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)

Previous work in this laboratory has suggested that antagonist action of 5-hydroxytryptamine2 (5-HT2) receptors and agonist action of 5-HT1 receptors results in antidepressant-like effects (increased reinforcement rate and decreased response rate) in rats performing under the differential-reinforcement-of-low-rate 72-sec schedule (DRL 72-s) of reinforcement. Serotonergic mediation of antidepressant drug effects on DRL 72-s behavior was assessed with a series of 5-HT agonists, and blockade of the effects of the antidepressant drugs clorgyline and fluoxetine (which presumably indirectly stimulate 5-HT1 receptors) was attempted in separate experiments with the 5-HT1 and 5-HT2 antagonist methysergide and the 5-HT neurotoxin 5,7-dihydroxytryptamine. Direct 5-HT1A agonists 8-hydroxy-2-(di-n-propylamino)tetralin and 5-methoxy-N,N-dimethyltryptamine and the 5-HT precursor 5-hydroxytryptophan all increased the reinforcement rate. The 5-HT1B and 5-HT1C agonists m-chlorophenylpiperazine and 1-(m-trifluoromethylphenyl)piperazine did not increase the reinforcement rate. The 5-HT2 agonist and 5-HT3 antagonist quipazine also did not increase the reinforcement rate. The monoamine oxidase inhibitor clorgyline and the 5-HT uptake inhibitor fluoxetine increased the reinforcement rate and decreased the response rate as seen with other antidepressant drugs on the DRL 72-s schedule. Methysergide antagonized the reinforcement rate increasing effects of both clorgyline and fluoxetine. Depletion of brain 5-HT with i.v.t. 5,7-dihydroxytryptamine blocked the antidepressant-like effects of clorgyline. These results suggest that central 5-HT1A receptors are involved in mediating the antidepressant-like effects of some drugs on DRL 72-s behavior. These results provide evidence that stimulation of 5-HT1A receptors and antagonism of 5-HT2 receptors lead to an antidepressant-like effect on the DRL 72-s schedule and implies that these two receptors may be important in mediating clinical drug effects in depression.
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PMID:Evidence for involvement of 5-hydroxytryptamine1 receptors in antidepressant-like drug effects on differential-reinforcement-of-low-rate 72-second behavior. 274 11

Slices of hippocampus from the rabbit were preincubated with [3H]5-HT), then superfused continuously and twice stimulated electrically. The stimulation-evoked overflow of tritium was inhibited by the 5-HT autoreceptor ligands 5-carboxamido-tryptamine (5-COHT), 5-HT, 5-methoxy-N,N-dimethyl-tryptamine (5-MeOMT), (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), methysergide and (+/-)-cyanopindolol in a concentration-dependent manner. These effects were competitively inhibited by the 5-HT autoreceptor antagonists, metitepin and metergoline. (+/-)-Cyanopindolol also reduced the evoked release of 5-HT from slices of cortex from the rat. The inhibitor of the uptake of 5-HT, 6-nitroquipazine diminished the autoreceptor-mediated depression of release of 5-HT. In cortex tissue from the rat, 6-nitroquipazine reversed the decreased release of 5-HT, due to (+/-)-cyanopindolol, to a facilitation. The disinhibition of the release of 5-HT by autoreceptor antagonists was further enhanced by 6-nitroquipazine. Non-linear regression analysis of concentration-response curves for 5-COHT yielded the following pKd of endogenous 5-HT at the autoreceptor: 7.753 +/- 0.116. This value corresponds to the pKd of 5-HT at the 5-HT1B binding site. The 5-HT biophase concentration at the autoreceptor of 10(-8.220 +/- 0.132)M was markedly enhanced by 6-nitroquipazine (10(-6)M) to 10(-7.476 +/- 0.132)M. It is concluded that the 5-HT autoreceptor belongs to the 5-HT1B subtype of receptor; the corresponding 5-HT biophase concentration can be estimated quantitatively; 8-OH-DPAT decreased the evoked release of 5-HT through both 5-HT autoreceptors and alpha 2-heteroreceptors and (+/-)-cyanopindolol acts as partial agonist at the 5-HT autoreceptor.
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PMID:The serotonin (5-HT) autoreceptor in the hippocampus of the rabbit: role of 5-HT biophase concentration. 295 18

1. To further investigate a previous postulate that increased serotonergic activity may cause depression, the effects of chronic mianserin administration on 5-HT, its metabolites, and the subtypes of 5-HT receptors were studied. 2. The levels of 5-HT, 5-hydroxyindoleacetic acid, 5-HTP, 5-HT turnover and their response to 5-HTP administration all exhibited no change following mianserin treatment. 3. The Bmax value of the high affinity site of the 5-HT-1A receptor increased and the Bmax value of 5-HT-2 receptor decreased with no change in the low affinity site of the 5-HT-1A receptor nor in the 5-HT-1B receptor. 4. The response to 5-HTP administration showed no change in any of these receptors. 5. These results suggest that the chronic mianserin administration might block both the 5-HT-2 and 5-HT-1A receptors in the 5-hydroxytryptophan depression model.
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PMID:Effects of chronic mianserin administration on serotonin metabolism and receptors in the 5-hydroxytryptophan depression model. 750 96

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.
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PMID:[5-hydroxytryptamine (serotonin) receptors--nomenclature and classification of types and subtypes]. 758 16

Male rats housed in mixed-sex groups quickly established dominance hierarchies in which subordinates appeared severely stressed. Subordinate rats had elevated basal corticosterone (CORT) levels relative to dominants and individually housed controls. Several subordinates had blunted CORT responses to a novel stressor, leading to the classification of subordinates as either stress-responsive or nonresponsive. Binding to 5-HT1A receptors was reduced in stress-responsive subordinates compared to controls throughout hippocampus and dentate gyrus. Decreased binding was observed in nonresponsive subordinates only in CA3 of hippocampus. In addition, 5-HT1A binding was decreased in CA1, CA3, and CA4 in dominants compared to controls. Binding to 5-HT2 receptors was increased in parietal cortex in both responsive and nonresponsive subordinates compared to controls. No changes were observed in binding to 5-HT1B receptors. These results are discussed in the context of regulation of the serotonergic system by stress and glucocorticoids and possible relevance to the pathophysiology of depression.
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PMID:Serotonin receptor binding in a colony model of chronic social stress. 777 47

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 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

The neuromodulator serotonin (5-hydroxytryptamine, 5-HT) has been associated with mood disorders such as depression, anxiety, and impulsive violence. To define the contribution of 5-HT receptor subtypes to behavior, mutant mice lacking the 5-HT1B receptor were generated by homologous recombination. These mice did not exhibit any obvious developmental or behavioral defects. However, the hyperlocomotor effect of the 5-HT1A/1B agonist RU24969 was absent in mutant mice, indicating that this effect is mediated by 5-HT1B receptors. Moreover, when confronted with an intruder, mutant mice attacked the intruder faster and more intensely than did wild-type mice, suggesting the participation of 5-HT1B receptors in aggressive behavior.
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PMID:Enhanced aggressive behavior in mice lacking 5-HT1B receptor. 809 Dec 14

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.
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PMID:Neurobiological mechanisms involved in antidepressant therapies. 822 1


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