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Home , Alprenolol, Catecholaminergic, Flunarizine, Histidine decarboxylase, Moclobemide, Octopamine

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••Chapter 14

◗ and Other Biogenic

Christian Waeber

Biogenic amines such as serotonin, , his- like G protein-coupled receptors (GPCRs) (56). Based on tamine, and are naturally occurring biologi- crystal structure data, hydropathy profile analyses, and cally active amines synthesized from three different amino phylogenetic comparisons, these receptors share the com- acids. is the precursor of ; trypto- mon motif of seven transmembrane (TM) domains. The phan is the precursor of serotonin (5-hydroxytryptamine membrane-spanning regions are linked by three extracel- or 5-HT); is the precursor of dopamine, nor- lular loops that alternate with three intracellular loops. epinephrine, and epinephrine as well as the trace amines Activation of the receptors occurs by binding of specific and . In the central nervous sys- biogenic amines to a binding pocket formed by the TM tem (CNS), biogenic amines control and modulate vari- regions. Specific residues in different TM segments inter- ous functions, including cardiovascular homeostasis, cir- act with functional groups of the biogenic amines. In par- cadian rhythms, emotional states, endocrine secretion, ticular, an residue in TM3, residues sexual behavior, and , as well as learning in TM5, and a residue in TM6 determine and memory. the -binding properties of biogenic receptors. Consistent with these pleiotropic effects, the etiology Ligand binding to its induces a conformational of several neural diseases, including , has been change, initiating the activation of second messenger sys- linked to impaired signaling. As described tems via specific G proteins. Residues in close vicinity to in detail in Chapter 29, 5-HT is the most the plasma membrane in intracellular loops 2, 3, and 4 de- frequently mentioned in relation with migraine. However, termine the specificity and efficacy of G-protein activation. if the pharmacologic profiles of acute and prophylactic an- Receptor-mediated signaling is turned off by phosphor- timigraine drugs can be taken as an indication of which ylation of serine and threonine residues in the C-terminus molecules play a role in migraine pathophysiology, bio- and third intracellular loops, as it is known from rhodopsin genic amines other than 5-HT are likely be involved. For (22). instance, β- and antagonists are commonly used to prevent or abort migraine attacks, and many prophylactic agents (e.g., flunarizine, amitripty- 5-HYDROXYTRYPTAMINE line, , , ) have anti- OR SEROTONIN histaminic properties. In addition, high levels of circulat- ing trace amines (tyramine, octopamine, and ) The initial step in the synthesis of 5-HT is the facili- have recently been reported in both migraine and cluster tated transport of L- from blood into . headache (17). This chapter discusses possible relation- Because other neutral amino acids, such as phenylala- ships between various biogenic amines and migraine, de- nine, leucine, and methionine, are transported by the scribes their synthetic pathways, and reviews some of their same carrier, tryptophan entry into brain is related not known mechanisms of action. only to its blood concentration but also to the concentra- tions of other neutral amino acids. Tryptophan hydroxy- lase catalyzes the tetrahydrobiopterin-dependent hydrox- COMMON STRUCTURAL PROPERTIES ylation of tryptophan to 5-hydroxytryptophan, the first and OF BIOGENIC AMINE RECEPTORS rate-limiting step in the of 5-HT. The next step involves the of 5-hydroxytryptophan With the exception of 5-HT3 receptors, all known biogenic by L-aromatic decarboxylase (this amine receptors belong to the superfamily of rhodopsin- is also present in , where it

