UNIPROT:P08908 - FACTA Search

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Query: UNIPROT:P08908 (5-HT1A)
5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The neuroendocrine profile of the serotonin 5-HT1A receptor agonist and potential anxiolytic drug (+)-4[N-(5-methoxy-chroman-3-yl)N-propylamino]butyl-8-azaspiro-(4, 5)-decane - 7,9-dione (S-20499) was examined in conscious male rats. S-20499 (0.01-20 mg/kg i.p.) dose-dependently elevated plasma adrenocorticotropin (ACTH) and corticosterone concentrations, with maximal effects observed at 15-30 and 30-60 min respectively. S-20499 also reduced plasma prolactin concentration, and did not alter plasma renin activity. S-20499 (1 mg/kg i.p.) also reduced blood pressure and heart rate within 10 min, suggesting reduced sympathetic output. Pretreatment with the 5-HT1A receptor antagonists (-)-pindolol (0.3 mg/kg i.p.) or spiperone (0.01 or 3 mg/kg s.c.) significantly attenuated the stimulatory effects of S-20499 on plasma ACTH and/or corticosterone concentrations. The data suggest that S-20499 stimulates the hypothalamic-pituitary adrenal axis by activating 5-HT1A receptors, although activation of dopamine D2 receptors may contribute to these responses. Like other 5-HT1A receptor agonists, S-20499 does not increase renin secretion. Additionally, it reduces prolactin secretion, presumably by acting as a weak dopamine D2 receptor agonist in the pituitary.
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PMID:Neuroendocrine profile of the potential anxiolytic drug S-20499. 776 66

Numerous studies have demonstrated the stimulatory effect of 5-HT1A receptor agonists, such as 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), on plasma corticotrophin (ACTH) levels in the rat. However, until recently the lack of a selective 5-HT1A receptor antagonist has hampered mechanistic studies in this area. In this study we examined the effects of the selective 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1- piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride (WAY100635) on plasma ACTH levels and on the elevation of ACTH induced by the 5-HT1A receptor agonist 8-OH-DPAT in the conscious rat. The basal plasma ACTH level was 41.0 +/- 1.8 pg/ml. 8-OH-DPAT increased ACTH levels at doses of 100 and 300 micrograms/kg with maximum increases of 551 and 546% respectively occurring 10 min post-injection. WAY100635 had no effects per se on plasma ACTH at doses up to 100 micrograms/kg, indicating it has no 5-HT1A receptor agonist properties. WAY100635 dose-dependently blocked the elevation of ACTH induced by 8-OH-DPAT, the minimum effective dose being 10 micrograms/kg. The present results indicate that 8-OH-DPAT elevates plasma ACTH levels by stimulating 5-HT1A receptors, a conclusion that is consistent with the findings of previous studies using non-selective 5-HT1A receptor antagonists such as pindolol.
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PMID:Inhibition of 8-OH-DPAT-induced elevation of plasma corticotrophin by the 5-HT1A receptor antagonist WAY100635. 782 50

We recently reported that chronic administration of the 5-HT1A receptor agonist, ipsapirone (0.5 milligrams in drinking water for 3 weeks), has anxiolytic activity in the rat. Herein, we investigated whether this treatment promotes tachyphylaxis to the acute neuroendocrine effects of ipsapirone. Rats chronically treated with ipsapirone displayed a 7% decrease in body weights, compared to vehicle-pretreated rats, thereby confirming previous observations. On the other hand, ipsapirone pretreatment did not affect basal plasma levels of adrenocorticotropin (ACTH), corticosterone, prolactin, aldosterone, and renin activity, nor did it affect their respective rises following an acute ipsapirone (50 mg/kg PO) challenge. Moreover, ipsapirone pretreatment did not affect the increase in plasma prolactin levels elicited by the dopaminergic receptor antagonist haloperidol. These results suggest that neither the 5-HT1A receptors nor the catecholamine receptors that mediate ipsapirone acute neuroendocrine effects develop tolerance to stimulation upon sustained ipsapirone treatment.
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PMID:Chronic treatment with an anxiolytic dose of the 5-HT1A agonist ipsapirone does not alter ipsapirone acute neuroendocrine effects. 790 66

