied in this model, from where the efferent fibers also innervate PAG.

Epilepsy and migraine: The dopamine hypotheses Possibly hypofunction of hypothalamus, PAG and DRN by turns can result in susceptibility to CSD. The CSD, or abnormal excitation of regional cortical neurons in migraine without aura, activate glutamatergic corticofugal projections, which terminate in midbrain and pontine nuclei. The headache and associated symptoms, such as nausea, vomiting, vasodilatation, and even allodynia, are produced due to abnormal activation of brain stem trigeminovascular system, area postrema, and nucleus of solitary tract (NTS), etc., which is supposed to be a downstream process. In the neurochemical model, interictal hypoactivation of dopaminergic neurons is proposed in previous reports, with resultant dopamine receptor hypersensitivity [14]. There may be reciprocal activation between 5HT1A receptors and dopamine D2 receptors (DRD2). During interictal period, the central hypofunction can be compensated by receptor up-regulation, but in case the DA activity falls lower, CSD and further receptor up-regulation ensue, which may take time of 12–24 h to occur – the prodrome. The glutamateric projection, in turn, increase DA release in the hypothalamus, midbrain and other brain stem nuclei, and therefore cause dopaminergic symptoms, including dural vasodilatation through D1 or D2 receptors. Regaining of DA and 5HT again stabilize the cortical excitability. The down-regulation of DA receptors may be the way to terminate a migraine attack, which also takes time of 12–24 h. DA antagonist blocks the excessive receptors in headache phase, and 5-HT1B agonist (e.g., triptans) may also have interaction with dopamine release. DA neurons in arcuate neucleus of hypothalamus are sensitive to the influence of estrogen [35,36]. So that estrogen withdrawal around menstruation period should be able to cause a fall in dopamine tone or to alter receptor sensitivity, thus triggering a menstrual migraine. This hypothesis of migraine suggests dopamine dysfunction and fluctuation in migrainers, and it can better explain the typical courses of migraine and the neuroendocrine involvement, in addition to the dopaminergic symptoms of migraine. But the dysfunction is restricted to certain axes in the dopaminergic system, particularly those involved in neuroendocrine, autonomic function and nociception (possibly hypothalamus-PAG connection). Therefore, this hypothesis also implies an abnormality of hypothalamus in migrainers. Besides the action of DA depends on the interaction with other neurotransmitters, such as 5HT and NE, in the brainstem and hypothalamus. The complex interaction needs to be disclosed by further detailed investigations.

469

Epilepsy The pathogenesis of seizure is supposed to be hypersynchronized neuronal discharges, in which impaired inhibitory mechanism is considered a key role. Recurrence of seizures may cause excitatotoxicity to neurons, and thereby lead to the well-known mesial temporal sclerosis in epileptic patients. Starr [9] postulated a dopamine mechanism of epileptogenesis in his thorough review in 1996. Glutamate–dopamine interaction was described in his neurochemical model that there is an increasing tonic excitation of DA neurons by Glu in an epileptic brain due to paroxysmal activity of the cortex. And the phasic release of DA then increases, leading to down-regulation of DA receptors and decreased phasic response. An important fact from Starr’s review is that DA can exert a profound inhibitory effect on epileptogenesis in the hippocampus, and this action is mediated by D2 receptors. D1 and D2 receptors have different actions on epileptogenesis, and D1 receptor agonist may be even proconvulsant. In the cortical level, experimental studies also showed the modulation of Glu receptor-mediated potentials by dopamine. D1 receptors may promote the activation of glutamate, and D2 receptors have direct or indirect inhibitory effect, which depends on the Glu receptor subtypes involved [37,38]. According to Hablitz [39], neuromodulators can significantly regulate excitability in neuronal circuits. Alterations in extrinsic neuromodulatory inputs from brain stem to a hyperexcitable circuit could be an important factor in controlling seizure initiation or frequency or both [39]. As mentioned earlier, D2 receptors located in the presynaptic sympathetic endings in central and peripheral sites can modulate norepinephrine release. This effect can be observed in neuroleptic malignant syndrome (NMS), in which dopamine withdrawal causes a sympathetic overactivity and extrapyramidal tract signs. Generalized seizure is frequently accompanied by sympathetic hyperactivity. The relationship between DA and NE is also implied in epileptogenesis.

