Functional reconstitution of the human serotonin receptor 5-HT(6) using synthetic transmembrane peptides.

Seven transmembrane (7TM) synthetic peptides mimicking the alpha-helical TM domains of the human serotonin receptor subtype-6 (5-HT(6)) were autonomously reconstituted in detergent micelle and liposome environments. The degree of assembly of the 7TM peptides was characterized by monitoring the fluorescence resonance energy transfer (FRET) between donor and acceptor probes labeled at the amino termini of the second and fourth TM-peptides, respectively. The FRET efficiency of these peptides significantly increased when the 7TM peptides were reconstituted in liposome compare to detergent micelles. Furthermore, the 7TM peptides reconstituted in liposomes selectively bound to free serotonin and serotonin-conjugated magnetic beads, yielding a dissociation constant of 0.84 microM. These results show that the seven individual TM domains of 5-HT(6) can spontaneously assemble into liposomes in a conformation that mimics a native structure, and further demonstrate that specific interactions between TM helices play a critical role in the folding and stabilizing of GPCRs. The autonomous assembly of 7TM-peptides can be applied to the screening of agonists for GPCRs that are difficult to manipulate.

Dose-ranging evaluation of the serotonin antagonist GR-C507/75 (GR38032F) when used as an antiemetic in patients receiving anticancer chemotherapy.

GR-C507/75 (GR38032F) antagonizes the 5-HT3 (serotonin) receptor and prevents cisplatin-induced emesis in animals. In this dose-ranging trial, 44 patients with cancer receiving chemotherapy known to produce nausea and vomiting (including cisplatin, cyclophosphamide, and doxorubicin) received three intravenous (IV) infusions of GR-C507/75 every two hours beginning 30 minutes before chemotherapy. Ten dosage levels were explored, ranging from 0.04 mg/kg to 0.35 mg/kg in each of the three infusions. Toxicities were mild and included sedation, dizziness, headache, transient elevations of SGOT or alanine aminotransferase (ALT), and dry mouth. No akathisia or acute dystonic reactions were observed. Antiemetic effects were seen in patients receiving cisplatin at 120 mg/m2. GR-C507/75 can be safely administered on this schedule at IV dosages up to 0.35 mg/kg in patients receiving chemotherapy. Further studies of this agent at higher dosages and by different schedules are appropriate.

Role of local anesthetics on both cholinergic and serotonergic ionotropic receptors.

A great body of experimental evidence indicates that the main target for the pharmacological action of local anesthetics (LAs) is the voltage-gated Na+ channel. However, the epidural and spinal anesthesia as well as the behavioral effects of LAs cannot be explained exclusively by its inhibitory effect on the voltage-gated Na+ channel. Thus, the involvement of other ion channel receptors has been suggested. Particularly, two members of the neurotransmitter-gated ion channel receptor superfamily, the nicotinic acetylcholine receptor (AChR) and the 5-hydroxytryptamine receptor (5-HT3R type). In this regard, the aim of this review is to explain and delineate the mechanism by which LAs inhibit both ionotropic receptors from peripheral and central nervous systems. Local anesthetics inhibit the ion channel activity of both muscle- and neuronal-type AChRs in a noncompetitive fashion. Additionally, LAs inhibit the 5-HT3R by competing with the serotonergic agonist binding sites. The noncompetitive inhibitory action of LAs on the AChR is ascribed to two possible blocking mechanisms. An open-channel-blocking mechanism where the drug binds to the open channel and/or an allosteric mechanism where LAs bind to closed channels. The open-channel-blocking mechanism is in accord with the existence of high-affinity LA binding sites located in the ion channel. The allosteric mechanism seems to be physiologically more relevant than the open-channel-blocking mechanism. The inhibitory property of LAs is also elicited by binding to several low-affinity sites positioned at the lipid-AChR interface. However, there is no clearcut evidence indicating whether these sites are located at either the annular or the nonannular lipid domain. Both tertiary (protonated) and quaternary LAs gain the interior of the channel through the hydrophilic pathway formed by the extracellular ion channel's mouth with the concomitant ion flux blockade. Nevertheless, an alternative mode of action is proposed for both deprotonated tertiary and permanently-uncharged LAs: they may pass from the lipid membrane core to the lumen of the ion channel through a hydrophobic pathway. Perhaps this hydrophobic pathway is structurally related to the nonannular lipid domain. Regarding the LA binding site location on the 5-HT3R, at least two amino acids have been involved. Glutamic acid at position 106 which is located in a residue sequence homologous to loop A from the principal component of the binding site for cholinergic agonists and competitive antagonists, and Trp67 which is positioned in a stretch of amino acids homologous to loop F from the complementary component of the cholinergic ligand binding site.