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converts 3,4-dihydroxyphenylalanine to dopamine, see 5-HT is primarily degraded by the enzyme monoamine below). oxidase (MAO), which occurs as two isoforms (MAO-A The highest 5-HT concentrations are found in blood and MAO-B). MAO converts 5-HT to 5-hydroxyindole platelets and in the gastrointestinal tract (enterochromaf- , which in turn is metabolized by fin cells of the mucosa contain more than 90% of the body’s dehydrogenase to produce 5-hydroxyindole acetic acid, 5-HT). Lesser amounts are found in the brain and retina. the major excreted 5-HT metabolite. Both 5-HT and Most soma are located in morphologically di- norepinephrine are metabolized preferentially by MAO-A. verse neurons clustered along the midline of the brainstem Inhibition of MAO-A activity has been linked to the an- and reticular formation. Dahlstrom and Fuxe (16) have de- tidepressant properties of a number of subtype selective scribed nine groups of 5-HT-containing bodies, desig- (e.g., ) and nonselective (e.g., ) nated B1 through B9, which correspond for the most part MAO inhibitors in clinical use. Interestingly, there is more with the raphe nuclei. Although there are only about 20,000 MAO-A than MAO-B throughout rat brain, whereas hu- serotonergic neurons in the rat brain (around 300,000 in man brain contains more MAO-B. Although serotoner- humans), the extensive axonal projection system arising gic cell bodies contain predominantly MAO-B (for which from these neurons densely innervates nearly all regions 5-HT is not a preferred substrate), treatment of rats with of the CNS. clorgyline, a selective MAO-A inhibitor, raises the brain As with other biogenic amine transmitters, 5-HT is content of 5-HT and reduces the conversion of 5-HT to stored in vesicles and released by a Ca2+-dependent exo- 5-hydroxyindole acetic acid. Thus, 5-HT may well be oxi- cytotic mechanism. The extent of 5-HT release depends on dized preferentially by MAO-A in vivo, as it is in vitro, even the firing rate of serotonergic neurons. Drugs that decrease though serotonergic neurons do not contain much of this the firing rate of serotonergic soma (e.g., 5-HT1A-receptor form of the enzyme. ) decrease the release of 5-HT in the projection ar- With the exception of 5-HT3 receptors, 5-HT receptors eas. Administration of 5-HT1B-receptor agonists into areas belong to the GPCR superfamily. With at least 14 dis- receiving serotonergic innervation activates serotonergic tinct members, they are one of the most complex families autoreceptors in terminal fields and decreases 5-HT syn- of neurotransmitter receptors. Adding to this complexity, thesis and release. However, in contrast to the activation splice variants of various subtypes (5-HT4, 5-HT7)orRNA- of 5-HT1A somatodendritic autoreceptors, these effects are edited isoforms (5-HT2C) have been described (27). The not caused by decreases in the firing rate of serotonergic 5-HT1 receptor class is composed of five receptor subtypes neurons. (5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E and 5-HT1F), which, in Most of the released 5-HT is recaptured by an active re- humans, share 40 to 63% overall sequence identity and uptake mechanism via the serotonin transporter (SERT) couple preferentially to Gi/o proteins, with resulting in- located on serotonergic neurons. SERT exhibits about hibition of cyclic monophosphate (cAMP) for- 50% homology with the transporters for norepinephrine mation. The 5-HT2 receptor class is composed of the and dopamine. The selectivity of monoamine 5-HT2A, 5-HT2B and 5-HT2C receptors, which exhibit 46 inhibitors for these transporters varies greatly. For in- to 50% overall sequence identity and couple preferentially stance, such as are to Gq/11 to increase the hydrolysis of inositol phosphates 25- to 150-fold more potent at inhibiting transport of nor- and elevate cytosolic [Ca2+]. epinephrine than 5-HT. In contrast, selective serotonin re- Based on their overall electrophysiologic features and uptake inhibitors (SSRIs), such as fluoxetine, , sequence, 5-HT3 receptors have been placed within the in- , and , are 15 to 75 times more po- trinsic ligand-gated receptor superfamily, to- tent at inhibiting the uptake of 5-HT than the uptake gether with nicotinic or GABAA receptors. of norepinephrine. Various heterocyclic antidepressants 5-HT3 receptors are found on both central and periph- (, , , , eral neurons, where they trigger rapid depolarization be- , ) are used in migraine prophylaxis, cause of a transient inward current, subsequent to the but the efficacy of tricyclic antidepressants in migraine opening of nonselective cation channels. A cDNA clone does not seem to depend on their action, encoding a single subunit of the 5-HT3A receptor was ini- and the strongest evidence of efficacy is for amitripty- tially isolated from a -derived cell line. Two splice line (2,62). , a structurally novel bicyclic an- variants were subsequently described in