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)

This study examined the influence of s.c. administration of 5-hydroxytryptamine (HT)1A agonists upon the antinociceptive action of s.c. injected morphine in tail-flick tests to noxious heat and pressure. The selective 5-HT1A agonist, (+-)-8-hydroxy-diprolaminotetralin HBr (8-OH-DPAT), dose-dependently antagonized morphine-induced antinociception (MIA) without affecting the latency to respond when applied alone. In the presence of increasing doses of 8-OH-DPAT (0.16-0.63 mg/kg), the morphine dose-response curve was shifted progressively in parallel to the right and the maximal effect of morphine was not altered; Schild analysis yielded a slope of close to -1.0. 8-OH-DPAT both prevented and reversed the action of morphine. The action of 8-OH-DPAT was reversible (at 24 hr). In distinction, 8-OH-DPAT neither blocked morphine-induced Straub tail nor precipitated withdrawal in morphine-dependent animals; thus, it lacked opioid-antagonist properties. The antagonism of MIA by 8-OH-DPAT was mimicked by additional drugs acting as high efficacy 5-HT1A agonists: lisuride, 5-methoxy-N,N-dimethyltryptamine hydrogen oxalate, RU 24969 [methoxy-3-(1,2,3.6-tetrahydropyridin-4-yl)-1H-indole] and d-lysergic acid diethylamide. In contrast, the 5-HT1B/1C agonist, TFMPP m-trifluromethylphenylpiperazine HCl, and the 5-HT1C/2 agonist, DOI (+-)-2,5-dimethoxy-4-iodophenyl-2-aminopropane HCI, were ineffective. The putative selective 5-HT1A antagonists, BMY 7378 [(8-[-[4-(2-,ethoxyphenyl)-1-piperazinyl]ethyl]-8-azaspirol[4]- decane-7,9-dione-2-HCL] and spiperone, did not reduce MIA. Indeed, BMY 7378 blocked the ability of 8-OH-DPAT to antagonize MIA. Under the present conditions, agonists and antagonists at adrenergic and dopaminergic receptors did not attenuate MIA. These data show that, over a certain range of doses, the systemic administration of 8-OH-DPAT and other high efficacy 5-HT1A agonists functionally antagonizes the antinociceptive action of systemically applied morphine in a competitive-like manner. It is suggested that 5-HT1A receptors play an important role in the modulation of opioidergic antinociceptive mechanisms.
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PMID:5-hydroxytryptamine (HT)1A receptors and the tail-flick response. II. High efficacy 5-HT1A agonists attenuate morphine-induced antinociception in mice in a competitive-like manner. 167 80