Serotoninergic mechanisms in hypertension. Focus on the effects of ketanserin.

Aggregating platelets release serotonin, which induces contraction of most vascular smooth muscle by activation of S2-serotoninergic receptors. Serotonin released in the circulation may contribute to the increase in peripheral resistance of hypertension as the responsiveness of blood vessels from hypertensive animals and humans to the vasoconstrictor action of the monoamine is augmented. The data obtained with the new antihypertensive agent ketanserin may favor that interpretation. Ketanserin is a selective S2-serotoninergic antagonist with additional alpha 1-adrenergic blocking properties. In humans, it has a terminal half-life of 12 to 25 hours and is eliminated predominantly by the liver. The hemodynamic profile of ketanserin is that of a vasodilator drug with actions on both resistance and capacitance vessels. On short-term intravenous administration, it lowers blood pressure in hypertensive patients with minimal reflex changes in cardiovascular function. When given orally long term to hypertensive patients, ketanserin causes a sustained reduction in arterial blood pressure, comparable to that obtained with either beta-adrenergic blockers or diuretics. Several studies have shown a greater efficacy in older (greater than 60 years of age) than in younger patients independent of starting pressure. Side effects mainly consist of dizziness, somnolence, and dry mouth, but they are usually not severe. The mechanism underlying the antihypertensive effect of ketanserin is unclear. It cannot be attributed to either S2-serotoninergic or alpha 1-adrenergic blockade alone, but an interaction between the two effects appears to be required.

Tianeptine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depression and coexisting anxiety and depression.

Tianeptine is a novel antidepressant agent, both structurally (modified tricyclic) and in terms of its pharmacodynamic profile. Unlike other antidepressant agents, tianeptine stimulates the uptake of serotonin (5-hydroxytryptamine; 5-HT) in rat brain synaptosomes and rat and human platelets, increases 5-hydroxyindoleacetic acid (5-HIAA) levels in cerebral tissue and plasma, and reduces serotonergic-induced behaviour. Tianeptine reduces the hypothalamic-pituitary-adrenal response to stress, antagonises stress-induced behavioural deficits and prevents changes in cerebral morphology. The antidepressant efficacy of tianeptine, as shown in 2 trials of patients with major depression or depressed bipolar disorder with or without melancholia, is greater than that of placebo. In patients with major depression without melancholia or psychotic features, depressed bipolar disorder or dysthymic disorder, the antidepressant efficacy of short term (4 weeks to 3 months) tianeptine therapy appears to be similar to that of amitriptyline, imipramine and fluoxetine and may be superior to that of maprotiline in patients with coexisting depression and anxiety. However, submaximal dosages of amitriptyline and maprotiline were used in these studies. Preliminary evidence suggests that tianeptine may also be effective in patients with endogenous depression. Progressive therapeutic improvements have been observed with up to 1 year of tianeptine treatment, and long term therapy may reduce the rate of relapse or recurrence. Tianeptine is effective in the treatment of depression in elderly and post-alcohol-withdrawal patient subgroups. Tianeptine was more effective in reducing psychic anxiety than placebo in patients with major depression or depressed bipolar disorder with or without melancholia. The overall anxiolytic properties of tianeptine in patients with coexisting depression and anxiety appear to be similar to those of amitriptyline, imipramine and fluoxetine and may be superior to those of maprotiline, although submaximal dosages of amitriptyline and maprotiline were used. Studies of tianeptine in patients with primary anxiety have not been conducted. Tianeptine is well tolerated in the short (3 months) and long (up to 1 year) term. The incidence of dry mouth (38 vs 20%), constipation (19 vs 15%), dizziness/syncope (23 vs 13%), drowsiness (17 vs 10%) and postural hypotension (8 vs 3%) are greater with amitriptyline than with tianeptine. Insomnia and nightmares occur in more tianeptine than amitriptyline recipients (20 vs 7%). The relative lack of sedative, anticholinergic and cardiovascular adverse effects with tianeptine makes it particularly suitable for use in the elderly and in patients following alcohol withdrawal; these patients are known to have increased sensitivity to the adverse effects associated with psychotropic drugs.(ABSTRACT TRUNCATED AT 400 WORDS)

