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PubMed1995

Ziprasidone (CP-88,059): a new antipsychotic with combined dopamine and serotonin receptor antagonist activity.

Ziprasidone (CP-88,059) is a combined 5-HT (serotonin) and dopamine receptor antagonist which exhibits potent effects in preclinical assays predictive of antipsychotic activity. Whereas the compound is a dopamine antagonist in vitro and in vivo, its most potent action is antagonism of 5-HT2A receptors, where its affinity is an order of magnitude greater than that observed for dopamine D2 sites. Laboratory and clinical findings have led to a hypothesis that antagonism of 5-HT2A receptors in the brain limits the undesirable motor side effects associated with dopamine receptor blockade and improves efficacy against the negative symptoms of schizophrenia. Ziprasidone possesses an in vitro 5-HT2A/dopamine D2 receptor affinity ratio higher than any clinically available antipsychotic agent. In vivo, ziprasidone antagonizes 5-HT2A receptor-induced head twitch with 6-fold higher potency than for blockade of d-amphetamine-induced hyperactivity, a measure of central dopamine D2 receptor antagonism. Ziprasidone also has high affinity for the 5-HT1A, 5-HT1D and 5-HT2C receptor subtypes, which may further enhance its therapeutic potential. The prediction of antipsychotic efficacy without severe motor side effects is supported by the relatively weak potency of ziprasidone to produce catalepsy in animals, contrasted with its potent antagonism of conditioned avoidance responding and dopamine agonist-induced locomotor activation and stereotypy. The compound is well tolerated in animals at doses producing effective dopamine antagonism in the brain. Ziprasidone should be a valuable addition to the treatment of psychotic disorders.

Adenylyl Cyclases↗

PubMed1995

Temporal differential adaptation of head-twitch and ear-scratch responses following administration of challenge doses of DOI.

Previously, we reported that administration of the 5-HT2A/C receptor agonist, DOI [(+/-)-1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane], can simultaneously produce the head-twitch response (HTR) and the ear-scratch response (ESR) in mice. Our recent studies have indicated that the HTR is a 5-HT2A receptor-mediated phenomenon, whereas the ESR is probably a 5-HT2C receptor-mediated event. The HTR and ESR exhibit subsensitivity to a challenge dose of DOI (2.5 mg/kg) administered 24 h after its acute or termination of its chronic (2.5 mg/kg, once daily for 13 days) administration. When the dose interval for the challenge dose of DOI was increased to 48 h, both the acute- and chronically treated mice exhibited a simultaneous supersensitive HTR response and a subsensitive ESR effect. The purpose of the present study was to investigate the dose-response effects of lower challenge doses of DOI 48 h following their respective first injections as well as determining the effects of repeated DOI injections at 2-h intervals for 8 h. Thus, in the present study, initial administration of DOI produced a dose- and time-dependent increase in the mean frequencies of both HTR and ESR. Significant HTRs were observed after administration of the lowest tested dose of DOI (0.25 mg/kg), whereas a robust frequency of ESR was only evident at 1 mg/kg or greater doses of DOI. A 48-h challenge administration of lower doses of DOI (0.25 and 0.5 mg/kg) did not significantly affect their respective first injection HTR scores.(ABSTRACT TRUNCATED AT 250 WORDS)

Adaptation, Physiological↗

PubMed1995

The role of the 5-HT2A and 5-HT2C receptors in the stimulus effects of m-chlorophenylpiperazine.

