Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P08908 (5-HT1A)
 5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The affinities of putative serotonin receptor agonists and antagonists for 5-HT1A, 5-HT1B, 5-HT1C, and 5-HT2 receptors were assayed using radioligand binding assays. The 5-HT1 sites were labeled with the agonist radioligands [3H]-8-hydroxy-2-(di-n-propylamino)-tetralin [3H]-8-OH-DPAT, [3H]-5-HT, and [3H]mesulergine. The 5-HT2 receptor was labeled with the antagonist radioligand [3H]ketanserin or the agonist radioligand [3H]-4-bromo-2,5-dimethoxyphenylisopropylamine ([3H]DOB). The apparent 5-HT1 receptor selectivity of agonist compounds was found to be 50- to 100-fold higher when the 5-HT2 receptor affinity was determined using the antagonist radioligand [3H]ketanserin than when the agonist radioligand [3H]DOB was used. Quipazine, a putative specific 5-HT2 agonist, appeared to be only 3-fold more potent at 5-HT2 than at 5-HT1A receptors when [3H]ketanserin was used as the 5-HT2 radioligand. When [3H]DOB was used as the 5-HT2 radioligand, quipazine was determined to be 100-fold more potent at 5-HT2 receptors than at 5-HT1A receptors. 1-(3-trifluoromethylphenyl)piperazine (TFMPP), a putative specific 5-HT1B receptor agonist was apparently 10-fold more potent at 5-HT1B receptors than at 5-HT2 receptors when [3H]ketanserin was used as the 5-HT2 radioligand. When [3H]DOB was used as the 5-HT2 radioligand, TFMPP was found to be equipotent at 5-HT1B and 5-HT2 receptors. Using the 5-HT2 antagonist radioligand [3H]ketanserin, a similar pattern of underestimating 5-HT2 receptor selectivity and/or overestimating 5-HT1A or 5-HT1B receptor selectivity was observed for a series of serotonin receptor agonists. Antagonist receptor selectivity was not affected significantly by the nature of the 5-HT2 receptor assay used. These data indicate that, by using an antagonist radioligand to label 5-HT2 receptors and agonist radioligands to label 5-HT1 receptors, the 5-HT1 receptor selectivity may be overestimated. This may be an especially severe problem in serotonin drug development as drugs that interact potently with 5-HT2 receptors have been reported to be psychoactive and/or hallucinogenic.
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PMID:Selectivity of serotonergic drugs for multiple brain serotonin receptors. Role of [3H]-4-bromo-2,5-dimethoxyphenylisopropylamine ([3H]DOB), a 5-HT2 agonist radioligand. 366 39

The present study assessed compounds displaying affinity for 5-HT1A, 5-HT1B, 5-HT2A and 5-HT2C receptors for their ability to substitute for, enhance or antagonize the discriminative stimulus effects of cocaine (10 mg/kg) in rats. In substitution tests, the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT; 0.2-1.6 mg/kg), the 5-HT1A/B receptor agonists RU 24969 (0.25-2 mg/kg) and CGS 12066B (2-16 mg/kg), the 5-HT1B/2C receptor agonists m-chlorophenylpiperazine (mCPP; 0.25-2 mg/kg) and m-trifluoromethylphenylpiperazine (TFMPP; 0.125-2 mg/kg), the 5-HT2A/2C receptor agonist 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane ([+/-]-DOB; 0.0625-0.5 mg/kg), the 5-HT2C receptor agonist MK 212 (0.25-1 mg/kg) and the nonselective 5-HT receptor agonist quipazine (1-8 mg/kg) engendered 30% to 70% cocaine-appropriate responding. The DA receptor antagonists SCH 23390 (0.025 or 0.05 mg/kg) and haloperidol (0.125 or 0.25 mg/kg) failed to block the partial substitution of RU 24969 (1 mg/kg) for cocaine. In combination tests, a fixed dose of either quipazine (4 mg/kg), RU 24969 (0.25, 0.5 or 1 mg/kg) or TFMPP (0.5 mg/kg) but not 8-OH-DPAT (0.4 mg/kg) or CGS 12066B (16 mg/kg) produced a leftward shift in the cocaine dose-response curve (0.625-5 mg/kg). In contrast, coadministration of either mCPP (0.25-2 mg/kg) or MK 212 (0.125-2 mg/kg) plus a dose of cocaine (5 mg/kg) that produced > 85% cocaine-appropriate responding when given alone partially antagonized cocaine; mCPP (1 mg/kg) also produced a rightward shift in the cocaine dose-response curve. Neither 8-OH-DPAT (0.2-1.6 mg/kg), (+/-)-DOB (0.125-0.5 mg/kg) nor quipazine (2-8 mg/kg) blocked the cocaine stimulus. The 5-HT1A receptor antagonist NAN 190 (0.2-0.8 mg/kg), the 5-HT2A/2C receptor antagonist LY 53857 (0.5-4 mg/kg) and the 5-HT/DA receptor antagonist pirenperone (0.5-4 mg/kg) neither substituted for nor enhanced cocaine; however, pirenperone but not NAN 190 or LY 53857 partially blocked the cocaine (10 mg/kg) response. Although 5-HT receptor compounds do not substitute for cocaine, several 5-HT receptor agonists (i.e., the indole derivative RU 24969 and the arylpiperazines mCPP, MK 212, TFMPP and quipazine), but not antagonists, differentially modulate the stimulus effects of cocaine.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Modulation of the discriminative stimulus properties of cocaine by 5-HT1B and 5-HT2C receptors. 756 16