Buspirone as an antidote to SSRI-induced bruxism in 4 cases.

BACKGROUND: One hypothesis to explain selective serotonin reuptake inhibitor (SSRI)-induced bruxism states that SSRIs increase extrapyramidal serotonin levels, thereby inhibiting dopaminergic pathways controlling movement. Previous reports have emphasized buspirone's postsynaptic dopaminergic effect as a partial antidote to the suppressed dopamine levels. CASE REPORTS: Four patients, recently started on treatment with the SSRI sertraline, presented with new-onset complaints attributable to SSRI-induced bruxism. All 4 responded to adjunctive buspirone, a serotonin-1A (5-HT1A) receptor agonist, with relief of bruxism and associated symptoms. DISCUSSION: We expand the hypothesis put forth in previous reports by proposing that buspirone is not only acting postsynaptically in the extrapyramidal system, but also presynaptically on serotonergic neurons that influence masticatory modulation in the mesocortical tract. Our 4 cases support the concept of buspirone acting as a full agonist at the presynaptic 5-HT1A somatodendritic receptors located on the cell bodies of raphe serotonergic neurons that project to the ventral tegmental area (VTA) of the midbrain. These serotonergic neurons modulate the firing of the mesocortical tract, which itself projects from the VTA to the prefrontal cortex and acts on masticatory muscle activity through inhibiting spontaneous movements such as bruxism. While the literature is confusing and contradictory on definitions of bruxism and etiologies of incompletely understood movement disorders, we believe SSRI-induced bruxism is best conceptualized as a form of akathisia.

Mechanism of action of antidepressant medications.

The psychopharmacology of depression is a field that has evolved rapidly in just under 5 decades. Early antidepressant medications--tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs)--were discovered through astute clinical observations. These first-generation medications were effective because they enhanced serotonergic or noradrenergic mechanisms or both. Unfortunately, the TCAs also blocked histaminic, cholinergic, and alpha1-adrenergic receptor sites, and this action brought about unwanted side effects such as weight gain, dry mouth, constipation, drowsiness, and dizziness. MAOIs can interact with tyramine to cause potentially lethal hypertension and present potentially dangerous interactions with a number of medications and over-the-counter drugs. The newest generation of antidepressants, including the single-receptor selective serotonin reuptake inhibitors (SSRIs) and multiple-receptor antidepressants venlafaxine, mirtazapine, bupropion, trazodone, and nefazodone, target one or more specific brain receptor sites without, in most cases, activating unwanted sites such as histamine and acetylcholine. This paper discusses the new antidepressants, particularly with regard to mechanism of action, and looks at future developments in the treatment of depression.

Local injections of the 5-hydroxytryptamine antagonist mianserin into substantia nigra pars reticulata block tremulous jaw movements in rats: studies with a putative model of Parkinsonian tremor.