neuroblastoma– tidepressant that inhibits the reuptake of 5-HT and nore- glioma cells and rat native tissues. A second subunit, pinephrine, has been shown to have a favorable efficacy 5-HT3B, has been cloned. It appears that the heteromeric and profile when compared to amitriptyline combination of 5-HT3A and 5-HT3B subunits is necessary (11). The use of the SSRIs (e.g., fluoxetine, sertraline, and to provide the full functional features of the 5-HT3 recep- paroxetine) has also been advocated in migraine prophy- tor (61). laxis, but data supporting the efficacy of these drugs are Although 5-HT4, 5-HT6, and 5-HT7 receptors all cou- scant (15). ple preferentially to Gs and promote cAMP formation, P1: KWW/KKL P2: KWW/HCN QC: KWW/FLX T1: KWW GRBT050-14 Olesen- 2057G GRBT050-Olesen-v6.cls July 8, 2005 1:24

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they are classified as distinct receptor classes because of D2 genotypes showed similar clinical and psychological their limited (<35%) overall sequence identities (9,24). features (49). These results are at odds with a previous There have been no published reports to date concerning study showing that D2 NcoI alleles significantly modify a physiologic functional response or specific binding to a the clinical susceptibility to migraine with aura (47). In 5-HT5 recognition site. Two subtypes of the 5-HT5 receptor addition, NcoI C allele frequency has been reported to (5-HT5A and 5-HT5B), sharing 70% overall sequence iden- be significantly higher in individuals with migraine with tity, have been found in rodents. The 5-HT5A subtype has aura, anxiety, or major than in individuals also been found in humans, but the human 5-HT5B re- who have none of these disorders (46). This observation ceptor does not encode a functional protein; there is unexpected, because the NcoI polymorphism involves are stop codons in its coding sequence. In the rat, the re- a silent change at amino acid His313 and the expression combinant 5-HT5A receptor may be negatively coupled to of different alleles results in identical receptor molecules. adenylate cyclase activity (24). Subsequent studies have in fact been unable to confirm Although most of the evidence for a direct role of 5-HT the association between migraine with aura and D2 in the pathophysiology of migraine is circumstantial, there NcoI alleles (20,33). In contrast to NcoI polymorphism, is a significant amount of literature linking this amine to the -141C Ins/Del polymorphism in the D2 receptor migraine (see Chapter 29). For example, platelet 5-HT lev- gene is functional and the -141C Ins allele frequency is els are reduced by 30% during attacks, and plasma con- significantly higher in schizophrenic patients than in centrations are 60% lower; the biogenic amine-depleting control subjects (41). However, no association has been drug reserpine causes a “typical headache” in migraineurs, found between this polymorphism and migraine (36). probably by inducing 5-HT release from intracellular Focusing on an isolated genetic population, Del Zompo et stores. Similarly, m-chlorophenylpiperazine (m-CPP), a al. (19) found a disequilibrium in D2 genotypes, but only major metabolite of the antidepressant trazodone, has in a subgroup of patients experiencing both nausea and been reported to cause migraine-like headaches in hu- yawning immediately before or during the pain phase of mans by activating 5-HT2B or 5-HT2C receptors. Perhaps migraine (so-called migraineurs). A recent the strongest evidence for a role of 5-HT in migraine is study assessed the association between polymorphism of provided by the fact that some acute antimigraine drugs other dopamine-related and susceptibility to mi- (ergot alkaloids, ) activate 5-HT1 receptors (most graine (38). No significant differences were found between probably the 5-HT1B, 5-HT1F, and/or 5-HT1F subtypes), control and migraine groups for the frequency of a 40-bp whereas various prophylactic agents (, pizo- tandem repeat in the dopamine transporter gene and that tifen, cyproheptadine) are 5-HT2 receptor antagonists (see of a dinucleotide repeat in the dopamine β-hydroxylase Chapters 21, 50, 51, and 55). gene, but migraine without aura, and not migraine with aura, showed significant genetic association with D4 re- ceptor polymorphism. The precise role of D2-like receptor DOPAMINE gene polymorphism in migraine is therefore presently unclear. There is no