Dopamine hypothesis in epilepsy This hypothesis is based on Starr’s model. As shown in Fig. 3, there is a balance between glutamatergic and dopaminergic transmissions in areas around hippocampus, while extensive corticofugal glutamatergic fibers also terminate in parahippocam-

470

Chen Corticofugal Glu 2 1

PFC

Hippocampus 3

HT

4

VS 4

VTA (A10) DA neurons

Figure 3 Posposed mechanism in epileptogenesis with anatomical correlation, based on Starr’s model. There is a balance between dopaminergic (DA, green arrow) and glutamateric (Glu, orange arrow) transmissions, both innervating the hippocampus. 1,2. Glutamateric corticofugal transmissions; 3. Mesolimbic projection (the phasic release of dopamine); 4. Mesocortical and mesolimbic projections. HT, hypothalamus; PFC, prefrontal cortex; VS, ventral striatum, including nucleus accumbens; VTA, ventral tegmental area. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

pus, possibly for the purpose of memory. The parahippocampus may serve as a ‘‘gatekeeper’’ for cortical discharges. The epileptic brain of generalized epilepsy or complex partial seizure might keep a high state of DA and Glu during the interictal period, and the trigger of seizure maybe either kindling effect (glutamate) or a decrease in DA activation. Depolarization block can be found in midbrain area when DA neurons are overdriven to a state of inactivity [11]. Therefore, the kindling effect may also cause secondary dopamine dysfuntion, and the balance further leans toward the excitatory side. Hyperactivity of excitatory neurotransmission may account for the diathesis of epilepsy, which can result from remote insults like encephalitis or perinatal hypoxia. But the paroxysm of epilepsy may be caused by the intermittent decrease of DA release or dopaminergic failure instead. This is the threshold phenomenon, while we know that antipsychotics can more or less lower the seizure threshold. This model can also explain the post-ictal phenomenon.

The post-ictal phenomenon The post-ictal phenomenon includes cognitive defect (post-ictal confusion and amnesia), post-ictal headache, vomiting and psychosis. Hyperprolactinemia is also a common laboratory finding shortly after a generalized seizure or a complex partial seizure. The importance of dopamine for prefrontal cortical cognitive functions is widely recognized [37]. And mesocortical dopaminergic blockade may lead

to a state of abulia or akinetic mustism. Therefore, the post-ictal confusion may be explained by the dopamine deficiency during the peri-ictal priod. There was a recent study about post-ictal headache (PIH) [5]. The incidence of PIH was significantly higher in generalized epilepsy, however, a strong correlation was found between migrainous PIH and occipital lobe epilepsy (OLE). According to the dopamine models of migraine, dopamine dysfunction may indirectly lead to susceptibility of CSD. CSD and epileptiform discharges can result from similar insult to the cortex, especially occipital lobe [40]. The epileptic brain keeps a higher state of dopamine with decreased receptor sensitivity, in opposite to the migrainers’, and it is reasonable that migrainous PIH is rather related to partial seizures, especially OLE, due to a DA deficiency. Dopamine is also known as prolactin releaseinhibitory factor. It was shown that dopamine is the key factor in postictal hyperprolactinemia [41,42]. At last, the post-ictal psychosis maybe due to the up-regulation of DA receptors triggered by seizure activity, and regaining of DA activity after seizure also has a role [9]. This dopamine hypothesis of epilepsy may at least explain several features of primary and secondary generalized seizures and peri-ictal conditions. Some neuromodulators have also been suggested to have protective effect on seizures, such as 5-HT1A and adrenergic a2 agonists. But due to the above evidences, dopamine is proposed to have a major neuromodulatory role in epileptogenesis [43,44].