RATIONALE: Atypical antipsychotics such as clozapine and olanzapine have a low liability for producing motor side effects. In addition to being D2 antagonists, these drugs have a complex binding profile that includes affinity for muscarinic, alpha, H1, and various serotonin receptors. Previous work in rats has shown that atypical antipsychotics suppress tremulous jaw movements induced by the anticholinesterase tacrine in rats. Cholinomimetic-induced jaw movements are a putative model of parkinsonian tremor, and the ability of antipsychotic drugs to suppress these movements in rats is correlated with motor side-effect liability in humans. OBJECTIVE: The present work was undertaken to study the role of central serotonin receptors in the generation of cholinomimetic-induced jaw movements. RESULTS: Systemic injections of the serotonin antagonist mianserin suppressed tacrine-induced jaw movements, with an ED(50) of 2.77 mg/kg. Local injections of mianserin directly into substantia nigra pars reticulata (SNr) also suppressed tacrine-induced jaw movements. Injections into ventrolateral neostriatum, or a control site dorsal to SNr, failed to have any effects on jaw movement activity. CONCLUSIONS: These studies suggest that atypical antipsychotics may act both on striatal muscarinic receptors and nigral serotonin receptors to suppress jaw movement activity. It is possible that the unique motor properties of atypical antipsychotics result from actions on multiple receptors in several brain areas. The precise serotonin receptor subtype involved in these effects is unknown, and future work will examine the effects of drugs that act selectively on 5-HT(2A) and 5-HT(2C) receptors.

Influence of serotonin receptor antagonists on substance P and serotonin release evoked by tooth pulp stimulation with electro-acupuncture in the trigeminal nucleus cudalis of the rabbit.

We studied the effect of NAN-190 (5-HT(1A) antagonist), ketanserin (5-HT(2) antagonist) and ICS 205-930 (5-HT(3) antagonist) on tooth pulp stimulation (TPS)-induced 5-HT release and substance P (SP) release in the superficial layers of the trigeminal nucleus caudalis (SpVc-I,II) in the presence or absence of electro-acupuncture (EAP). TPS slightly increased 5-HT release and significantly increased SP release. In combination with EAP, TPS-induced 5-HT release was remarkably enhanced, whereas SP release was significantly suppressed. Pretreatment with NAN-190 (3.5 mg/kg, i.v.) significantly enhanced the increase in TPS-induced 5-HT release in the presence of EAP. On the other hand, the increase of 5-HT release induced following TPS in the presence of EAP was inhibited by pretreatment with ketanserin (2.5 mg/kg, i.v.) and ICS 205-930 (1 mg/kg, i.v.). When NAN-190 was pre-treated in the animals combined TPS and EAP, the amount of SP release was significantly reduced compared with the absence of this drug. On the other hand, pretreatment with ketanserin and ICS 205-930 reversed the inhibitory effect of EAP on the TPS-generated SP release, especially ICS 205-930, which remarkably enhanced TPS-induced SP release compared with the absence of this drug. On the basis of the obtained results, we concluded that NAN-190 and ICS 205-930 act on EAP-induced analgesia positively and suppressively, respectively, by regulation of TPS-generated SP release through activation of their subtype receptors. On the other hand, ketanserin does not affect TPS-induced 5-HT release and SP release in the presence of EAP.

Involvement of 5-HT7 receptors in serotonergic effects on spike afterpotentials in presumed jaw-closing motoneurons of rats.

