Showing papers on "Serotonin published in 1993"

Cloning and expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs.

Abstract: We have used the polymerase chain reaction technique to selectively amplify a guanine nucleotide-binding protein-coupled receptor cDNA sequence from rat striatal mRNA that exhibits high homology to previously cloned serotonin receptors. Sequencing of a full length clone isolated from a rat striatal cDNA library revealed an open reading frame of 1311 base pairs, encoding a 437-residue protein with seven hydrophobic regions. Within these hydrophobic regions, this receptor was found to be 41-36% identical to the following serotonin [5-hydroxytryptamine (5-HT)] receptors: 5-HT2 > 5-HT1D > 5-HT1C > 5-HT1B > 5-HT1A > 5-HT1E. Northern blots revealed a approximately 4.2-kilobase transcript localized in various brain regions, with the following rank order of abundance: striatum >> olfactory tubercle > cerebral cortex > hippocampus. Expression of this clone in COS-7 cells resulted in the appearance of high affinity, saturable binding of (+)-[2-125I] iodolysergic acid diethylamide ([125I]LSD) with a Kd of 1.26 nM. Among endogenous biogenic amines, only 5-HT completely inhibited [125I]LSD binding (Ki = 150 nM). The inhibition of [125I]LSD binding by other serotonergic agonists and antagonists revealed a pharmacological profile that does not correlate with that of any previously described serotonin receptor subtype. In addition, this receptor exhibits high affinity for a number of tricyclic antipsychotic and antidepressant drugs, including clozapine, amoxipine, and amitriptyline. In HEK-293 cells stably transfected with this receptor, serotonin elicits a potent stimulation of adenylyl cyclase activity, which is blocked by antipsychotic and antidepressant drugs. The distinct structural and pharmacological properties of this receptor site indicate that it represents a completely novel subtype of serotonin receptor. Based on its affinity for tricyclic psychotropic drugs and its localization to limbic and cortical regions of the brain, it is likely that this receptor may play a role in several neuropsychiatric disorders that involve serotonergic systems.

Interleukin-1 beta augments release of norepinephrine, dopamine, and serotonin in the rat anterior hypothalamus

Abstract: We investigated the effects of interleukin-1 beta (IL-1 beta), administered directly into the rat anterior hypothalamus (AHY), on monoamine release in the same region by using a brain microdialysis technique and an HPLC-electrochemical detection system. First, to study the local effects of IL-1 beta, we used a microdialysis probe equipped with a microinjection tube for administering IL-1 beta in the same region into which the probe had been inserted. IL-1 beta (1 ng) injected directly into the AHY elicited release of norepinephrine (NE), dopamine (DA), and 5-HT, as well as increases in their metabolites, 4-hydroxy-3-methoxyphenylglycol, 3,4-dihydroxyphenylacetic acid, 4-hydroxy-3-methoxyphenylacetic acid, and 5-hydroxyindole-3-acetic acid, in the AHY. Vehicle alone exerted no effect on monoamine release. Although the elevated levels of NE and DA persisted for more than 6 hr after injection of IL-1 beta, the elevated levels of 5-HT were transient. Second, in order to investigate whether this effect of IL-1 beta is a direct action in the AHY, we performed in vitro experiments using hypothalamus slices. IL-1 beta (0.1 and 1 nM) increased the levels of each monoamine released from hypothalamic slices in a dose-dependent manner. These findings suggest that IL-1 beta acts directly on the hypothalamus to induce release of NE, DA, and 5-HT. Third, the roles of prostaglandins (PGs) in NE release in the AHY elicited by direct injection of IL-1 beta were examined.(ABSTRACT TRUNCATED AT 250 WORDS)

Serotonin-deficient mutants and male mating behavior in the nematode Caenorhabditis elegans