evidence for allelic association Dopamine is a neurotransmitter found pre- between D1-like (D1,D3, and D5) dopamine receptor gene dominately in the CNS. It is synthesized from tyrosine, polymorphism and migraine with or without aura (55). which is converted to L-dihydroxyphenylalanine (L-DOPA) Various antidopaminergic drugs abort migraine at- by the enzyme . Dihydroxyphenylala- tacks, and dopamine agonists may be useful for pro- nine is converted to dopamine by the cytoplasmic enzyme phylaxis (6,58,59). Pharmacologic studies with dopamin- DOPA decarboxylase (or decarboxy- ergic agents like suggest that migraineurs lase). might present a dopaminergic hypersensitivity even be- Five subtypes of dopamine receptor have been cloned. tween migraine attacks (8,14). Finally, patients with mi- The D1-like receptors (D1 and D5) are closely related. They graine show an increased density of D2-like receptors on couple to the G protein subunit Gsα and stimulate adeny- lymphocytes (5). Nevertheless, if dopamine and its recep- lyl cyclase activity. In contrast, D2,D3, and D4 receptors tors are indeed involved in migraine, its treatment, or both, (D2-like) couple to Giα and inhibit the formation of cAMP. the precise site of this action is unclear (44). The ner- The human D2 gene consists of eight exons separated vous and vascular systems are both likely to be involved by seven introns (25). It undergoes alternative splicing in migraine pathophysiology, and both systems respond to generate two molecularly distinct isoforms, D2S and to dopamine. Dopamine is found in three major pathways D2L, that have distinct functions in vivo (39). D2 receptor in the CNS. A dopamine projection from the hypothala- polymorphism has been hypothetically connected to a mus plays an important role in the regulation of large number of neuropsychiatric disorders (65), but no release from the pituitary gland. Dopamine is also syn- conclusive link or association has been found. In a recent thesized by neurons in the ventral tegmental area, which study, a large group of migraine patients with different projects to the prefrontal cortex and the basal forebrain, P1: KWW/KKL P2: KWW/HCN QC: KWW/FLX T1: KWW GRBT050-14 Olesen- 2057G GRBT050-Olesen-v6.cls July 8, 2005 1:24

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including the nucleus accumbens. Another important cle and exhibit a higher affinity for norepinephrine than dopamine pathway is from the substantia nigra pars com- epinephrine. β-Adrenoceptor antagonists, either non– pacta to the neostriatum. Dopamine or dopamine agonists subtype selective or selective for the β1-subtype, are widely have vasoactive effects on blood vessels in vitro and in vivo, used as antihypertensives, whereas β2-adrenoceptor ag- producing vasoconstriction or vasodilatation, depending onists are commonly used as bronchodilators. Selective on the vascular bed and dose. Vasodilatation is seen in re- β3-adrenoceptor agonists are being developed for the treat- nal, mesenteric, coronary, and cerebral blood vessels, and, ment of type II diabetes and obesity. because it is inhibited by dopamine receptor antagonists, Both α- and β-adrenoceptors are part of the large fam- is probably mediated by specific dopamine receptors. In ily of GPCR. α1-Adrenoceptors mediate their functions contrast, dopamine has vasoconstrictor effects in most vas- through Gq/G11 proteins and phospholipase C, whereas cular beds, including that of the brain, but it is believed to α2-adrenoceptors activate Go/Gi proteins and are nega- be mediated by α-adrenergic and 5-HT receptors. tively coupled to adenylate cyclase. In addition, there is 2+ evidence linking α2-adrenoceptor to stimulation of Ca influx and activation of K+ channels, phospholipase A2, NOREPINEPHRINE AND EPINEPHRINE and Na+/H+ exchange (13). All three β-adrenoceptor sub- types are positively coupled to adenylate cyclase via acti- In the substantia nigra and some other brain regions, cat- vation of Gs δ proteins. echolamine synthesis proceeds only to dopamine, but in A wide variety of clinical signs and diagnostic tests sug- neurons of the locus coeruleus dopamine is further me- gest that dysfunction of the sympathetic nervous system tabolized to norepinephrine by the enzyme dopamine-β- exists in migraineurs (recently reviewed by Peroutka [45]). hydroxylase. After release, can be taken Furthermore, non–subtype-selective β-blockers (pro- up