Intracellular recordings were obtained from rat presumed jaw-closing motoneurons in slice preparations to investigate the involvement of the serotonin(7) (5-HT(7)) receptors in serotonergic inhibition of the postspike medium-duration afterhyperpolarization (mAHP) and enhancement of the afterdepolarization (ADP). 5-HT-induced suppression of the mAHP and enhancement of the ADP were mimicked by application of the 5-HT(1A/7) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and antagonized by the 5-HT(2/6/7) receptor antagonist clozapine, whereas the 5-HT(2) receptor agonist alpha-methyl-5-hydroxytryptamine (alpha-methyl-5-HT) did not affect the mAHP and ADP. 8-OH-DPAT-induced attenuation of the mAHP and enhancement of the ADP were also antagonized by clozapine and another 5-HT(2/6/7) receptor antagonist ritanserin, whereas the 5-HT(1A) receptor antagonist pindolol failed to block the 8-OH-DPAT-induced effects on the mAHP and ADP. 8-OH-DPAT-induced suppression of the mAHP and enhancement of the ADP were also antagonized by a protein kinase A (PKA) inhibitor H89, whereas 8-OH-DPAT could inhibit the mAHP and enhance the ADP in the presence of a protein kinase C (PKC) inhibitor chelerythrine. The 8-OH-DPAT-induced suppression of the mAHP was enhanced under raised [Ca(2+)](o) and this enhancement was reduced by chelerythrine. It is suggested that the 5-HT(7) receptors are involved in 5-HT-induced attenuation of the mAHP and enhancement of the ADP through activation of PKA, and the attenuation of mAHP through the 5-HT(7) receptors is enhanced under raised [Ca(2+)](o) by PKC activation.

Effect of 5-HT1A and 5-HT2A/2C receptor modulation on neuroleptic-induced vacuous chewing movements.

Tardive dyskinesia is a serious motor side effect of chronic neuroleptic therapy. Chronic treatment or rats with neuroleptics leads to the development of abnormal oral movements called vacuous chewing movements. Vacuous chewing movements in rats are widely accepted as an animal model of tardive dyskinesia. Atypical antipsychotics such as clozapine and rispiridone are associated with a lower incidence of extrapyramidal side effects and tardive dyskinesia. The present study was aimed to explore the role of 5-HT1A, 5-HT2A/2C receptors in the expression of neuroleptic-induced orofacial dyskinesia. In the present study rats were chronically (for 21 days) treated with haloperidol (1.5 mg/kg, i.p.) to elicit vacuous chewing movements. The neuroleptic-induced vacuous chewing movements, viz., vertical jaw movements, tongue protrusions and bursts of jaw tremors, were counted during a 5-min observation period. Acute treatment with 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a 5-HT1A receptor agonist, dose-dependently (0.05, 0.1 and 0.2 mg/kg, i.p.) reduced the haloperidol-induced vacuous chewing movements and headshakes. Both acute and chronic administration of seganserin, ketanserin and ritanserin, 5-HT2A/2C receptor antagonists, also reduced haloperidol-induced vacuous chewing movements in a dose-dependent (0.05, 0.1 and 0.2 mg/kg, i.p.) manner. In acute studies a higher dose of ritanserin (1 mg/kg) but not ketanserin (1 mg/kg) increased vacuous chewing movements, whereas a higher dose of seganserin (1 mg/kg) did not have any effect on vacuous chewing movements. All the drugs reduced haloperidol-induced headshakes in a dose-dependent fashion. These findings indicate that the serotonergic system, and particularly 5-HT1A and 5-HT2A/2C receptors, may be involved in haloperidol-induced orofacial dyskinesia, and that 5-HT receptors may provide novel targets for the development of drugs that can be used to reverse or prevent the extrapyramidal side effects associated with long-term antipsychotic treatment.

A regulatory role in mammalian salivary glands for 5-hydroxytryptamine receptors coupled to increased cyclic AMP production.