m-Chlorophenylpiperazine (mCPP), a major metabolite of the atypical antidepressant trazadone, has been observed to produce marked physiological and behavioral effects in both humans and animals. These effects have been attributed to the interaction of mCPP with serotonergic receptors. The present study was designed to characterize those interactions of mCPP with central serotonergic receptors which mediate mCPP-induced stimulus control. A series of serotonergic antagonists (mesulergine, pizotyline, ketanserin, spiperone, risperidone, ritanserin, metergoline, pirenpirone, and LY53857) was tested for the ability to block the mCPP stimulus. The affinity of these antagonists for 5-HT2A and 5-HT2C receptors was then correlated with maximal percent inhibition of the mCPP stimulus. Kd at the 5-HT2C receptor was inversely proportional (r = -0.75, P < 0.05), and Kd at the 5-HT2A receptor directly proportional (r = +0.67, P < 0.05) to the maximal percent inhibition of the mCPP stimulus. The 5-HT2C selectivity ratio [Kd(5-HT2A)/Kd(5-HT2C)] of the antagonists was directly proportional (r = +0.86, P < 0.01) to maximal percent inhibition of the mCPP stimulus. A multiple regressions analysis indicated that 81% of the variance in the ability of a given antagonist to block the mCPP stimulus could be predicted on the basis of its affinity for 5-HT2A and 5-HT2C receptors. It is concluded that the stimulus effects of mCPP are mediated predominantly by a combination of agonist activity at 5-HT2C receptors and antagonist activity at 5-HT2A receptors.

Animals↗

PubMed1995

Effect of pindolol pretreatment on MK-212-induced plasma cortisol and prolactin responses in normal men.

Previous reports based on studies with serotonin (5-HT) precursors or direct acting agonists have suggested that postsynaptic 5-HT1A and 5-HT2A/5-HT2C receptors may stimulate cortisol and prolactin (PRL) secretion in man. To further clarify the role of these receptors in the regulation of cortisol and PRL secretion in man, the effects of 6-chloro-2-(1-piperazinyl) pirazine (MK-212), a centrally acting direct 5-HT2A/5-HT2C agonist, on the above hormones were studied in 11 normal men with and without pretreatment with pindolol, a 5-HT1A partial agonist. MK-212 induced a significant increase in plasma concentrations of cortisol and PRL. The MK-212-induced response in plasma cortisol was not diminished by pindolol pretreatment, whereas the MK-212-induced PRL response was significantly inhibited by pindolol pretreatment. These data suggest that the MK-212-induced cortisol response may be mediated by 5-HT2A or 5-HT2C receptor activation, or both, despite 5-HT1A inhibition; however, PRL secretion by MK-212 requires 5-HT1A receptor availability as well as 5-HT2A/5-HT2C receptor activation, since blockade of the former appears to blunt the PRL responses to MK-212. These findings may be explained by postulating a cooperativity between 5-HT1A and 5-HT2A/5-HT2C receptors with regard to the 5-HT-dependent stimulation of PRL secretion.

Adrenergic beta-Antagonists↗

PubMed1994

Blockade of the discriminative stimulus effects of DOI by MDL 100,907 and the 'atypical' antipsychotics, clozapine and risperidone.

In a drug discrimination paradigm, the 5-HT2A/2C receptor antagonists, ritanserin, ICI 169,369 (2-(2-dimethylaminoethylthio-3-phenylquinoline hydrochloride) and mianserin, and the preferential 5-HT2A receptor antagonist, ketanserin, antagonised the discriminative stimulus effects of the 5-HT2A/2C receptor agonist, DOI ((2,5-dimethoxy-4-iodohenyl)-2-aminopropan) (0.63 mg/kg i.p.). Effective dose50 (ED50) values were: 0.32, 0.39, 0.15 and 0.03 mg/kg s.c., respectively. While the novel, selective 5-HT2C receptor antagonist, SB 200,646 (N-(1-methyl-5-iodolyl)-N'-(3-pyridyl) urea hydrochloride) was inactive (10 mg/kg s.c. and 20 mg/kg p.o.), the highly selective 5-HT2A receptor antagonist, MDL 100,907 (R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl]-4- piperidine-methanol) very potently (ED50 = 0.0006) abolished the action of DOI. MDL 100,907 may display antipsychotic properties and the 'atypical' antipsychotics, clozapine, risperidone and sertindole, each of which possesses marked affinity at 5-HT2A receptors, abolished the discriminative stimulus effects of DOI (ED50 values of 0.07, 0.03 and 0.33 mg/kg, respectively). In contrast, haloperidol (0.16) was ineffective. These data demonstrate that 5-HT2A receptors mediate the discriminative stimulus effects of DOI and support the hypothesis that an antagonistic action at 5-HT2A receptors contributes to the in vivo actions of 'atypical' antipsychotics.

