Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the effect of electroconvulsive shock (ECS), administered five times over 10 days, on 5-HT1A and 5-HT2A receptor mRNA and binding site densities in the rat brain using in situ hybridization histochemistry and quantitative autoradiography. ECS treatment increased 5-HT1A receptor mRNA abundance and binding site densities in the dentate gyrus, but decreased these parameters in the CA3c layer of the hippocampus. No changes in 5-HT1A receptor mRNA and binding sites occurred in other hippocampal subfields, neocortex or raphe nuclei. Repeated ECS was also found to increase 5-HT2A receptor binding site densities in the neocortex and this was accompanied by a non-significant increase in cortical 5-HT2A receptor mRNA abundance. Our study demonstrates that in the rat, repeated ECS produces anatomically and molecularly discrete effects on 5-HT1A and 5-HT2A receptor gene expression. These changes may be relevant to the therapeutic effect of repeated ECS in depression.
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PMID:Repeated ECS differentially affects rat brain 5-HT1A and 5-HT2A receptor expression. 761 79

Nefazodone is a new antidepressant drug with a pharmacologic profile distinct from that of the tricyclic, monoamine oxidase inhibitor, and serotonin selective reuptake inhibitor antidepressants. Nefazodone was initially discovered for its ability to block 5-HT2A receptors and its reduced potency as an alpha 1-adrenergic blocker. It was later shown to inhibit both serotonin and norepinephrine uptake in vitro, attributes which most likely impart its clinical efficacy and which differentiate nefazodone from its chemical predecessor trazodone. The combination of these two mechanisms may ultimately result in a facilitation of 5-HT1A-mediated neurotransmission, which may be beneficial for treating symptoms of depression as evidenced by recent clinical findings. In addition, the preclinical profile of nefazodone demonstrates that it has decreased anticholinergic and antihistaminic activity relative to traditional agents. Clinical findings to date are consistent with these observations.
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PMID:Pharmacology and neurochemistry of nefazodone, a novel antidepressant drug. 1081 10

Extrapyramidal side effects induced by some selective serotonin reuptake inhibitors (SSRIs), i.e. fluoxetine and sertraline, have been previously reported in patients with depression and obsessive-compulsive disorder (OCD). However, the occurrence and management of akathisia induced by fluvoxamine have not been described. In the presented case fluvoxamine-induced akathisia in an OCD patient was partially resistant to the anticholinergic agent biperiden, and was successfully treated with the 5-HT2A/5-HT2C antagonist mianserin. Mianserin (15 mg/day at 21.00 h) was discontinued and then reinstituted (off-on-off-on design). Biperiden was transiently effective in the acute akathisia, while the more persistent akathisia was alleviated by mianserin. Discontinuation of mianserin resulted in recurrence of akathisia, while full amelioration of the symptoms of akathisia was noted when mianserin was reinstituted. No aggravation of OCD symptoms was noted during mianserin administration.
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PMID:Beneficial effect of low-dose mianserin on fluvoxamine-induced akathisia in an obsessive-compulsive patient. 767 53

The hypothesis that a dysfunction of serotonergic neurotransmission is implicated in depression is supported by the clinical efficiency of selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors (SSRIs) in the treatment of depressive disorders. These drugs, such as fluoxetine and paroxetine, exert their antidepressant activity by increasing 5-HT concentration in the synaptic cleft and thus enhancing serotonergic neurotransmission. However, two to three weeks of treatment are necessary to see the first signs of clinical efficiency. Several hypothetical mechanisms have been put forward to account for this delay, taking into account pharmacokinetic considerations, neurotransmitter metabolism, and/or adaptive regulation of pre and/or post-synaptic receptors. The aim of this study was to look for such adaptive changes in the course of a 3-week treatment with fluoxetine (5 mg/kg/day, i.p.) or paroxetine (5 mg/kg/day, i.p.) in adult rats. In vitro binding and quantitative autoradiographic studies showed that neither 5-HT1A, 5-HT1B, 5-HT2A, nor 5-HT3 receptor binding sites in various brain areas were affected by these treatments. Furthermore, comparison of the specific binding of [3H]8-OH-DPAT to 5-HT1A receptors functionally coupled to G proteins with that of [3H]WAY 100635 to all 5-HT1A receptor binding sites (i.e. coupled and uncoupled with regard to G proteins) revealed no significant change in rats treated with either SSRI. Accordingly, the proportion of functional 5-HT1A receptors (i.e. those physically coupled to G proteins) appeared to remain unaltered all along a 3-week treatment with either fluoxetine or paroxetine. Nevertheless, in vitro electrophysiological recordings of serotonergic neurons in the dorsal raphe nucleus allowed the demonstration of a clearcut functional desensitization of somatodendritic 5-HT1A autoreceptors. Thus, the potency of the 5-HT1A autoreceptor agonist, 8-OH-DPAT, to depress the firing of serotonergic neurons in brain stem slices was significantly reduced as soon as after a 3-day treatment with either SSRI. The proportion of recorded neurons showing desensitization of somatodendritic 5-HT1A autoreceptors then increased along the treatment, and was generally larger with fluoxetine than with paroxetine. As 5-HT1A autoreceptor desensitization can contribute to facilitate serotoninergic neurotransmission, the remarkable efficiency of fluoxetine to trigger this adaptive regulatory mechanism might account, at least partly, for its potent antidepressant activity.
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PMID:[Central serotonin receptors and chronic treatment with selective serotonin reuptake inhibitors in the rat: comparative effects of fluoxetine and paroxetine]. 778 83