Although a functional role for serotonin (5-hydroxytryptamine, 5-HT) has been defined in the salivary glands of some lower species, relatively few data supporting a role for 5-HT in the regulation of mammalian salivary glands have been presented. Our initial results from polymerase chain reaction studies in cells of mammalian submandibular gland origin using consensus sequence primers from G protein-coupled receptors suggested the presence of mRNA for a 5-HT receptor in these cells. Based on this observation, the question of a role for 5-HT in mammalian submandibular gland function was re-addressed, using isolated, perfused rat submandibular glands and dispersed-cell aggregates from this gland. In perfused glands, 5-HT decreased the rate of saliva flow initiated by acetylcholine by about 50% and increased the amount of protein in the saliva two-fold. In dispersed-cell aggregates, 5-HT elicited a concentration-dependent increase in the accumulation of adenosine 3',5' monophosphate (cyclic AMP; EC50 = 660 +/- 110 nM). In addition, functional studies, as well as radioligand binding experiments, indicated that the effects of 5-HT are independent of beta-adrenoceptors. Accumulation of cAMP in gland cells was consistent with a direct action of 5-HT on adenylyl cyclase. Similar cyclic AMP responses to 5-HT were observed in cells isolated from mouse and opossum submandibular glands and rat sublingual and parotid glands. Our findings suggest the presence of a 5-HT receptor in mammalian salivary glands coupled to the stimulation of adenylyl cyclase and, at least in rat submandibular gland, involved in modifying the volume and protein content of saliva.

Effects of trazodone and m-chlorophenylpiperazine (m-CPP) on acute dependence in mice.

The antidepressant trazodone and its main metabolite, m-CPP, having an antiserotoninergic and serotoninergic activity respectively, were studied in an acute dependence model in mice, to establish whether 5-hydroxytryptaminergic systems are involved in the manifestations of acute opiate dependence and in its development. When drugs were administered 15 min before naloxone, all signs of abstinence decreased, with the exception of teeth chattering that was increased by m-CPP and unaffected by trazodone. When injected 15 min before morphine, jump episodes were decreased by the highest doses of both drugs, while teeth chattering was decreased by m-CPP only. When administered 1 h before morphine, trazodone increased paw and head shakes and mCPP decreased teeth chattering and both left the other signs unaffected. Serotoninergic systems seem to have a significant role in events involved in the withdrawal syndrome and a minor one in those leading to the development of dependence.

Neuromodulatory role of serotonin in the anticonvulsant activity of 2-phenylbenzoate of 3-diethylamino-1-propanol.HCl (JAW-669).

The role of serotonin in the mediation of the anticonvulsant activity of JAW-669 was investigated against maximal electric shock (MES)-induced seizures in mice. A dose-dependent protection against seizures was provided by JAW-669 (4, 6 and 8 mg/kg, IP) and the calculated ED50 value was 6.01 mg/kg, IP. Pretreatment of mice with 5-hydroxytryptophan (50 mg/kg, IP) 2 hr before the administration of JAW-669 (6.01 mg/kg, IP) was found to cause a 40% increase in the ability of JAW-669 to provide protection against MES-induced seizures. Similar pretreatment with tryptophan (100 mg/kg, IP, 1 hr) caused a 30% decrease in the anticonvulsant activity of JAW-669. Prior administration of p-chlorophenylalanine (300 mg/kg, IP, 48 hr) and methysergide (10 mg/kg, IP; 0.5 hr) before administration of JAW-699 caused a 66% and 74% decrease, respectively, in the ability of JAW-669 to provide protection against MES-induced seizures. These results suggest a facilitatory role of serotonin in the anticonvulsant activity of JAW-669.

Central 5-HT(3) receptors and water intake in rats.