into neurons via the dopamine transporter, or metabo- pranolol, , ) and β1-selective blockers lized by MAO (to 3,4,-dihydroxyphenylacetic acid) or cat- (, ) show efficacy as migraine prevent- echol O-methyltransferase (to 3-methoxytyramine). These ing agents. In contrast, other β1-selective () are major mechanisms for inactivation of cate- or nonselective β-adrenoceptor antagonists (, cholamines (and monoamines). Action by both enzymes , and ) do not appear to be effective results in the formation of . in migraine therapy (1). Some β-blockers interact with Adrenoceptors are located throughout the body on 5-HT1A receptors in both animal and human (43), neuronal and non-neuronal tissues where they medi- but no obvious correlation appears to exist between drug ate a diverse range of responses to norepinephrine and affinity at 5-HT1A sites and potency of β-adrenergic agents epinephrine. The adrenoceptor family was first divided in terms of migraine prevention. There are some indica- into α- and β-adrenoceptors based on pharmacologic tions that β-blockers exert their antimigraine effects on studies in isolated tissue (3). α-Adrenoceptors located on central catecholaminergic systems (52), suggesting that an peripheral sympathetic nerve terminals were later des- action in the CNS might be responsible for the migraine ignated α2-adrenoceptors and those located postsynapti- prophylactic effect. However, although atenolol penetrates cally were designated α1-adrenoceptors (31). Subsequent the CNS only poorly, it is an efficient antimigraine prophy- studies using pharmacologic and molecular biological lactic agent. Thus, the mechanism of action of β-blockers techniques have further subdivided the α-adrenoceptor in migraine still remains to be established, and no single family; three subtypes within each group have now property accounts for antimigraine prophylactic activity, been cloned and pharmacologically characterized. The suggesting either that a combination of characteristics is α1-adrenoceptor subtypes have been classified as α1A, α1B, necessary or that various β-blockers act via different mech- and α1D-adrenoceptors; α2-adrenoceptors have been clas- anisms. The only consistent feature of effective β-blockers sified as the α2A-, α2B-, and α2C-adrenoceptors (rat, mouse, is that only silent β-adrenergic antagonists (without guinea pig, and cow α2A-receptors exhibit a pharmacologic partial activity or without intrinsic sympath- profile designated as α2D). omimetic activity) are effective agents. Finally, it is worth β-Adrenoceptors are also heterogeneous and subdi- mentioning that mirtazapine, an α2- vided into three distinct subtypes based on functional, re- antagonist with a complex pharmacologic profile (18), ceptor binding, and genetic studies: β1-, β2-, and the atyp- has been reported to be effective in migraine prevention. ical β3-adrenoceptors. An additional subtype, identified mucate is a mild vasoconstrictor used in cardiac tissue as a putative, atypical subtype termed in combination with acetaminophen and a mild seda- β4, might be an affinity state of the β1-adrenoceptor (30). tive for the treatment of moderate tension-type and β1-Adrenoceptors predominate in the and on adi- migraine headaches. It has been suggested that isomethep- pose tissue and display equal affinity for epinephrine and tene owes its therapeutic effect to a sympathomimetic norepinephrine. In contrast, β2-adrenoceptors are pre- action leading to cranial blood vessel constriction via α2A- dominant on vascular, uterine, and airway smooth mus- and α2C-adrenoceptors (63). However, the contribution of P1: KWW/KKL P2: KWW/HCN QC: KWW/FLX T1: KWW GRBT050-14 Olesen- 2057G GRBT050-Olesen-v6.cls July 8, 2005 1:24

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vasoconstriction to the efficacy of acute antimigraine diate headache during infusion and a delayed migraine drugs is unclear (40,64). Because intravenous adminis- headache that peaks approximately 5 hours after infusion tration of the nonselective α2-adrenoceptor agonist UK- (32). The intensity of the immediate headache is signif- 14,304 blocks plasma protein extravasation within rat icantly attenuated and the delayed migraine completely dura mater following unilateral electrical trigeminal gan- abolished when patients are pretreated with the H1 recep- glion stimulation (35), it is possible that prejunctional α2- tor antagonist, . Histamine