Serotonergic neurotransmission represents a complex mechanism involving pre- and post-synaptic events and distinct 5-HT receptor subtypes. Serotonin (5-HT) receptors have been classified into several categories, and they are termed as 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7 type receptors. 5-HT1 receptors have been further subdivided into 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E and 5-HT1F. 5-HT2 receptors have been divided into 5-HT2A, 5-HT2B and 5-HT2C receptors. All 5-HT2 receptor subtypes are linked to the multifunctional phosphoinositide (PI) signalling system. 5-HT3 receptors are considered ion-gated receptors and are also linked to the PI signalling system by an unknown mechanism. The 5-HT2A receptor subtype is the most widely studied of the 5-HT receptors in psychiatric disorders (for example, suicide, depression and schizophrenia) as well as in relation to the mechanism of action of antidepressant drugs. The roles of 5-HT2C and 5-HT3 receptors in psychiatric disorders are less clear. These 5-HT receptors also play an important role in alcoholism. It has been shown that 5-HT2A, 5-HT2C and 5-HT3 antagonists cause attenuation of alcohol intake in animals and humans. However, the exact mechanisms are unknown. The recent cloning of the cDNAs for 5-HT2A, 5-HT2C and 5-HT3 receptors provides the opportunity to explore the molecular mechanisms responsible for the alterations in these receptors during illness as well as pharmacotherapy. This review article will focus on the current research into the pharmacological properties, molecular biology, and clinical correlates of 5-HT2A, 5-HT2C and 5-HT3 receptors.
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PMID:Phosphoinositide system-linked serotonin receptor subtypes and their pharmacological properties and clinical correlates. 778 83

The purpose of the current study was to investigate genetic differences between two inbred strains of rats, Fisher-344 (F344/N) and Wistar Albino Glaxo (WAG/GSto), in a number of drug-naive and drug-related behaviors, including oral and intravenous morphine self-administration. F344/N and WAG/GSto rats differed in drug-naive behaviors such as nociception, rearing and sensitivity to lick suppression tests but did not differ in locomotor activity, ambulation or grooming behavior. F344/N rats were less sensitive to thermal stimuli as measured via tail-flick response, and more sensitive to the suppressive effects of intermittent shock in a lick suppression test. The F344/N rats demonstrated a significantly greater amount of rearing in open field tests but did not differ from WAG/GSto rats in locomotor activity, ambulation or grooming behavior. In addition to the behavioral results, naive F344/N and WAG/GSto rats were found to differ in mu and alpha 2 receptor concentrations (F344/N > WAG/GSto) and in 5HT2 and D2 affinity constants (WAG/GSto > F344/N). These two inbred rat strains also differed in drug-related behaviors. F344/N rats showed significantly greater depression of locomotor activity at morphine 3 mg/kg than WAG/GSto rats. In addition, F344/N rats consumed significantly greater amounts of morphine in a two-bottle choice procedure and morphine maintained significantly greater amounts of behavior during intravenous self-administration sessions. Importantly, drug maintained behavior was significantly greater than with vehicle only in the F344/N rats during operant self-administration sessions.
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PMID:Differences in morphine reinforcement property in two inbred rat strains: associations with cortical receptors, behavioral activity, analgesia and the cataleptic effects of morphine. 787 Oct 17

1. Experiments were carried out to characterize the receptors mediating the indirect excitatory response to 5-hydroxytryptamine (5-HT) in the guinea-pig isolated trachea. 2. 5-HT caused concentration-dependent contractions of tracheal strips, and the resulting concentration-response curve was biphasic in nature. The first phase was obtained with agonist concentrations in the range of 0.01-3 nM and achieved a maximum which was 30% of the total 5-HT response, while the second phase was in the range 10 nM-1 microM. 3. Atropine (0.1 microM) and tetrodotoxin (TTX: 0.3 microM) significantly reduced both phases of the 5-HT curve. Morphine (10 microM), which can act to inhibit neuronal acetylcholine release, abolished the first phase and reduced the second phase. This suggests that the first phase is mainly neurogenic (cholinergic) in nature, while the second phase is in part neurogenic and in part due to direct activation of the effector cells. 4. The 5-HT2A receptor antagonist, ketanserin (0.01, 0.1 microM) markedly depressed the first phase and shifted the second phase to the right in a parallel manner, with some depression of the 5-HT response maximum. The less selective (5-HT1/5-HT2A) antagonist, methiothepin (0.1 microM) mimicked the action of ketanserin, albeit with less potency. Concomitant administration of ketanserin and methiothepin (each at 0.1 microM) produced an antagonism similar to that caused by ketanserin (0.1 microM) alone. 5. The 5-HT3 receptor antagonists, ondansetron (0.1 microM) and granisetron (0.01 microM) slightly but significantly inhibited the first phase of the 5-HT curve without altering the second phase. SDZ 205,557(0.3 MicroM), a 5-HT4 receptor antagonist, was ineffective.6. Our results suggest that neural 5-HT2A and, to a lesser extent, 5-HT3 receptor subtypes mediate the first phase of the 5-HT curve in the guinea-pig trachea. The second phase is mediated by 5-HT2Areceptors, which are probably located at both the neural and muscular level. No evidence for the participation of 5-HT1 receptors in the 5-HT response has been obtained.
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PMID:A pharmacological analysis of receptors mediating the excitatory response to 5-hydroxytryptamine in the guinea-pig isolated trachea. 792