Abstract: Defining a behavior that requires the function of specific neurons in the free-living nematode Caenorhabditis elegans can allow one to screen for mutations that disrupt the specification or function of those neurons. We identified serotonin-immunoreactive neurons required for tail curling or “turning” behavior exhibited by C. elegans males during mating. Males mutant in three different genes that reduce serotonin expression, cat-1, cat-4, and bas-1, exhibited defects in turning behavior similar to those of wild-type males in which these neurons were ablated. The turning defect of cat-4 males was rescued by exogenous serotonin, consistent with the idea that their behavioral defect is caused by a lack of serotonin. While the serotonin-deficient mutants we analyzed shared certain behavioral traits, they were blocked for serotonin synthesis at different steps. Analysis of these and additional serotonin-deficient mutants may help us understand how a neuron controls the expression of a serotonergic phenotype.

Serotonin-facilitated dopamine release in vivo: pharmacological characterization.

Abstract: The receptor specificity of serotonin (5-HT) agonist-induced facilitation of dopamine (DA) release was assessed by using in vivo microdialysis. The 5-HT receptor selective agonists RU 24969 [5-methoxy-3(1,2,3,6-tetrahydro-4-pyridinyl)-1H indole succinate], 2-methylserotonin maleate, 5-methoxytryptamine HCl, 8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl were perfused through probes located in the anterior lateral striata of chloral hydrate-anesthetized rats. The agonists increased extraneuronal levels of DA in a dose-dependent manner, suggesting receptor selectivity in the order of 5-HT1b > 5-HT4 >> 5-HT2 = 5-HT1a. Coperfusion of the 5-HT1 antagonist pindolol with RU 24969 reduced the efficacy of RU 24969. The 5-HT2 antagonist ritanserin (6-[2-[4[bis(4-fluorophenyl)methylene]-1-piperadinyl]- ethyl]-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one) did not antagonize the effect of either 5-HT or 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl on DA levels. MDL 72222 (3-tropanyl-3,5-dichlorobenzoate) and ICS 205930 (3-tropanyl-indole-3-carboxylate), both 5-HT3 antagonists, decreased the efficacy of 5-HT. The partial 5-HT4 antagonist ICS 205930 reduced DA released by perfusion of the 5-HT1/2/4 agonist 5-methoxytryptamine HCl. Coperfusion of antagonists with agonists indicated involvement of 5-HT1 and 5-HT3 receptors and a lack of involvement of 5-HT2 receptors in the 5-HT-induced facilitation of DA release. Determination of the role of 5-HT4 receptors will require additional work with more selective ligands.(ABSTRACT TRUNCATED AT 250 WORDS)

Serotonin 5‐HT1A Autoreceptor Blockade Potentiates the Ability of the 5‐HT Reuptake Inhibitor Citalopram to Increase Nerve Terminal Output of 5‐HT In Vivo: A Microdialysis Study

Abstract: The present study addressed the possibility that disinhibition of serotonin (5-HT) autoreceptor-mediated negative feedback might potentiate the elevation of nerve terminal 5-HT output induced by selective 5-HT reuptake blockade. To this end, rats were given citalopram and the 5-HT autoreceptor-blocking agents (S)-UH-301 (5-HT1A) and (-)-penbutolol (5-HT1A/1B), and the effect on extracellular 5-HT in the ventral hippocampus was monitored by means of in vivo microdialysis. Citalopram (5 mg/kg, s.c.) approximately doubled the 5-HT output, a response that was markedly augmented by (S)-UH-301 (3 mg/kg, s.c.) and (-)-penbutolol (8 mg/kg, s.c.) and by combined treatment with (S)-UH-301 (3 mg/kg, s.c.) plus (-)-penbutolol (1 microM; via the dialysis perfusion medium), but not by (-)-penbutolol (1 microM) alone. These findings provide evidence that 5-HT, in particular 5-HT1A, autoreceptor-mediated negative feedback mechanisms are pivotal in determining the nerve terminal 5-HT output level after 5-HT reuptake inhibition. These findings have important implications for the interplay between different processes controlling 5-HT transmission in vivo and might possibly offer a lead toward novel, therapeutically exploitable principles.