Amphetamines↗

PubMed1992

New mouse 5-HT2-like receptor. Expression in brain, heart and intestine.

A novel member of the family of G protein-coupled receptors has been isolated from a mouse brain cDNA library by screening with polymerase chain reaction (PCR) generated fragment of mouse genomic DNA amplified using degenerated primers. Sequence comparison demonstrates that the encoded protein sequence shows the highest homology to the 5-HT2 family of receptors. The pharmacological profile of membranes from COS cells transfected with this cDNA, corresponds to a new 5-HT2-like receptor that we propose to call 5-HT2C. Its major sites of expression are in the mouse intestine and heart, also with detectable expression in brain and kidney. We speculate that it could account at least in part for the 'atypical' functions attributed to the 5-HT1C/5-HT2 receptors.

Amino Acid Sequence↗

PubMed1995

5-Hydroxytryptamine-interacting drugs in animal models of anxiety disorders: more than 30 years of research.

An overview of the behavioral data arising from the vast literature concerning the involvement of 5-hydroxytryptamine (5-HT) neurotransmission in the regulation of anxiety is presented. More than 1300 experiments were carried out in this area and they provide evidence that: (1) results obtained in ethologically based animal models of anxiety with drugs stimulating 5-HT transmission are most consistent with the classic 5-HT hypothesis of anxiety in that they show an increase in animals' emotional reactivity; (2) no category of anti-anxiety models are selectively sensitive to the anxiolytic-like effects of drugs targetting 5-HT1A, 5-HT2A or 5-HT2C receptor subtypes; (3) anxiolytic-like effects of 5-HT3 receptor antagonists, in the great part, are revealed by models based on spontaneous behaviors. Taken together, these observations lead to the conclusion that different 5-HT mechanisms, mediated by different receptor subtypes, are involved in the genesis of anxiety.

Animals↗

PubMed1995

Possible involvement of botulinum ADP-ribosyltransferase sensitive low molecular G-protein on 5-hydroxytryptamine (5-HT)-induced inositol phosphates formation in 5-HT2c cDNA transfected cells.

To clarify the involvement of botulinum ADP-ribosyltransferase sensitive low molecular G-proteins in 5-hydroxytryptamine (5-HT)-induced stimulation of phosphatidylinositol turnover, we examined the effects of 5-HT on inositol phosphates formation in COS 7 cells transfected with 5-HT2c receptor cDNA, but did not in non-transfected or vector-transfected cells. A typical 5-HT2c receptor antagonist mianserin (0.3-3 microM) inhibited the 5-HT-induced inositol phosphates formation. Treatment with botulinum toxin D preparation (20 micrograms/ml, 8 h) that contained botulinum C3 ADP-ribosyltransferase, blocked the 5-HT-induced inositol phosphate formation, although botulinum toxin A preparation that did not contain the enzyme did not have an influence. These results support our previous findings suggesting that low molecular weight G-proteins ADP-ribosylated by botulinum ADP-ribosyltransferase are involved in phospholipase C activity.

ADP Ribose Transferases↗

PubMed1995

Ketanserin analogues: the effect of structural modification on 5-HT2 serotonin receptor binding.

Ketanserin (1) is a fairly selective 5-HT2 antagonist that binds both at 5-HT2A and 5-HT2C receptors. A previous structure-affinity relationship study revealed that the structure of the piperidine-containing ketanserin molecule could be rather severely abbreviated with little effect on 5-HT2A affinity. The present investigation explores several inconsistencies identified in the earlier study and suggests that multiple modes of binding may be possible for ketanserin analogues. Perhaps the nature of the benzylic substituent is the most significant determinant of the manner in which these agents bind at 5-HT2A receptors, and it is possible that certain orientations may avail themselves of an auxiliary binding site. Depending upon the length of the piperidine N-alkyl chain, variation of the benzylic substituent from a carbonyl, to an alcohol, to a methylene group has a nonparallel influence on binding, and this may be further affected by the presence of a second ring nitrogen atom. The results of the present investigation provide evidence that although the structure of ketanserin can be abbreviated, and even modified by conversion of the piperidine ring to a piperazine, the resultant analogues may bind in more than one orientation at the receptors. A key structural feature that may play a prominent role in anchoring or orienting these compounds at 5-HT2A receptors is the benzylic carbonyl group.