Serotonergic transmission is thought to be central to the aetiology of depression and the therapeutic actions of antidepressant drugs, and the latters' delayed effect has given rise to the hypothesis that an adaptive change may be involved, possibly at the level of gene expression. We have examined this hypothesis by treating rats over a time course of up to 32 days with either imipramine, mianserin, fluvoxamine, citalopram, amoxapine or saline and measuring the levels of mRNAs encoding the 5HT1A, 5HT1B, 5HT1C and 5HT2 receptors, the enzymes tryptophan hydroxylase and aromatic amino acid decarboxylase, and the 5HT transporter. None of the treatments gave rise to significant changes in any of the mRNA levels at any time point. These results suggest that the reported changes in 5HT receptor numbers do not occur as a result of changes in the abundance of their encoding mRNAs, and that changes to the latter is not central to the therapeutic effects of antidepressant drugs.
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PMID:Lack of effect of antidepressant drugs on the levels of mRNAs encoding serotonergic receptors, synthetic enzymes and 5HT transporter. 798 81

The serotonin (5-HT) is implicated in many centrally-regulated functions and has shown to be involved in affective disorders, such as depression and anxiety disorders. Recent progress in pharmacology and molecular neurobiology have confirmed the concept of the heterogeneity of 5-HT receptors and permitted reformulation of new hypothesis concerning antidepressant mechanisms of action, in particular those concerning serotoninergic receptors. Up to date, among the 5-HT defined sites, only 13 have been cloned, and several subfamilies have been described. Particularly, the 5-HT1 family containing receptors: 5-HT1A, 5-HT1B/1D, 5-HT1E and 5-HT1F. The 5-HT2 family includes receptors that stimulate phospholipase C: 5-HT2A (previously termed 5-HT2), 5-HT2B and 5-HT2C (previously termed 5-HT1C). Concerning 5-HT2 family, it is possible that some 5-HT binding drugs properties initially attributed to 5-HT2A receptors, might well be mediated by 5-HT2C receptors. Recently, medifoxamine (Cledial) activities on 5-HT systems have been shown. In particular, these activities are related on 5-HT2C and/or 5-HT2A binding sites. Results indicate that, in vitro, medifoxamine affinities (Ki) are near to 1 microM, for both 5-HT2C and 5-HT2A sites (ratio = 1.42). On the other hand, m-CPP, an 5-HT2C agonist, considered as a reference compound, has the same affinities that medifoxamine, but a higher one for 5-HT2A (ratio = 3.42). In animals models considered as predictive for psychotropic activity in human, we investigate in rat the impact of medifoxamine on 5-HT2C receptors, using Learned-Helplessness model (LH) and the social interaction test.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[The role of type 2 serotonin receptors, 5-HT2A and 5-HT2C, in depressive disorders: effect of medifoxamine]. 798 7

Nefazodone (2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl- 2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one) has been reported to be effective in the treatment of depression. Antagonism of serotonin type 2A (5HT2A) receptors, as well as inhibition of the serotonin (5HT) uptake carrier, has been suggested to contribute to the antidepressant action of nefazodone in vivo (Eison et al., 1990). Nefazodone weakly antagonized the quipazine-induced rise in rat serum corticosterone levels and the quipazine-induced increase in rat hypothalamic 3-methoxy-4-hydroxy-phenylglycol sulfate, suggesting blockade of 5HT2A receptors in vivo. Nefazodone, however, failed to antagonize the p-chloroamphetamine-induced depletion of mouse or rat brain 5HT, displaying a lack of effect on the 5HT uptake carrier. These data extend previous in vitro and in vivo data (Eison, et al. 1990) reporting nefazodone to be an antagonist at 5HT2A receptors, but fail to show inhibition of the 5HT uptake carrier in the same dose range.
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PMID:Evaluation of nefazodone as a serotonin uptake inhibitor and a serotonin antagonist in vivo. 804 Dec 27


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