In the present paper, we studied in rats the effect of third ventricle administration of m-chlorophenylbiguanide hydrochloride (1-(3-chlorophenyl)biguanide (m-CPBG), a selective 5-HT(3) agonist, on water intake induced by three different physiological stimuli: water deprivation, acute salt load and hypovolemia. Central acute m-CPBG injections in the doses of 80 and 160 nmol significantly reduced water intake elicited by an acute salt load. Third ventricle injections of m-CPBG in the dose of 160 nmol significantly inhibited water intake in hypovolemic animals, whereas third ventricle injections of m-CPBG in a higher dose (320 nmol) were necessary to decrease water intake in water-deprived rats. Pretreatment with 1-methyl-N-[8-methyl-8-azabicyclo(3.2.1)-oct-3-yl]-1H-indazole-3-carboxamide (LY-278,584), a selective 5-HT(3) antagonist, abolished the inhibitory effect on water intake seen after central administration of m-CPBG in all groups studied. The central administration of m-CPBG was also able to inhibit water intake induced by pharmacological activation of central cholinergic and angiotensinergic pathways. Third ventricle injections of m-CPBG in the highest dose employed in this study (320 nmol) were unable to modify food intake in food-deprived rats. An aversion test has shown that acute third ventricle injections of m-CPBG do not induce illness-like effects that could explain the water intake inhibition here observed. Also, central administration of m-CPBG did not modify the intake of a "dessert" meal consisting of diluted condensed milk. It is concluded that central 5-HT(3) receptor activation exerts a specific inhibitory effect on water intake.

The effects of the novel anxiolytic drug lesopitron, a full and selective 5-HT1A receptor agonist, on pupil diameter and oral temperature in man: comparison with buspirone.

We investigated the effects of two 5-HT1A receptor agonists, buspirone and lesopitron, upon pupil size in human volunteers at an ambient luminance level of 32 Cd m(-2) and in darkness. Pupil diameter was monitored with a binocular infrared television pupillometer, before and after the administration of treatments for 4 h at 20-min intervals. Two experiments were conducted. In Experiment 1, 14 healthy male volunteers participated in seven weekly sessions, each associated with the ingestion of one capsule (buspirone 5, 10 and 20 mg, lesopitron 10, 20 and 40 mg and placebo), according to a double-blind balanced, cross-over design. Both buspirone and lesopitron tended to decrease pupil diameter. In darkness, only the highest dose of buspirone (20 mg) caused a miosis that was statistically significant. However, at the luminance level of 32 Cd m(-2) buspirone 10 and 20 mg evoked statistically significant miotic effects, as did the highest dose of lesopitron (40 mg). The miotic effect was significantly greater at 32 Cd m(-2) than in darkness after each dose of buspirone and the highest dose (40 mg) of lesopitron. In Experiment 2, pupil diameter and oral temperature were monitored with an electronic thermometer at 40-min intervals. Twenty healthy male volunteers participated in two weekly sessions, each associated with the sublingual application of 100 microl hydroalcoholic solution (lesopitron 20 mg, placebo), according to a double-blind balanced cross-over design. Lesopitron caused a significant miosis both in darkness and at the luminance level of 32 Cd m(-2); the miosis was greater at 32 Cd m(-2) than in darkness. Lesopitron tended to decrease oral temperature; this effect however, was not statistically significant. The greater effectiveness on the pupil of lesopitron administered sublingually in a solution indicates the importance of first-pass metabolism in reducing the effectiveness of the drug when administered by the mouth. The miosis observed in both experiments may be due to either a sympatholytic or a parasympathomimetic effect of the drugs, or both. The light-dependence of the miosis indicates that the 5-HT1A receptor agonists can modulate the light reflex, possibly via the noradrenergic control of central cholinergic neurones in the Edinger-Westphal nucleus.

Clinical implications of the pharmacology of serotonin reuptake inhibitors.

The selective serotonin reuptake inhibitors (SSRIs) are a tribute to the ingenuity of pharmacologists and designers of molecules. Not only do these drugs have remarkable selectivity for the reuptake of serotonin compared with other monoamines, but also they have a commendable lack of affinity for receptors including the serotonin receptor. In contrast, the classical tricyclic antidepressants (TCAs) are less specific in their pharmacological action. In addition to inhibiting the reuptake of serotonin, TCAs inhibit the uptake of noradrenaline, dopamine and tyramine, and antagonize cholinergic (muscarinic), adrenergic and histaminergic receptors. Moreover, TCAs have quinidine-like anti-arrhythmic activity and lower the seizure threshold. Clinical investigations have shown that the SSRIs have equivalent therapeutic efficacy compared with the TCAs in the treatment of depression. However, the pharmacological specificity of the SSRIs is a clinical advantage since they lack the propensity to cause dry mouth, blurred vision, urinary hesitancy, constipation, hypotension and arrhythmia. Furthermore, the SSRIs are relatively safe in overdosage. The similarities between the SSRIs are more obvious than their differences: all are highly potent and selective inhibitors of serotonin reuptake with efficacy in the treatment of depression. Nevertheless, each has a distinctive pharmacological profile. In this review the characteristics desired in an "ideal" antidepressant are examined, and the ways in which the TCAs and SSRIs fit this ideal are compared.