Migraine and Epilepsy Antipsychotics have been proved effective in the acute treatment of migraine headaches. The evidence is especially strong for parenteral neuroleptics, particularly droperidol and prochlorperazine, and they are recommended as adjunctive treatment in migraine attacks [10]. Clinically, atypical antipsychotics have also been tried for prophylatic treatment of migraine. Considering the dopamine model, antipsychotics are effective in blocking the up-regulating D2 receptors. However, they do not solve the basic problem of migraine, i.e., hypoactivation of dopamine system. Furthermore, the side effects of antipsychotics carry a worry in long-term use. Continuous DA agonist treatment was found to be more effective than cyclic use in preventing intractable menstrual migraine [45]. This is a good

Epilepsy and migraine: The dopamine hypotheses way of thinking: Using DA agonist for migraine prevention. Long-acting DA agonist is supposed to be more effective to induce down-regulation of DA receptors. But it should be given with caution: If you give a migrainer DA agonist during the prodromal period, it shall facilitate a migraine attack. The presynaptic D2 receptors are more sensitive to DA agonist, and they are also sensitive to DA antagonist. A low dose D2 antagonist may increase the dopamine turnover, which may explain the efficacy of flunarizine, with dopamine antagonist effect, in migraine prevention. Maintaining a stationary DA tone with DA agonist or antagonist is supposed to be useful in migraine prevention. In consideration of epilepsy treatment, selective D2 agonist is beneficial in animal studies [9], but there is no yet a clinical trial for it. According to the hypothesis, it is a small dosage of D2 agonist that is needed for seizure prophylaxis, mainly for the prevention of dopaminergic failure. Small dose of dopamine agonist would not induce further down-regulation in postsynaptic dopamine receptors because the simultaneous action on presynaptic autoreceptors decreases the DA release. In personal experiences, bromocriptine, a selective dopamine D2 agonist and a weak D1 antagonist, has been tried in several patients for adjunctive treatment of epilepsy. The outcomes were mostly favorable. The dosage of bromocriptine is suggested to be 2.5–10 mg per day. A well-designed clinical trial is warranted to test its efficacy. Selective dopamine D2 receptor activation can also exert a protective action on hippocampal and dopaminergic neurons against excitatotoxicity, which are most vulnerable to injuries from hypoxia and seizures [46,47]. The mechanisms may include an agonist-specific trophic neuroprotection, and inhibitory modulation on glutamate transmission, as mentioned earlier. The monoaminergic receptors with inhibitory neuromodulatory function, such as 5-HT1A receptor and DRD2, could be potential targets for neuroprotection, not only in migraine and epilepsy, but also in early cerebral ischemia [34], head trauma and hypoxia.

Conclusion In summary, according to the dopamine hypotheses, there is a low dopamine tone in migrainers, compared with a high state of dopamine in an epileptic brain (generalized epilepsy). But the paroxysmal attacks of headaches and seizures maybe both due to a fall in dopamine tone. These hypothetical models give structures how neurotransmitters possess their neuromodulatory actions,

471 although the influences of the neurotransmitters on cortical excitability need to be confirmed by further in vitro and in vivo studies. The use of dopamine agonist is suggested in both disorders to prevent the attacks, but the medication and usage maybe different.