Animals↗

PubMed1995

(+/-)-(N-alkylamino)benzazepine analogs: novel dopamine D1 receptor antagonists.

(+/-)-(N-Alkylamino)benzazepine analogs were prepared as novel dopamine D1 receptor antagonists to further elucidate the role of these receptor subtypes in the pharmacology and toxicology of cocaine. In the first series of compounds, (+/-)-7-chloro-8-hydroxy-3- [6-(N,N-dimethylamino)-hexyl]-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepi ne (15) showed the highest affinity (Ki = 49.3 nM) and subtype-selectivity for dopamine D1 over dopamine D2, 5-HT2a, and 5-HT2c receptors. Compounds 7a [(+/-)-7-Chloro-8-hydroxy-3-[4-(N,N-dimethylamino)butyl]-1-phenyl- 2,3,4,5-tetrahydro-1H-3-benzazepine], 11 [(+/-)-7-chloro-8-hydroxy-3-[6-[(N,N-dimethylamino)hexyl]-1- phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-cyanoborane], and 15 were moderately potent dopamine D1 receptor antagonists as evidenced by their ability to block dopamine-stimulated adenylyl cyclase activity in rat caudate (predicted Ki values = 60, 34, and 21 nM, respectively). Compound 7a appears to be unique in that, despite its relatively potent inhibition of dopamine stimulated adenylyl cyclase, it demonstrated relatively weak binding affinity at the dopamine D1 receptors (Ki = 811 nM). Unlike previously reported N-alkylbenzazepines, where a significant loss in dopamine D1 receptor binding affinity was observed when successive increases in the alkyl side chain size at the benzazepine nitrogen were made, several of these novel N-alkylamino analogs demonstrated high-affinity binding with an optimal chain length of six carbons. This initial series of compounds appears to be identifying another binding domain on the dopamine D1 receptor protein that has not previously been characterized and that accepts an amino function. Further, these compounds may serve as templates for the design of peripherally active dopamine D1 receptor antagonists.

Animals↗

PubMed1995

Regulation of 5-HT receptors by corticosteroids: where do we stand?

Twenty five years ago, experimental procedures such as adrenalectomy and corticosteroid administration (to intact rats) allowed the recognition of direct and indirect controls of central 5-HT synthesis rate by corticosteroids. These effects indicated that the activity of the hypothalamo-pituitary-adrenal (HPA) axis, whether under basal conditions or during stress, is endowed with a modulatory action upon serotonergic neurons. Nowadays, in situ hybridisation, in vitro autoradiography, and radioligand binding on the one hand, and electrophysiological, behavioural, and neuroendocrinological responses on the other hand, are tools that allow the analysis of direct corticosteroid effects upon 5-HT receptors. Among the dozen of 5-HT receptors identified so far, four receptors (namely the 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT2C receptors)--and the 5-HT uptake system--have been the focus of studies aimed at detecting corticosteroid modulatory effects. The results that are reviewed herein indicate that hippocampal 5-HT1A receptors are under the tonic inhibitory control of corticosterone. This control is directly exerted at the level of the 5-HT1A receptor gene, essentially through mineralocorticoid receptors; as well, electrophysiological findings bring support for an additional modulation of hippocampal 5-HT1A receptor-mediated functions by indirect (ie 5-HT1A receptor gene-independent) genomic actions of corticosteroids. In keeping with the respective effects of stressful stimuli and psychotropic drugs upon the HPA axis and central serotonergic systems, it is likely that these corticosteroid-5-HT1A receptor interactions in the hippocampus have consequences in the pathophysiology of mood disorders. However, because the data regarding a corticosteroid control of other 5-HT receptors are either scarce and contradictory (eg 5-HT1B, 5-HT2A, 5-HT2C receptors and 5-HT uptake systems) or lacking, it is at the present time unknown whether corticosteroids exert other effects on 5-HT receptor-mediated functions, including those related to homeostasis.