The influence of cocaine exposure on serotonergic neurons and postsynaptic 5-HT1A receptor-mediated responses was evaluated by measuring neuroendocrine responses to a serotonin (5-HT) releaser or a 5-HT1A agonist. Male rats received cocaine (15 mg/kg, i.p.) or saline twice daily for 7 days. Forty-two hr after the final cocaine injection, the 5-HT releaser d-fenfluramine (0, 0.2, 0.6, 2, or 5 mg/kg, i.p.) or the 5-HT1A agonist, 8-OH-DPAT (0, 10, 50, 200 or 500 micrograms/kg, s.c.) were administered. Blood samples were then collected for analysis of plasma ACTH, prolactin, and renin concentrations. The ACTH responses to d-fenfluramine and 8-OH-DPAT were inhibited in cocaine pretreated rats. However, the prolactin responses to d-fenfluramine and 8-OH-DPAT were not significantly modified by cocaine exposure. Additionally, the renin response to d-fenfluramine was unaltered by repeated cocaine administration, while 8-OH-DPAT did not alter renin secretion in either pretreatment group. In contrast to published reports which show that cocaine exposure produces supersensitive 5-HT2A and/or 5-HT2C receptor-mediated responses, the present data suggest that repeated cocaine exposure produces subsensitivity to at least some postsynaptic 5-HT1A receptors. Cocaine-induced deficits in the ACTH response to 5-HT releasers may reflect 5-HT1A receptor subsensitivity, but presynaptic deficits cannot be excluded. Examination of the ACTH response to 5-HT1A agonists may represent a valuable approach to determine deficits in 5-HT function in human cocaine abusers.
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PMID:Repeated cocaine exposure inhibits the adrenocorticotropic hormone response to the serotonin releaser d-fenfluramine and the 5-HT1A agonist, 8-OH-DPAT. 798 71

The present studies determined whether serotonin 5-HT1A receptor-mediated function is modified by chronic exposure to antidepressants. Hormone responses to the 5-HT1A agonist, 8-OH-DPAT, were evaluated after long-term exposure to two antidepressants, the 5-HT uptake blocker, fluoxetine, and the norepinephrine uptake blocker, desipramine (DMI). In addition, the density and affinity of 5-HT1A receptors in the hypothalamus and cerebral cortex were measured. Male rats received fluoxetine (10 mg/kg i.p.), DMI (5 mg/kg i.p.) or saline injections once daily for 21 days. 8-OH-DPAT (0-500 micrograms/kg s.c.) was administered 18 h after the final antidepressant injection and 15 min before sacrifice. 8-OH-DPAT significantly increased plasma ACTH, corticosterone, oxytocin and prolactin, but not renin or vasopressin concentrations. Chronic injections of fluoxetine inhibited the ACTH, corticosterone and oxytocin responses to 8-OH-DPAT, suggesting reduced 5-HT1A receptor function. In contrast, chronic DMI did not alter the hormone responses to 8-OH-DPAT. The density and affinity of 5-HT1A receptors in the frontal cortex or hypothalamus were not altered by either fluoxetine or DMI. To verify that the observed effects require prolonged exposure to fluoxetine, rats received a single injection of fluoxetine (10 mg/kg, i.p.), 3 h before 8-OH-DPAT (0-500 micrograms/kg s.c.). Acute fluoxetine did not reduce any of the hormone responses to 8-OH-DPAT. In conclusion, the results suggest that chronic, but not acute, exposure to fluoxetine decreases 5-HT1A receptor function. This effect is not seen in rats chronically exposed to DMI.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Long-term fluoxetine, but not desipramine, inhibits the ACTH and oxytocin responses to the 5-HT1A agonist, 8-OH-DPAT, in male rats. 811 81

The present study was undertaken to evaluate the serotonin (5-HT) receptor subtype(s) by which 5-HT acts on the pituitary to stimulate ACTH secretion. We tested the effects of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), the 5-HT1C receptor agonist metachloro-phenylpiperazine (m-CPP), which also binds to other 5-HT receptors with lower affinity, and the 5-HT2/1C receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) on basal, corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP)-stimulated ACTH release from primary rat anterior pituitary cell cultures. 5-HT, 8-OH-DPAT and DOI significantly increased basal ACTH release, an effect which was antagonized by 5-HT receptor antagonists. 5-HT and DOI were effective at nanomolar concentrations whereas 8-OH-DPAT was effective at higher concentrations. 5-HT, 8-OH-DPAT (both at 10 nmol/l) and DOI (at higher concentrations) blunted the stimulatory effect of CRH. The suppressive effects of 8-OH-DPAT and DOI on CRH-stimulated ACTH release were antagonized by (-)propranolol, a beta-adrenergic receptor antagonist which binds the 5-HT1A receptor with elevated affinity, and ketanserin, a 5-HT2 receptor antagonist respectively. 5-HT, 8-OH-DPAT and DOI showed additive stimulatory effects with AVP but only at the highest concentration tested, whereas m-CPP potentiated AVP-induced ACTH release at concentrations of 1 nmol/l or more. This effect was antagonized by metergoline, a non-selective 5-HT receptor antagonist and mianserin, an antagonist which binds the 5-HT1C receptor with elevated affinity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of selective serotonin agonists on basal, corticotrophin-releasing hormone- and vasopressin-induced ACTH release in vitro from rat pituitary cells. 838 13