References [1] Robert M, Post MD, Silberstein SD. Shared mechanisms in affective illness, epilepsy, and migraine. Neurology 1994;10:S37–47. [2] Michael WK. Brain hyperexcitability: The basis for antiepileptic drugs in migraine prevention. Headache 2005;45:S25–32. [3] Leniger T, Driesch D, Sandra I, et al. Clinical characteristics of patients with comorbidity of migraine and epilepsy. Headache 2003;43:672–7. [4] Leniger T, Isbruch K, Driesch SD, et al. Seizure-associated headache in epilepsy. Epilepsia 2001;42:1176–9. [5] Ito M, Adachi N, Nakamura F, et al. Characteristics of postictal headache in patients with partial epilepsy. Cephalalgia 2004;24:23–8. [6] Bigal ME, Lipton RB, Cohen J, et al. Epilepsy and migraine. Epilepsy Behav 2003;4:S13–24. [7] Carolis P, Tinuper P, Sacquegna T. Migraine with aura and photosensitive epileptic seizures: a case report. Cephalalgia 1991;11:151–3. [8] Donnet A, Bartolomei F. Migraine with visual aura and photosensitive epileptic seizures. Epilepsia 1997;38:1032–4. [9] Starr MS. The role of dopamine in epilepsy. Synapse 1996;22:159–94. [10] Siow HC, Young WB, Silberstein SD. Neuroleptics in headache. Headache 2005;45:358–71. [11] Roth RH, Elsworth JD. Biochemical pharmacology of midbrain dopamine neurons. ACNP 2000; Psychopharmacology: the 4th generation of progress. [12] Arsenault MY, Parent A, Seguela P, et al. Distribution and morphological characteristics of dopamine-immunoreactive neurons in the midbrain of the squirrel monkey (Saimiri sciureus). J Comp Neurol 1988;267:489–506. ´ fra J, Schoenen J. Dopamine and migraine: a [13] Mascia A, A review of pharmacological, biochemical, neurophysiological, and therapeutic data. Cephalalgia 1998;18:174–82. [14] Peroutka SJ. Dopamine and migraine. Neurology 1997;49:650–6. [15] Fanciullaci M, Rosso AD. Dopamine involvement in the migraine attack. Funct Neurol 2000;15:171–81. [16] Barbanti P, Fabbrini G, Vanacore N, et al. Dopamine and migraine: does Parkinson’s disease modify migraine course. Cephalalgia 2000;20:720–3. [17] Weiller C, May A, Limmroth V, et al. Brain stem activation in spontaneous human migraine attacks. Nature Med 1995;1:658–60. [18] Lim EH, Smith EW, Chong J, et al. Seeing the light: brainstem glioma causing visual auras and migraine. Cephalalgia 2005;25:154–6. [19] Katsarava Z, Egelhof T, Kaube H, et al. Symptomatic migraine and sensitization of trigeminal nociception associated with contralateral pontine cavernoma. Pain 2003;105:381–4. [20] Afridi S, Goadsby PJ. New onset migraine with a brain stem cavernous angioma. J Neurol Neurosurg Psychiatry 2003;74:680–3.

472 [21] Veloso F, Kumar KCT. Headache secondary to deep brain implantation. Headache 1998;38:507–15. [22] Haas DC, Kent PF, Friedman DI. Headache caused by a single lesion of multiple sclerosis in the periaqueductal gray area. Headache 1993;33:452–5. [23] Benloucif S, Keegan MJ, Galloway MP. Serotonin-facilitated dopamine release in vivo: pharmacological characterization. J Pharmacol Exp Ther 1993;265:37–57. [24] Nissbrandt H, Waters N, Hjorth S. The influence of serotoninergic drugs on dopaminergic neurotransmission in rat substantia nigra, striatum and limbic forebrain in vivo. Naunyn Schmiedebergs Arch Pharmacol 1992;346:12–9. [25] Guan XM, McBride WJ. Serotonin microinfusion into the ventral tegmental area increases accumbens dopamine release. Brain Res Bull 1989;23:541–7. [26] Martin-Ruiz R, Ugedo L, Honrubia MA, et al. Control of serotonergic neurons in rat brain by dopaminergic receptors outside the dorsal raphe nucleus. J Neurochem 2001;77:762–75. [27] Haj-Dahmane, Samir. D2-like dopamine receptor activation excites rat dorsal raphe 5-HT neurons in vitro. Eur J Neurosci 2001;14:125–34. [28] Valentini V, Cacciapaglia F, Frau R, et al. Selective serotonin reuptake blockade increases extracellular dopamine in noradrenaline-rich isocortical but not prefrontal areas: dependence on serotonin-1A receptors and independence from noradrenergic innervation. J Neurochem 2005;93:371–82. [29] Straube A, Forderreuther S. Sleeping behaviour and headache attacks in cases of primary headache. Possible pathological mechanisms. Schmerz 2004;18:300–5. [30] Pietrobon D. Migraine: new molecular mechanisms. The Neuroscientist 2005;11:373–86. [31] Somjen GG. Mechanisms of spreading depression and hypoxic spreading depression-like depolarization. Physiol Rev 2001;81:1065–96. [32] Jelacic TM, Kennedy ME, Wickman K, et al. Functional and biochemical evidence for G-protein-gated inwardly rectifying K1 (GIRK) channels composed of GIRK2 and GIRK3. J Biol Chem 2000;275:36211–6. [33] Jeong HJ, Han SH, Min BI, et al. 5-HT1A receptor-mediated activation of G-protein-gated inwardly rectifying K+ current in rat periaqueductal gray neurons. Neuropharmacology 2001;41:175–85. [34] Kruger H, Heinemann U, Luhmann HJ. Effects of ionotropic glutamate receptor blockade and 5-HT1A receptor activa-