Adrenal Cortex Hormones↗

PubMed1995

RS 39604: a potent, selective and orally active 5-HT4 receptor antagonist.

1. Selective antagonism of 5-HT4 receptors may provide therapeutic benefit in certain disorders of the myocardium, alimentary and lower urinary tract. We now report on RS 39604, a novel and selective 5-HT4 receptor antagonist and compare its pharmacological properties with those of SB 204070. 2. In guinea-pig striatal membranes, both RS 39604 and SB 204070 inhibited specific binding of [3H]-GR 113808 in a concentration-dependent manner yielding pKi estimates of 9.1 and 10.9, respectively. RS 39604 displayed a low affinity (pKi < 6.5) for 5-HT1A, 5-HT2C, 5-HT3, alpha 1c, D1, D2, M1, M2, AT1, B1 and opioid mu receptors and moderate affinity for sigma 1, (pKi = 6.8) and sigma 2 (pKi = 7.8) sites. 3. In the rat isolated oesophagus, precontracted with carbachol, RS 39604 (30-300 nM) behaved as a competitive antagonist towards 5-HT-induced relaxation (pA2 = 9.3; Schild slope = 1.0). We and others have shown previously that SB 204070 behaves as an unsurmountable antagonist in this preparation (pA2 approximately 10.5). In the guinea-pig isolated ileal mucosa, RS 39604 (30 nM) antagonized 5-MeOT-induced increase in short-circuit current (pA2 = 9.1). 4. In anaesthetized vagotomized micropigs, RS 39604, administered by the i.v. or intraduodenal (i.duod.) route, produced dose-dependent inhibition of 5-HT-induced tachycardia (ID50 = 4.7 micrograms kg-1, i.v. and 254.5 micrograms kg-1, i.duod). At maximal doses of 30 micrograms kg-1, i.v. and 6 mg kg-1, i.duod., the inhibitory effects of RS 39604 lasted for more than 6 h. In this preparation, SB 204070 was as potent as RS 39604by the i.v. route but was inactive by the intraduodenal route at doses up to 3 mg kg-1.5. In conscious mice, RS 39604, administered by the i.p. or p.o. route, produced dose-depend entinhibition of 5-hydroxytryptophan (5-HTP)-induced diarrhoea (ID50= 81.3 microg kg-1, i.p. and 1.1 mg kg-1,p.o.). In this assay, SB 204070 was inactive by the oral route at doses up to 30 mg kg-1.6. In anaesthetized guinea-pigs, RS 39604 antagonized the contractile effect of 5-HT in the proximal colon by producing parallel, dextral displacement of the dose-response curve to 5-HT. The mean dose ratios to 5-HT at 0.1 mg kg-1, i.v., 1 mg kg-1, i.v. and 10 mg kg-1, i.duod. were 4.6, 30.7 and 10.8,respectively. SB 204070 behaved as an unsurmountable antagonist in this assay.7. In a model of visceral pain in conscious rats, RS 39604 (0.01-1 mg kg-1, i.v.) did not affect colorectal distension-induced increases in arterial pressure whereas morphine (1 mg kg-1, i.v.) produced significant inhibition of the response, implying that 5-HT4 receptors are not involved in nociception in this model.8. The data suggest that RS 39604 is a high affinity and selective 5-HT4 receptor antagonist that is orally active and long-lasting in vivo. It is concluded that RS 39604 may be the preferable probe to use for investigating the physiological and pathophysiological role of 5-HT4 receptors in vivo.

Administration, Oral↗

PubMed1995

Serotonin-evoked calcium transients in airway smooth muscle cells.