does not cross the adrenoceptors on trigeminovascular afferents play a role blood–brain barrier (54) and it has been suggested that in the efficacy of isometheptene or ergot derivatives (57). histamine acts on H1 receptors located on the endothe- lium of cerebral arteries which, when activated, cause the formation of . HISTAMINE Several H3 receptor agonists have been reported to in- hibit neurogenic inflammation in various tissues, includ- Histamine biosynthesis is performed in one step by the ing the lungs and dura mater (34,35). These observations enzyme L-. Histamine degradation indicate a potential use of H3-receptor agonists in inflam- occurs mainly via two pathways: oxidation by diamine ox- mation, asthma, and migraine. Phase II clinical trials have idase (DAO), leading to imidazole acetic acid, or methy- so far resulted in negative outcomes in exercise-induced lation by histamine N-methyltransferase, producing tele- asthma (21) or migraine (53). Interestingly, in an open methylhistamine, which is further metabolized by MAO-B, , N-α-methylhistamine was reported to reduce producing tele-methylimidazole acetic acid. In the verte- headache intensity, frequency, and duration in 18 patients brate CNS, histamine is almost exclusively methylated and with migraine. At the highest dose tested, however,patients only small amounts of DAO are detectable. Unlike the other reported intense headaches, which were possibly caused amine transmitters, nerve terminals do not by residual H1-receptor agonistic effects (37). exhibit a high-affinity uptake system for histamine (54). In the mammalian brain, histamine is synthesized in a restricted population of neurons located in the TRACE AMINES tuberomammillary nucleus of the posterior hypothala- mus. These neurons project diffusely to most cerebral ar- In addition to the classical biogenic amine neurotransmit- eas and have been implicated in several brain functions ters discussed, a series of less well-characterized amines (e.g., sleep/wakefulness, hormonal secretion, cardiovascu- derived from the of amino acids are also lar control, thermoregulation, food intake, and memory present in many tissues, especially in the brain. In mam- formation). In peripheral tissues, histamine is stored in mals, these amines include tyramine, β-phenylethylamine, mast cells, , and enterochromaffin cells. , and octopamine. Tyramine, derived from the Histamine H1,H2, and H3 receptors are all G-protein– tyrosine through enzyme activity,is coupled molecules and transduce extracellular signals via metabolized by dopamine-β-hydroxylase into octopamine, Gq, Gs, and Gi/o proteins, respectively (26). Generally, his- and N-methyltransferase enzyme ac- tamine modulates inflammatory and allergic responses via tivity transforms octopamine into synephrine, the final H1 receptors, secretion through H2 receptors, biochemical step in the synthesis of trace amines. and neurotransmitter release in the CNS via H3 receptors. Although the presence of trace amines in neural tissues The expression pattern of the recently cloned H4 subtype is has been known for many years (60), and alterations in highly suggestive of a role for this receptor in immune and the amount of trace amines in the nervous system are as- inflammatory modulation. Unlike the H1 and H2 receptor sociated with pathologic conditions (48), the physiologic genes, analysis of the H3 receptor gene shows the presence effects of trace amines are poorly understood. Tyramine of several introns and several H3 receptor isoforms have and β-phenylethylamine act peripherally by promoting been identified (34). the efflux of catecholamines from sympathetic neurons Plasma histamine levels have been shown to be signif- and adrenals, which results in the indirect stimulation of icantly elevated in patients with migraine, both during adrenoceptors (7). In addition, trace amines can bind to headache and symptom-free periods (23,29). These ele- classical amine receptors. For instance, because it shares vated plasma histamine levels in migraine patients may structural and functional similarities with norepinephrine, be associated with increased spontaneous histamine re- octopamine has numerous effects on the adrenergic sys- lease by leukocytes (29), or result from activation of du- tem (4), and tryptamine, very similar to 5-HT, has a high ral mast cells, which might play a role in migraine patho- affinity for 5-HT1D, 5-HT2B, 5-HT2C, and 5-HT7 receptors genesis (50). There is, however, little evidence for a direct (51). correlation of plasma histamine levels and attack precip- The recent identification of GPCR activated by trace itation, other than the observation that histamine, when amines is an important advance in the understanding infused intravenously to migraineurs, causes an imme- of the roles of these amines in the mammalian nervous P1: KWW/KKL P2: KWW/HCN QC: KWW/FLX T1: KWW GRBT050-14 Olesen- 2057G GRBT050-Olesen-v6.cls July 8, 2005 1:24