Selective Abnormalities of Prefrontal Serotonergic Receptors in Schizophrenia: A Postmortem Study

Abstract: Background: This study investigates serotonergic receptors in prefrontal cortex of patients with schizophrenia. Methods: We measured serotonin 2 receptors and serotonin uptake sites in prefrontal and occipital cortex of schizophrenics, patients with chronic schizoaffective disorders, nonpsychotic suicides, and controls. Diagnoses were established according to DSM-III-R criteria from medical chart reviews. Results: In prefrontal cortex, serotonin 2 density was decreased in chronic psychotics dying of natural causes, as opposed to psychotics dying of suicide, controls, and nonpsychotic suicide victims. Serotonin uptake sites were decreased in prefrontal cortex of schizophrenics and nonpsychotic suicides, but not in patients with schizoaffective disorder. None of the observed differences were clearly related to antemortem pharmacological treatments. In the occipital pole, no differences were found among the groups. Conclusions: Selective prefrontal alterations of both presynaptic and postsynaptic serotonin receptor densities are present in at least some schizophrenic patients.

On serotonin and migraine: a clinical and pharmacological review

Abstract: Migraine patients have chronically low systemic 5-HT, predisposing them to develop migrainous headache once an attack has been initiated. Changes in platelet 5-HT content are not causally related, but reflect similar changes at a neuronal level. Stimulation of vascular 5-HT1 receptors, probably located in the vessel wall within the dural vascular bed, may alleviate the headache and associated symptoms, but does not interact with earlier mechanisms within the pathophysiological cascade. These receptors are of an as yet unidentified 5-HT1 subtype, closely resembling, but not identical to 5-HT1D receptors. Activation of these receptors results in vasoconstriction, inhibiting depolarization of sensory perivascular afferents within the trigemino-vascular system and thus stopping the headache. Additional inhibition of the release of vasoactive neuropeptides may be involved, but seems to be of only secondary clinical importance.

Neurobiological Mechanisms Involved in Antidepressant Therapies

Abstract: Selective serotonin reuptake inhibitors (SSRIs) are effective in alleviating the symptoms of depression. However, clinical improvement is only obtained after several weeks of treatment. SSRIs, when administered acutely to animals, have little effect on synaptic levels of serotonin. This suggests the existence of one or more regulatory mechanisms controlling serotonergic neurotransmission. The firing rate of dorsal raphe serotonergic neurons is under the control of somatodendritic 5-hydroxytryptamine 1A (5-HT1A) autoreceptors, the release of serotonin from nerve terminals is under the control of 5-HT autoreceptors (5-HT1B subtype in rodents, 5-HT1D in other species), whereas the control of the activity of tryptophan hydroxylase, the rate-limiting enzyme of serotonin synthesis, is complex, involving 5-HT1A but possibly other 5-HT receptors including the 5-HT1B/D subtype. During prolonged administration with a SSRI, these three feedback systems become desensitized and their regulatory effects on serotonergic neurotransmission are weakened or lost. This has the effect of allowing the synaptic levels of serotonin to rise with a consequently increased stimulation of one or more types of postsynaptic 5-HT receptor. Thus, it is only after prolonged administration that the pharmacological activity of SSRI is fully expressed in terms of synaptic serotonin levels. This may explain the latency of antidepressant action seen with these drugs in humans. Various other classes of antidepressant therapies (tricyclic antidepressants and monoamine oxidase inhibitor drugs, electroconvulsive therapy) have long-term effects on one or more of the feedback mechanisms such that an increase in synaptic concentrations of serotonin may be a common mechanism of many antidepressant therapies.

Nitric oxide increases dopamine and serotonin release in the medial preoptic area.