Serotonin (5-HT) is an important mediator of allergic airway narrowing in several animal species. The present study was designed to characterize the receptor subtypes that mediate 5-HT-induced airway responses in the rat. To do this, we measured Ca2+ transients and adenosine 3',5'-cyclic monophosphate (cAMP) production evoked by 5-HT in cultured rat tracheal smooth muscle cells as well as 5-HT-induced contractions of isolated tracheal rings. 5-HT (10(-6) to 10(-4) M) triggered a rapid increase in intracellular Ca2+ concentration ([Ca2+]i) followed by a second phase of sustained, elevated, and sometimes oscillating levels of [Ca2+]i. Sustained but not peak [Ca2+]i levels were dependent on Ca2+ influx but were not attenuated by nifedipine (10(-5) M). Oscillations were observed in cells in Ca2+ -free medium, suggesting Ca2+ -induced Ca2+ release independent of Ca2+ influx. The effects of 5-HT were inhibited by thapsigargin (10(-6) M) and ketanserin (10(-7) M). In cells incubated with LY-278,584 (5-HT3 antagonist) and (-)pindolol (5-HT1 antagonist), 5-HT-evoked responses were not significantly different from the control values. 5-methyltryptamine (5-MT), a ligand with higher affinity for 5-HT2C receptors than "classical" 5-HT2 receptors, elicited higher responses than dipropyl-5-carboxamidotryptamine (DP-5-CT), which possesses lower affinity for 5-HT2C receptors than 5-MT, but an affinity for the classical 5-HT2 receptor similar to 5-MT, but an affinity for the classical 5-HT2 receptor similar to 5-MT.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Neurochemical and behavioral evidence that quipazine-ketanserin discrimination is mediated by serotonin2A receptor.

The purposes of this study were to determine: first, if animals could be trained to discriminate a serotonin (5-HT)2 receptor agonist from a 5-HT2 receptor antagonist; second, which 5-HT2 receptor subtype was mediating the cues; and third, the usefulness of this model for studying adaptive changes in the 5-HT2 receptor system. Rats were trained to discriminate quipazine (0.5 mg/kg) from ketanserin (1.0 mg/kg) on a variable interval-20 schedule of reinforcement. After acquisition, the quipazine and ketanserin dose-response curves were found to be orderly and reproducible. Additional 5-HT2 receptor agonists (2,5-dimethoxy-4-iodoamphetamine and MK 212) and antagonists (pizotifen, mianserin, pirenperone and MDL 100,907) were tested for generalization and found to substitute for the quipazine and ketanserin cues, respectively. In antagonist studies, MDL 100,907 potently blocked quipazine discrimination. Results of ex vivo binding studies designed to estimate occupancy of 5-HT2A and 5-HT2C receptors suggested that the training dose of ketanserin blocked only 5-HT2A receptors and not 5-HT2C receptors. The combined results from the substitution, antagonism and ex vivo receptor autoradiographic studies suggest that the discriminative stimuli of quipazine and ketanserin are mediated at least in part by the 5-HT2A receptor. Additional experiments were designed to study adaptive changes in the 5-HT2A receptor. A single large dose of quipazine produced a rebound ketanserin-like effect at 20 hr after administration; however, a single large dose of ketanserin (10 mg/kg) did not produce a rebound quipazine-like effect.

Animals↗

PubMed1995

5-Hydroxytryptamine-induced synovial plasma extravasation is mediated via 5-hydroxytryptamine2A receptors on sympathetic efferent terminals.

5-Hydroxytryptamine (5-HT) is known to act in peripheral tissues to produce pain and inflammation, yet the mechanisms underlying 5-HT-induced inflammation have not been well studied. The present study uses a rat knee joint model of inflammation (synovial plasma extravasation) and molecular biological techniques to determine the site of action of 5-HT and the specific 5-HT receptor subtype mediating synovial 5-HT-induced plasma extravasation. 5-HT (1 microM) stimulates synovial plasma extravasation 7-fold above base-line levels. Surgical lumbar sympathectomy, but not C-fiber depletion by neonatal capsaicin, dramatically reduces 5-HT-induced synovial plasma extravasation (P < .001), indicating that sympathetic efferents mediate this effect. Polymerase chain reaction amplification of 5-HT receptor cDNA demonstrates that 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A and 5-HT3, but not the 5-HT2C, receptor subtypes are present in lumbar sympathetic ganglia. With selective ligands for these receptor subtypes, we demonstrate that 5-HT-induced synovial plasma extravasation is mediated via the 5-HT2A receptor. These findings suggest a role for 5-HT2A antagonists in various synovial inflammatory pain states.