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system (10). The 15 members of these two distinct fam- 5. Barbanti P, Fabbrini G, Ricci A, et al. Migraine patients show an ilies of GPCR show a high degree of similarity with increased density of dopamine D3 and D4 receptors on lymphocytes. Cephalalgia.2000;20:15–19. traditional G-protein–coupled biogenic amine receptors. 6. Bigal ME, Bordini CA, Speciali JG. Intravenous in One of these receptors (TA1) is activated by both β- the emergency department treatment of : a randomized phenylethylamine and tyramine with high affinity, leading controlled trial. JEmerg Med.2002;23:141–148. 7. Black JW, Jenkinson DH, Kenakin TP. Antagonism of an indirectly to increased cAMP production. TA1 displays low affinity acting agonist: block by and of the action of tyra- for tryptamine, octopamine, and dopamine. The related mine on rat heart. Eur J Pharmacol. 1980;65:1–10. TA2 receptor appears to be specific for β-phenylethylamine 8. Blin O, Azulay JP, Masson G, et al. Apomorphine-induced yawning in migraine patients: enhanced responsiveness. Clin Neuropharmacol. and tryptamine. Both of these G-protein–coupled receptor 1991;14:91–95. families possess many of the structural hallmarks of the 9. Bockaert J, Claeysen S, Compan V, et al. 5-HT4 receptors. Curr Drug rhodopsin receptor superfamily (see above). Among these Targets CNS Neurol Disord.2004;3:39–51. 10. Borowsky B, Adham N, Jones KA, et al. Trace amines: identification are several highly conserved stretches of residues in the of a family of mammalian G protein-coupled receptors. Proc Natl predicted TM regions, as well as potential sites of regu- Acad Sci U S A. 2001;98:8966–8971. latory phosphorylation in the C-terminal domain. Thus, 11. Bulut S, Berilgen MS, Baran A, et al. Venlafaxine versus amitriptyline in the prophylactic treatment of migraine: randomized, double-blind, these receptors are likely to couple to conventional signal- crossover study. Clin Neurol Neurosurg.2004;107:44–48. ing pathways as demonstrated for TA1 (10) and their sig- 12. Bunzow JR, Sonders MS, Arttamangkul S, et al. , 3,4- naling is likely to be regulated through mechanisms similar methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine are agonists of to those for other GPCR. Several of these new receptors are a rat receptor. Mol Pharmacol. 2001;60:1181–1188. expressed within specific regions of the CNS, whereas oth- 13. Bylund DB. Pharmacological characteristics of alpha-2 adrenergic ers appear to be found in specific peripheral tissues such as receptor subtypes. Ann N Y Acad Sci.1995;763:1–7. 14. Cerbo R, Barbanti P, Buzzi MG, et al. Dopamine hypersensitivity the stomach, , lung, and small intestine. In the CNS, in migraine: role of the apomorphine test. Clin Neuropharmacol. the mRNA for the TA1 and TA2 receptor proteins can be 1997;20:36–41. found sparsely expressed in certain cells of the substantia 15. Cutrer F, Waeber C, Moskowitz M. Headache. In: Enna S, Coyle J, eds. Pharmacological management of neurological and psychiatric dis- nigra/ventral tegmental area, locus coeruleus, and dorsal orders.New York: McGraw-Hill; 1998:525–568. raphe nucleus, areas where the cell bodies for the classic 16. Dahlstrom A, Fuxe K. Evidence for the existence of monamine- biogenic amines neurons are found. containing neurons in the . I. Demonstration of monamines in the cell bodies of brainstem neurons. Acta Physiol Chocolate, cheese, citrus fruits, and other foods rich Scand. 1964;62:1–55. in trace amines are widely thought to trigger migraine at- 17. D’Andrea G, Terrazzino S, Leon A, et al. Elevated levels of circulating tacks in susceptible individuals (42), but careful evaluation trace amines in primary headaches. Neurology. 2004;62:1701–1705. 18. de Boer T. The pharmacologic profile of mirtazapine. 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