Abstract: Nitric oxide (NO) is becoming recognized as an important intercellular messenger in the brain The present experiment used microdialysis to examine the potential role of NO in the regulation of dopamine (DA) and serotonin (5-HT) release in the medial preoptic area (MPOA) of freely moving male rats The NO precursor L-arginine (L-Arg, 100 microM), administered into the MPOA via the dialysis probe, increased extracellular levels of DA, 5-HT, and the major metabolites of DA These increases were blocked by the coadministration of the NO synthase inhibitor N-monomethyl L-arginine (NMMA, 400 microM) The inactive isomer D-arginine (100 microM) was ineffective, and NMMA by itself decreased DA below baseline levels Thus, NO may modulate the release of DA and 5-HT in the MPOA

Two members of a distinct subfamily of 5-hydroxytryptamine receptors differentially expressed in rat brain.

Abstract: We report two serotonin (5-hydroxytryptamine, 5-HT) receptors, MR22 and REC17, that belong to the G-protein-associated receptor superfamily. MR22 and REC17 are 371 and 357 amino acids long, respectively, as deduced from nucleotide sequence and share 68% mutual amino acid identity and 30-35% identity with known catecholamine and 5-HT receptors. Saturable binding of 125I-labeled (+)-lysergic acid diethylamide to transiently expressed MR22 in COS-M6 cells was inhibited by ergotamine > methiothepin > 5-carboxamidotryptamine > 5-HT. For REC17, the rank of potency was ergotamine > 5-carboxamidotryptamine > methiothepin > methysergide > 5-HT. Both were insensitive to 5-HT1A, 5-HT1D or 5-HT2 serotonergic ligands [8-hydroxy-2-(di-n-propylamino)tetralin, sumatriptan, and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane]. The mRNAs encoding MR22 were detected in the CA1 region of hippocampus, the medial habenula, and raphe nuclei. In contrast, mRNAs encoding REC17 were found throughout the rat central nervous system. We propose that REC17 and MR22, designated as 5-HT5 alpha and 5-HT5 beta, represent a distinct subfamily of 5-HT receptors.

Regulation of serotonin synthesis.

Abstract: This review covers the regulation of serotonin synthesis in serotonergic neurons of the central nervous system over the short term, that is minutes to hours, as opposed to days or weeks. Its purpose is to outline regulatory mechanisms that permit acute adjustments to be made in the synthesis of this transmitter in response to short term changes in physiological demand, and where possible to illustrate the functional significance of such adaptive responses. The reader is referred to earlier reviews on serotonin synthesis (Hamon et al., 1979b, 1981a,b; Boadle-Biber, 1982a; Fernstrom, 1983, 1991; Korf, 1985; Leathwood, 1987).

Use and Abuse of Appetite-Suppressant Drugs in the Treatment of Obesity

Abstract: Most of the available appetite-suppressant drugs act on noradrenergic and possibly dopaminergic receptors to produce satiety. A smaller number increase excess neuronal serotonin levels by blocking ...

Monoamines and the mechanism of antidepressant action: effects of catecholamine depletion on mood of patients treated with antidepressants.

Abstract: Brain catecholamines can be rapidly reduced by inhibiting their synthesis with alpha-methyl-para-tyrosine (AMPT). In order to assess the role of catecholamines in antidepressant action AMPT challenges were administered in a double-blind, placebo-controlled, crossover fashion to 14 depressed patients having maintained a therapeutic antidepressant response for > or = 2 weeks (3 desipramine, 2 mazindol, 5 fluoxetine, 4 sertraline). Each patient participated in two challenges one week apart. Each challenge included a baseline, two days of either AMPT or diphenhydramine (active placebo), and a followup. Antidepressant drugs were continued throughout testing. The 3 desipramine- and 2 mazindol-responders had a rapid increase in depression score during AMPT but not placebo (diphenhydramine) challenge whereas only 1 of 9 selective serotonin reuptake inhibitor (SSRI)-treated patients did. The implication of this is that the antidepressant response to desipramine may be more acutely dependent on brain catecholamine content than the response to SSRIs. In the context of our previous work with tryptophan depletion, these results suggest that the neurobiological mechanisms underlying the antidepressant responses to different drugs involve alterations in the functioning of different neurotransmitter systems and reinforce the importance of changes in both the serotonin and catecholamine systems for successful antidepressant responses.