Animals↗

PubMed1995

Role of serotonin in the action of atypical antipsychotic drugs.

Clozapine is the first of a new generation of antipsychotic drugs which constitutes a major advance in the treatment of schizophrenia. Numerous theories have been proposed to explain the advantages of clozapine over typical neuroleptics. Most of these focus on its effects on dopaminergic and serotonergic neurotransmission. This article reviews the effects of clozapine and related antipsychotic drugs on dopamine (DA) D1, D2, and D4, and serotonin (5-HT) 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 receptors, as well as its ability to modulate DA and 5-HT release. Clozapine and other atypical antipsychotic drugs share the ability to cause fewer extrapyramidal symptoms at clinically effective doses. This may be related to their potent 5-HT2A and weak D2 receptor blocking properties, a profile shared by risperidone, melperone, olanzapine, amperozide, HP-873, seroquel, sertindole, and ziprasidone. The basis for the superior ability of clozapine to treat negative symptoms and enhance cognitive function compared to typical neuroleptic drugs in schizophrenic patients has not yet been ascertained, but there is evidence that its effect on 5-HT2A, D2, or D4 receptors may be important. Other aspects of the pharmacology of clozapine which may contribute to its actions include potent alpha 1-adrenergic, M1, M2, M3, and M5 receptor blocking properties, as well as M4 agonist effects.

Antipsychotic Agents↗

PubMed1995

[5-hydroxytryptamine (serotonin) receptors--nomenclature and classification of types and subtypes].

5-HT receptors represent a superfamily of receptors with the largest known number of receptor subtypes. At present 15 receptor subtypes of three groups has been recognized. The 5-HT1 subfamily of receptors contains subtypes 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F; activation of all of them results in the inhibition of adenylylcyclase. The subfamily of 5-HT2 contains subtypes 5-HT2A, 5-HT2B, and 5-HT2C; their activation leads to the stimulation of PLC. Finally, subfamily of miscellaneous 5-HT receptors contains subtypes 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7; some of them has been cloned, however, our knowledge on their function is still minimal. 5-HT receptors participate in many physiological functions and a disturbance in serotonergic neurotransmission might cause several types of disease. 5-HT plays an important role in depression; to cure this disease, drugs which increase levels of this neurotransmitter are used. A new drug group called Selective Serotonin Reuptake Inhibitors (SSRI) has been recently discovered. These drugs block the reuptake of 5-HT into nerve endings. There is an intensive search for new selective agonists as well as antagonists which could be use not only in the classification of receptor subtypes but which also possess certain therapeutic potential.

Animals↗

PubMedDate not supplied

Interactions of serotonin with multiple receptors and neurotransmitters in the guinea-pig isolated colon.

The motor effects of 5-hydroxytryptamine (5-HT; serotonin) on the guinea-pig isolated proximal colon were studied and analyzed. A classical organ bath setup was used to measure the longitudinal muscle responses isotonically. 5-Hydroxytryptamine induced concentration-dependent contractions which were preceded by relaxations at low concentrations. By means of the neurotoxin, tetrodotoxin, the muscarinic cholinoceptor antagonist, atropine, and selective 5-HT receptor antagonists, it was shown that the contractions to 5-HT are mediated by 5-HT2A receptors, localized on the smooth muscle, and by 5-HT3 and 5-HT4 receptors, localized on cholinergic nerves. The relaxation was abolished by tetrodotoxin and appeared to be mediated by two 5-HT receptor subtypes; the pharmacological profile of the high affinity 5-HT receptor resembled that of 5-HT2C receptors though it displayed also pronounced differences. Subsequently, it was shown that nitric oxide is the mediator released by lower concentrations of 5-HT, while, at higher concentrations, adenosine triphosphate could be involved as an end neurotransmitter as well. No evidence for a peptidergic neurotransmitter, such as vasoactive intestinal polypeptide, was obtained. Results with two 5-HT analogues confirmed the presence of a dual 5-HT receptor system (high and low affinity) regulating each the release of a different neurotransmitter (nitric oxide and adenosine triphosphate, respectively). The above described results stress the important role of 5-HT as a neurotransmitter involved in gastrointestinal motility.

Animals↗