The effects of the relatively specific serotonergic agonists 8-OH-DPAT (5-HT1A), TFMPP (5-HT1B), and DOB (5-HT2) were studied on defensive aggressive behavior in rats using the water competition test, 8-OH-DPAT (up to 0.25 mg/kg) and TFMPP (up to 1 mg/kg) were found to be ineffective, whereas DOB (up to 0.4 mg/kg) significantly reduced aggressive behavior in this test as well as in the offensive aggression test of the resident-intruder model. These results, combined with those from other studies, suggest that stimulation of 5-HT1A, 5-HT1B, and 5-HT2 receptors reduces offensive aggression, whereas defensive aggression is only decreased by 5-HT2 stimulation.
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PMID:Effects of selective serotonergic agonists on aggressive behavior in rats. 761 17

Bilateral infusion of 5-hydroxytryptamine (5-HT) agonists into the substantia nigra pars reticulata (SNr) of awake rats was shown to influence oral behavior. The 5-HT1A agonist (R)-8-hydroxy-2-(di-propylamino)- tetralin (8-OH-DPAT) (1.3-13 nmol on each side) produced a dose-dependent depression of vacuous chewing movements (VCMs) that lasted about 20 min. The (R)-8-OH-DPAT-induced depression of VCMs was blocked by the simultaneous intranigral infusion of a specific 5-HT1A antagonist [(-)-(S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin HCl (UH-301)], which had no effect when given alone. Another 5-HT1A agonist [(5-methoxy-N,N-dimethyltryptamine hydrogen oxalate (5-MeO-DMT)] also reduced VCM frequencies. Intranigral infusion of the nonspecific 5-HT-agonists 1-(3-triflouro-methylphenyl) piperazine (TFMPP) and 1(m-chlorophenyl)-piperazine (mCPP) and a 5-HT3 agonist [2-methyl-5-hydroxytryptamine (2-Me-5-HT)] increased VCM after 5- to 10-nmol doses. Another 5-HT3 agonist (1-phenylbiguanide) and a 5-HT2 agonist [1-(4-bromophenyl-2,5-dimethoxy)-2-aminopropane (DOB)] had no significant effect. As most 5-HT receptors in the SNr are of the 5-HT1B subtype, these results suggest that the increased VCM frequency was mediated via nigral 5-HT1B receptors. The importance of 5-HTergic mechanisms in the development of drug-induced dyskinesias is discussed.
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PMID:Modulation of oral movements by intranigral 5-hydroxytryptamine receptor agonists in the rat. 826 98