The RN46A cell line was derived from embryonic day 13 rat medullary raphe cells by infection with a retrovirus encoding the temperature-sensitive mutant of SV40 large T antigen (tsT-ag). The RN46A cell line is neuronally restricted and constitutively differentiates following a shift to nonpermissive temperature. Differentiated RN46A cells express low levels of tryptophan hydroxylase (TPH) but no detectable levels of serotonin (5-HT). Treatment of cultures with the adrenocorticotropic hormone peptide ACTH4-10 up-regulates the expression of TPH immunoreactivity in differentiated RN46A cells, but 5-HT synthesis requires initial treatment with ACTH4-10, followed by partial membrane depolarizing conditions. Up-regulation of TPH by ACTH4-10 is apparently due to activation of adenylate cyclase, whereas the increased 5-HT synthesis with membrane depolarization can be blocked with the voltage-sensitive Ca(2+)-channel blockers nifedipine and omega-conotoxin. ACTH4-10 treatment also markedly up-regulates the expression of the 5-HT reuptake transporter, as do dibutyryl cyclic AMP and forskolin; chronic membrane depolarization has no effect on 5-HT reuptake. The expression of the high-affinity 5-HT1A receptor is increased threefold by ACTH4-10 treatment during differentiation and fivefold by differentiation under partial membrane depolarizing conditions. Combining ACTH4-10 treatment and membrane depolarization does not increase expression of the 5-HT1A receptor further. 5-HT release is constitutive in ACTH-treated RN46A cells and linked to spontaneous synaptic vesicle fusion in RN46A cells. Considered with previous results, these data indicate that multiple effectors, ACTH, brain-derived neurotrophic factor, and membrane depolarization, have both distinct and overlapping effects that regulate specific elements of the serotonergic neuronal phenotype during differentiation and maturation.
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PMID:Adrenocorticotropic hormone activation of adenylate cyclase in raphe neurons: multiple regulatory pathways control serotonergic neuronal differentiation. 859 7

These studies demonstrate that prenatal cocaine produces differential changes in neuroendocrine responses following challenge with a 5-HT releaser versus a 5-HT1A agonist and suggest differential functional alterations in both pre- and postsynaptic components of 5-HT pathways. The attenuated neuroendocrine responses in adult male progeny following challenge with a 5-HT releaser, in the absence of reductions in 5-HT receptors, provide additional evidence in support of a presynaptic 5-HT deficit in adult male cocaine-exposed progeny. Furthermore, since prenatal cocaine produced a differential profile of alterations in 5-HT-mediated neuroendocrine responses in adult male (i.e., decreases ACTH and renin) versus prepubescent female (i.e., decreases ACTH and corticosterone) progeny following challenge with a 5-HT releaser, these data indicate that the differences could be due to gender and/or postnatal developmental ages. Gender differences in prenatal cocaine effects on postsynaptic receptor function were more clearly shown in study II, which demonstrated that at the same postnatal age, 5-HT1A-mediated neuroendocrine responses were significantly potentiated in male but not female cocaine-exposed progeny. In summary, the data presented in this chapter indicate that the biochemical and functional changes in 5-HT systems observed following prenatal exposure to cocaine are unique with respect to pre- versus postsynaptic alterations, pre- versus postpubescent developmental times, and differences between genders. A number of general conclusions can be drawn from the data presented. The presence of marked neurochemical deficits at both pre- and postpubescent timepoints, in the absence of any visually apparent physical terata, emphasizes the importance of investigating the neurochemical teratogenic potential of cocaine and other psychostimulants. Furthermore, data from these studies demonstrate the importance of investigating male and female progeny separately, as prenatal cocaine exposure may produce gender-specific alterations in some, but not all, aspects of brain neurotransmitter systems. Another important point that can be discerned from the present data is the necessity of subjecting cocaine-treated animals to challenge tests in order to reveal alterations that might not be readily apparent from measuring basal values for specific biochemical or functional parameters (e.g., basal hormone levels). In addition, the differential biochemical and functional changes in 5-HT systems, manifested at pre- versus postpubescent times, suggests that prenatal cocaine may adversely affect the normal maturational changes occurring in 5-HT systems. This may be of consequence in evaluating developmental stages in human offspring exposed to cocaine in utero. Furthermore, the ability of prenatal cocaine to alter 5-HT-mediated ACTH and renin responses in progeny suggest that offspring may exhibit alterations in their response to physiologic stimuli such as stress. Since neuroendocrine challenge tests can be performed in humans, the present data indicate the potential clinical utility of this approach to provide peripheral markers that can be used to identify changes in brain 5-HT pathways in human offspring exposed in utero to cocaine. Prenatal cocaine-induced alterations in brain 5-HT systems may be of significant clinical importance as dysfunction of 5-HT systems has been implicated in various psychiatric disorders including depression, anxiety, aggression, and drug-seeking behavior.
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PMID:Prenatal cocaine produces biochemical and functional changes in brain serotonin systems in rat progeny. 859 82