Chen

[35]

[36] [37]

[38]

[39] [40]

[41]

[42]

[43]

[44]

[45] [46]

[47]

tion on spreading depression in rat neocortical slices. Neuroreport 1999;10:2651–6. Card, et al. The hypothalamus: an overview of regulatory systems. In: Squire et al., editors. Fundamental neuroscience, 2nd ed.; 2002. p. 897–909. Gore, Roberts. Neuroendocrine systems. In: Fundamental neuroscience; 2002. p. 1031–65. Tseng KY, O’Donnell P. Dopamine-glutamate interactions controlling prefrontal cortical pyramidal cell excitability involve multiple signaling mechanisms. J Neurosci 2004;24:5131–9. Cepeda C, Li Z, Cromwell HC, et al. Electrophysiological and morphological analyses of cortical neurons obtained from children with catastrophic epilepsy: dopamine receptor modulation of glutamatergic responses. Dev Neurosci 1999;21:223–35. Hablitz JJ. Regulation of circuits and excitability: implications for epileptogenesis. Epilepsy Curr 2004;4:151–3. Kager H, Wadman WJ, Somjen GG. Simulated seizures and spreading depression in a neuron model incorporating interstitial space and ion concentrations. J Neurophysiol 2000;84:495–512. Zis AP, McGarvey KA, Clark CM, et al. The role of dopamine in seizure-induced prolactin release in humans. Convuls Ther 1992;8:126–30. Burris TP, Stringer LC, Freeman ME. Pharmacological evidence that a D2 receptor subtype mediates dopaminergic stimulation of PRL secretion from the anterior pituitary gland. Neuroendocrinology 1991;54:175–83. Gariboldi M, Tutka P, Samanin R, et al. Stimulation of 5HT1A receptors in the dorsal hippocampus and inhibition of limbic seizures induced by kainic acid in rats. Br J Pharmacol 1996;119:813–8. Szot MP, Lester ML, Laughlin R, et al. The anticonvulsant and proconvulsant effects of a2-adrenoreceptor agonists are mediated by distinct populations of a2a-adrenoreceptors. Neuroscience 2004;126:795–803. Herzog AG. Continuous bromocriptine therapy in menstrual migraine. Neurology 1997;48:101–2. Bozzi Y, Vallone D, Borrelli E. Neuroprotective role of dopamine against hippocampal cell death. J Neurosci 2000;20:8643–9. Nair VD, Sealfon SC. Agonist-specific transactivation of phosphoinositide 3-kinase signaling pathway mediated by the dopamine D2 receptor. Biol Chem 2003;278: 47053–61.