Acute uptake inhibition increases extracellular serotonin in the rat forebrain.

Abstract: The effect of acute uptake inhibition on serotonin (5-HT) in the rat central nervous system was monitored by using in vivo dialysis. Peripheral administration of the selective 5-HT uptake blocker, fluoxetine, caused a dose-dependent increase in extracellular 5-HT in both the diencephalon and the striatum. Administration of fluoxetine or sertraline, another selective 5-HT uptake inhibitor, caused a prolonged (24 hr) increase in 5-HT and decrease in 5-hydroxyindoleacetic acid. In addition, fluoxetine and sertraline attenuated the 5-HT releasing effect of fenfluramine administered 24 hr later. Local infusion of fluoxetine into the diencephalon caused an increase in 5-HT that was twice as large as the effect of peripheral injection. Peripheral fluoxetine, by enhancing extracellular 5-HT in the raphe, probably resulted in activation of somatodendritic autoreceptors and inhibition of 5-HT neuronal discharge. Thus, the increase in 5-HT in the diencephalon after peripheral fluoxetine presumably reflected a balance between decreased release and inhibition of reuptake. In support of this, after first infusing fluoxetine into the diencephalon to maximally block reuptake, peripheral injection of the uptake inhibitor caused a decrease in 5-HT.

Chronic caffeine alters the density of adenosine, adrenergic, cholinergic, GABA, and serotonin receptors and calcium channels in mouse brain

Abstract: 1. Chronic ingestion of caffeine by male NIH strain mice alters the density of a variety of central receptors. 2. The density of cortical A1 adenosine receptors is increased by 20%, while the density of striatal A2A adenosine receptors is unaltered. 3. The densities of corticalβ1 and cerebellarβ2 adrenergic receptors are reduced byca. 25%, while the densities of corticalα1 andα2 adrenergic receptors are not significantly altered. Densities of striatal D1 and D2 dopaminergic receptors are unaltered. The densities of cortical 5 HT1 and 5 HT2 serotonergic receptors are increased by 26–30%. Densities of cortical muscarinic and nicotinic receptors are increased by 40–50%. The density of cortical benzodiazepine-binding sites associated with GABAA receptors is increased by 65%, and the affinity appears slightly decreased. The density of cortical MK-801 sites associated with NMDA-glutaminergic receptors appear unaltered. 4. The density of cortical nitrendipine-binding sites associated with calcium channels is increased by 18%. 5. The results indicate that chronic ingestion of caffeine equivalent to about 100 mg/kg/day in mice causes a wide range of biochemical alterations in the central nervous system.

Expression of mRNA for the serotonin 5-hydroxytryptamine1D beta receptor subtype in human and bovine cerebral arteries.

Abstract: Serotonin [5-hydroxytryptamine (5-HT)] has been implicated in the pathophysiology of migraine, and the clinical efficacy of the 5-HT1B/5-HT1D receptor agonist sumatriptan points to neural and/or vascular 5-HT1D receptors as relevant targets in migraine therapy. We characterized the human and/or bovine 5-HT1D receptor subtype in cerebral blood vessels pharmacologically by correlation analysis and molecularly by Northern blot hybridization of cerebrovascular RNA extracts. Pharmacological analysis showed that sumatriptan was less potent than 5-HT in inducing contraction in freshly isolated human cerebral arteries and revealed an overall pharmacological profile positively and significantly correlated with that published for the 5-HT1D alpha (r = 0.746, p = 0.021) and 5-HT1D beta (r = 0.942, p = 0.0001) cloned human receptor subtypes. These results are suggestive of a contractile 5-HT1D beta receptor subtype but are not conclusive. However, Northern blots revealed the presence of mRNA transcripts for the 5-HT1D beta subtype, but not the 5-HT1D alpha subtype, in bovine (approximately 2.2 kilobases) and human (approximately 4.5 kilobases) cerebral blood vessels. Expression of either subtype could not be detected in intraparenchymal microvessels or capillaries isolated from bovine or human cerebral cortex. These results clearly indicate that the beneficial effect of sumatriptan in migraine attack, if vascularly related, is mediated by contractile 5-HT1D beta receptors most likely located on cerebral blood vessels at the surface of the brain. This study points to the 5-HT1D beta receptor subtype as the putative cerebrovascular target for migraine therapeutic agents.