The effects of acute and chronic treatment of rats with the tricyclic antidepressant imipramine, the 5-HT1A receptor partial agonist tandospirone, or its metabolite 1-PP were compared on behavioral responses produced by the activation of 5-HT receptors and on brain monoamine receptors. The behaviors examined were the 5-HT behavioral syndrome elicited by the 5-HT1A receptor agonist 8-OH-DPAT and the head shake response produced by the 5-HT2 receptor agonist DOB. Drug treatments were administered either by subcutaneous infusion from implanted minipumps or by repeated injection and the effects of chronic drug treatment were assessed when the drug was present and absent at the time of testing. The infusion of tandospirone blocked elicitation of the 5-HT behavioral syndrome when tested after 1 or 14 days of drug treatment (drug present) and 24 hr after the drug was withdrawn (drug absent). When administered by injection, tandospirone blocked the production of the 5-HT syndrome 1 hr (drug present), but not 24 hr (drug absent), following either 1 day or 14 days of drug treatment. Chronic infusion of imipramine did not alter the 5-HT syndrome. Chronic, but not acute, injections of imipramine blocked the 5-HT syndrome when tested 1 hr but not 24 hr, after the final injection. Treatment with 1-PP did not alter the 5-HT syndrome. The head shake response was attenuated by acute and chronic injection of tandospirone either 1 or 24 hr after treatment, although chronic infusion of tandospirone did not alter this behavior. Head shaking was attenuated by the infusion and injection of imipramine after acute treatment, chronic treatment, or following drug withdrawal. Chronic injection of 1-PP also inhibited the head shake response 24 hr after injection, although 1-PP was ineffective at all other times and when given by infusion. The density of hippocampal 5-HT1A receptors was unaltered by the chronic drug treatments. 5-HT2 receptor density in frontal cortex was reduced by the chronic infusion of either tandospirone, imipramine, and 1-PP, but only by chronic injections of imipramine. The density of cortical beta-adrenergic receptors was reduced following chronic imipramine injections or infusion. The results suggest that both tandospirone and imipramine may regulate 5-HT-mediated responses and 5-HT2 receptor density, which may contribute to their efficacy as antidepressants, although their effects were dependent upon the method of administration and may involve different neuropharmacological mechanisms.
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PMID:Effect of chronic treatments with tandospirone and imipramine on serotonin-mediated behavioral responses and monoamine receptors. 839 53

1. The effects of the 5-HT2A/2C agonist DOB, the selective 5-HT1A agonist NDO 008 (3-dipropylamino-5-hydroxychroman), and the two enantiomers of the selective 5-HT1A agonist 8-OH-DPAT (R(+)-8-OH-DPAT and S(-)-8-OH-DPAT) were studied in a step-through passive avoidance (PA) test in the male rat. 2. The 5-HT1A agonists injected prior to training (conditioning) produced a dose-dependent impairment of PA retention when examined 24 h later. R(+)-8-OH-DPAT was four times more effective than S(-)-8-OH-DPAT to cause an impairment of PA retention. Both NDO 008 and the two enantiomers of 8-OH-DPAT induced the serotonin syndrome at the dose range that produced inhibition of the PA response, thus, indicating activation of postsynaptic 5-HT1A receptors. 3. Neither NDO 008 nor R(+)-8-OH-DPAT induced head-twitches, a behavioural response attributed to stimulation of postsynaptic 5-HT2A receptors. In contrast, DOB induced head-twitches at the 0.01 mg kg(-1) dose while a 200 times higher dose was required to produce a significant impairment of PA retention. 4. The impairment of PA retention induced by both NDO 008 and R(+)-8-OH-DPAT was fully blocked by the active S(+)- enantiomer of the selective 5-HT1A antagonist WAY 100135 and the mixed 5-HT1A/beta-adrenoceptor antagonist L(-)-alprenolol. In contrast, the mixed 5-HT2A/2C antagonists ketanserin and pirenperone were found to be ineffective. Moreover, the beta2-adrenoceptor antagonist ICI 118551, the beta-antagonist metoprolol as well as the mixed beta-adrenoceptor blocker D(+)-alprenolol all failed to modify the deficit of PA retention by NDO 008 and R(+)-8-OH-DPAT. None of the 5-HT1A or 5-HT2A/2C receptor antagonists tested or the beta-blockers altered PA retention by themselves. 5. A 3 day pretreatment procedure (200+100+100 mg kg(-1)) with the tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA) did not alter PA retention and did not prevent the inhibitory action of the 5-HT1A agonists, indicating that their effects on PA do not depend on endogenous 5-HT. 6. The effects of NDO 008 on PA were also studied using a state-dependent learning paradigm. NDO 008 was found to produce a disruption of PA when given either prior to training or retention or both prior to training and retention but it failed to affect PA retention when given immediately after training. .7 These findings indicate that the deficit of passive avoidance retention induced by the 5-HT1A agonists is mainly a result of stimulation of postsynaptic 5-HT1A receptors but not 5-HT2A receptors. The 5-HT1A receptor stimulation appears to interfere with learning processes operating at both acquisition and retrieval.
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PMID:Analysis of the 5-HT1A receptor involvement in passive avoidance in the rat. 980 33


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