Behavioral effects of the intraventricular administration of 5-HT and dopamine in the common marmoset (Callithrix jacchus).

The effects of IVT serotonin [5-hydroxytryptamine (5-HT)] and dopamine (DA) administration have been studied in rats and marmosets (Callithrix jacchus). In rats, 5-HT (114 and 170 micrograms/10 microliters) produced the same behavioral effects observed after IP administration of its precursors and agonists. The same doses of 5-HT used for rats produced only part of the behavioral effects in marmosets after IP administration of 5-HT precursors and agonists. Ataxia, vomiting, and decreased motor activity were observed, but not drowsiness or teeth-chattering. However, IVT administration of DA (400 micrograms/10 microliters dose) produced head movements or checking, ataxia, tongue out, and decreased motor activity. These findings differ from those observed after IP administration of l-DOPA and DA agonists, which increase motor activity.

VB20B7, a novel 5-HT-ergic agent with gastrokinetic activity. II. Evaluation of the gastroprokinetic activity in rats and dogs.

The gastrokinetic activity of 2[1-(4-piperonyl)piperazinyl]benzothiazole (VB20B7), a new compound with 5-HT4 receptor agonist and weak 5-HT3 receptor antagonist properties has been studied in rats and dogs. The effects of VB20B7 were investigated in physiological conditions and in a model of gastroparesis induced by the alpha 2-adrenergic agonist UK-14304 and compared with cisapride. In rats, both VB20B7 and cisapride enhanced gastric emptying of indigestible solids (steel spheroids) and liquids (phenol red) at doses of 5-10 mg kg-1 by mouth. Gastric emptying of solid radiopaque markers in fasted beagle dogs was enhanced significantly by VB20B7 (0.25-1 mg kg-1 p.o.) whereas the effect of cisapride (0.5-2 mg kg-1 p.o.) did not reach statistical significance. Similar results were found when the radiopaque markers were given to the dogs following a standard solid meal. The delayed gastric emptying of indigestible solids and radiopaque markers by UK-14304 was reversed by oral administration of VB20B7 in both rats and dogs. Cisapride, however, was only effective in rats. In addition, gastric emptying of a digestible solid/liquid meal was assessed by quantitating the rate of appearance of the radioactive markers in the duodenum of dogs. VB20B7 (0.2-1 mg kg-1, i.v.) enhanced gastric emptying of both solid and liquid phases while cisapride only enhanced emptying of the solid phase. The present study indicates that acute oral and intravenous administration of VB20B7 accelerates gastric emptying of both solids and liquids in different animal models.

[The effect of bromantane on the dopamin- and serotoninergic systems of the rat brain]. / Vliianie bromantana na dofamin- i serotoninergicheskie sistemy mozga krys.

The effect of acute and chronic administration (50 mg/kg, p.o.) of a new immunostimulator, bromantan exhibiting psychostimulant features on the content of NE, DA and 5-HT, and their metabolites are studied. Bromantan induced a significant increase in the 5-HT and 5-HIAA content in the frontal cortex and delayed an increase in their content in subcortical brain regions. A stable decrease in the 5-HT and 5-HIAA levels in the cerebellum is observed. The drug also affected the DA parameters of the brain thus suggesting an important role of dopaminergic system in the mechanism of pharmacological effects of the drug.