In vivo brain dialysis study of the somatodendritic release of serotonin in the Raphe nuclei of the rat: effects of 8-hydroxy-2-(di-n-propylamino)tetralin.

Abstract: The characteristics of the serotonin (5-HT) output in the dorsal and median raphe nuclei of the rat were studies using in vivo microdialysis. The basal output of 5-HT increased after KCl was added to the perfusion fluid. In contrast, neither the omission of calcium ions nor the addition of 0.5 microM tetrodotoxin affected dialysate 5-HT or 5-hydroxyindoleacetic acid (5-HIAA). Reserpine did not decrease the output of 5-HT and 5-HIAA 24 h later and p-chloroamphetamine increased 5-HT in both vehicle- and reserpine-treated rats severalfold. 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), at 1 or 10 microM, perfused into the raphe did not change the outputs of 5-HT or 5-HIAA. Higher doses (0.1, 1, and 10 mM) increased extracellular 5-HT in the raphe, probably via an inhibition of uptake. In animals bearing two probes (raphe nuclei and ventral hippocampus), only the 10 mM dose of 8-OH-DPAT perfused into the raphe decreased the hippocampal output of 5-HT and 5-HIAA. The systemic injection of 0.1 mg/kg 8-OH-DPAT decreased dialysate 5-HT and 5-HIAA in the raphe and hippocampus. These results suggest that extracellular 5-HT in raphe nuclei originates from a cytoplasmic pool and is not dependent on either nerve impulse of 5-HT neurons or local activation of 5-HT1A receptors.

Activation of transcription factor genes in striatum by cocaine: role of both serotonin and dopamine systems.

Abstract: Acute administration of cocaine increases expression of the transcription factor genes c-fos and zif268 in the striatum. This response is thought to be mediated via D1 dopamine (DA) receptors, as it is blocked by the selective D1 receptor antagonist SCH 23390. However, the directly acting D1 receptor agonists, apomorphine and SKF 38393, do not mimic cocaine's activation of these genes raising the possibility that D1 receptor activation is necessary, but not sufficient, to trigger transcription factor expression. Because cocaine blocks uptake of norepinephrine (NE) and serotonin (5-HT), as well as DA, we examined whether cocaine's ability to inhibit NE and 5-HT uptake may contribute to its induction of c-fos and zif268 expression in striatum. In examining the effects of selective monoamine uptake inhibitors, we observed that fluoxetine or citalopram, selective inhibitors of 5-HT uptake, potentiated the ability of mazindol, a DA and NE uptake inhibitor, to induce zif268 and c-fos expression, even though these 5-HT uptake inhibitors had no effect when administered alone. In contrast, the selective NE uptake inhibitor, desipramine, administered alone, or in combination with fluoxetine, did not increase expression of zif268 or c-fos. Furthermore, selective denervation of 5-HT projections by p-chloroamphetamine treatment attenuated the increase in zif268 and c-fos expression induced by cocaine in the striatum. In contrast, selective lesions of NE projections with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride failed to block cocaine's activation of these genes in the striatum. Taken together, these findings indicate that cocaine's ability to induce striatal expression of c-fos and zif268 is mediated by its effects on both the 5-HT and DA systems.