The prevailing neurochemical theory about biological correlates of suicidal behavior focuses on the serotonergic system. In this study, we assessed the cortisol, ACTH, GH, prolactin and temperature responses to flesinoxan, a5-HT1A agonist, in 30 DSM-III-R major depressed inpatients subgrouped into suicide attempters (n = 15) and nonattempters (n = 15). The patients were assessed after a drug-free period of at least 3 weeks. A subsample of 16 patients completed the Buss-Durkee Hostility Inventory as a measure of impulsive aggressive behavior. Mean delta cortisol responses to flesinoxan were significantly lower in the group of depressed patients with a history of suicide attempts than in the group without history of suicidal behavior: for the delta cortisol values 14.5 +/- 16.3 micrograms/l vs 101 +/- 94 micrograms/l (F = 8.9, df = 5.25, p = 0.006). There was also a very significant difference between suicide attempters and nonattempters for the temperature (delta T degrees) responses to flesinoxan: 0.20 +/- 0.24 degrees C vs. 0.60 +/- 0.24 degrees C (F = 18.1, df = 5.25, p = 0.0003). Hormonal and temperature responses to flesinoxan were not correlated with BDHI irritability or assault subscale scores. The results of the present study support the implication of the serotonergic system, particularly 5-HT1A receptors, in the control of self-directed aggressive behavior. Moreover, in depressed patients, serotonergic abnormalities do not appear to be related to aggressive behavior.
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PMID:The flesinoxan 5-HT1A receptor challenge in major depression and suicidal behavior. 861 6

Benzodiazepines and the novel anxiolytic buspirone share a common capacity to relieve clinical anxiety but do not share any side effects. Anxiety releases stress hormones and, at moderate doses, anxiolytic benzodiazepines block this release. It is interesting, therefore, that buspirone and other 5-HT1A agonists release stress hormones at moderate doses. Both the U-shaped dose-response curve seen with buspirone in some animal tests of anxiety and its slow onset of clinical action could be attributed to this release of stress hormones. Metyrapone (200 mg/kg), an inhibitor of 11-beta-hydroxylase, was used in the present experiments as a form of chemical adrenalectomy and was combined with administration of corticosterone (1 mg) to produce rats with presumed approximately normal corticosterone levels but no capacity to release endogenous corticosterone. This treatment reduced the difference normally observed in the effects of chlordiazepoxide (5 mg/kg) and buspirone (0.37 mg/kg) on a fixed interval schedule particularly in the early part of the interval when release of behavioral inhibition would be expected to contribute most to the effects. These results are consistent with the previous suggestion of Johnston and File (8) that the anxiolytic action of buspirone may be counteracted by activation of the pituitary-adrenal axis. Corticosterone appears to be the most likely critical agent for this antagonist action in the present experiments, although CRF and ACTH are also possibilities. It is likely that there is a mutual functional opposition between endogenous anxiolytic factors and stress hormones.
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PMID:The pituitary-adrenal axis and the different behavioral effects of buspirone and chlordiazepoxide. 872 38

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