This study pharmacologically characterizes a novel behavioral response as a potential in vivo model of serotonin (5-HT)1A receptor-mediated activity. In rats restrained in horizontal cylinders, the selective 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino) tetralin HBr (8-OH-DPAT), dose-dependently (0.04-10.0 mg/kg s.c.) elicited spontaneous tail-flicks (STFs). This action was mimicked by other ligands possessing high affinity and high efficacy at 5-HT1A sites: RU 24969 [(5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole], lisuride, (+)-lysergic acid diethylamide and 5-methoxy-N,N-dimethyltryptamine hydrogen oxalate. The response could not be elicited by CGS 12066B [7-trifluormethyl-4-(4-methyl-l-piperazonyl)-pyrrolol- [1-2-a] quinoxaline dimaleate], mCPP 1-(3-chlorophenyl)-piperazine-2-HCl, TFMPPm-trifluromethylphenylpiperazine HCl, MK 212 [6-chloro-2-(l-piperzinyl)pyrazine], quipazine and DOI (+-)-2,5-dimethoxy-4-iodophenyl-2-aminopropane HCl, which act in vivo as agonists at 5-HT1B, 5-HT1C and/or 5-HT2 receptors, or by the 5-HT3 agonist, 2-methyl-5-HT. p-chloroamphetamine, which releases endogenous 5-HT, also evoked STFs; in contrast, d-amphetamine, a preferential releaser of catecholamines, was inactive, as were agonists and antagonists at alpha-1, alpha-2, beta-1, beta-2, dopamine D1 and D2 sites. 8-OH-DPAT-elicited STFs were blocked by the 5-HT1/2 antagonist, methiothepin, but not by the 5-HT1C/5-HT2 antagonists, mianserin, ritanserin and ICI 169,369 [2-(2-dimethylaminoetheylthio)-3-phenylquinoline] nor by the 5-HT3 antagonists, GR 38032F [(1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-l-yl)methyl]-4H- carbazol-4-one HCl], ICS 205,930 [(3 alpha-tropanyl)-1H-indol-3-carboxylic acid ester] and MDL 72222 [(1 alpha H, 3 alpha, 5 alpha H)-tripan-3-yl-3,5- dichlorobenzoate]. beta-Blockers with 5-HT1A affinity i.e., (-)-alprenolol, (+/-)-isamoltane and, stereoselectivity, (-)-but not (+)-pindolol, blocked the action of 8-OH-DPAT. Spiperone and spiroxatrine, D2 antagonists with high 5-HT1A affinity, also inhibited 8-OH-DPAT-induced STFs. Selective beta-blockers and D2 antagonists with low 5-HT1A affinity were inactive. 5-HT1A partial agonists, the pyrimidinylpiperazines, buspirone, gepirone and ipsapirone, the halogenated phenylpiperazine, LY 165,163 [1-(2-(4-aminophenyl) ethyl-4-(3-trifluoromethylphenyl)-piperazine], and the benzodioxane, MDL 72832 [8-(4-(1,4-benzodioxan-2-yl-methylamino)-butyl-8-azaspiro-(4 ,5)-decane- 7,9-dione] did not elicit STFs and antagonized the effect of 8-OH-DPAT.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:5-hydroxytryptamine (5-HT)1A receptors and the tail-flick response. I. 8-hydroxy-2-(di-n-propylamino) tetralin HBr-induced spontaneous tail-flicks in the rat as an in vivo model of 5-HT1A receptor-mediated activity. 182 33

A group of ten rats was trained to obtain food pellets in an 8-arm radial maze. The effects of pretreatment with (+)-Lysergic acid diethylamide (+)-tartrate (LSD), m-trifluoromethylphenylpiperazine (TFMPP), 5-methoxy-N,N-dimethyltryptamine oxalate (5-MeO-DMT), racemic 8-hydroxy-2-(di-n-propylamino)tetralin HBr (8-OH-DPAT), and 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole succinate (RU 24969) were then evaluated. All drugs were administered IP 15 min before testing. With the exception of an increased rate of responding at a dose of 0.1 mg/kg of 8-OH-DPAT, all drugs produced a dose-related decline in response rate. In addition, LSD, RU 24969, and 8-OH-DPAT caused a statistically significant decrease in efficiency of responding. Of the three, 8-OH-DPAT was clearly the most active. Doses of 0.3, 1.0, and 3.0 mg/kg resulted in efficiencies of 61%, 53%, and 44%, respectively. The present results taken in light of 8-OH-DPAT's preferential binding to 5-HT1A receptors, the high density of these receptors in hippocampus, and the observation that the number of 5-HT1A receptors is decreased in Alzheimer's disease, suggest a possible role for this serotonergic receptor subtype in memory.
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PMID:The effects of 8-hydroxy-2-(di-n-propylamino)tetralin and other serotonergic agonists on performance in a radial maze: a possible role for 5-HT1A receptors in memory. 295 85

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

Systemic administration of 5-hydroxytryptophan (5-HTP) to guinea pigs causes species-specific, rhythmic, whole body jerks (myoclonic jerks), the frequency and amplitude of which were measured in an automated apparatus. The brain penetrant 5-HT1D receptor agonist 3-(2-dimethylaminoethyl)-4-chloro-5-propoxyindole hemifumarate (SKF 99101H) (3-30 mg/kg i.p.) and the selective 5-HT1A receptor agonist (+/-)8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (0.3-3 mg/kg s.c.) dose dependently potentiated the frequency and intensity of myoclonic jerks caused by 5-HTP (100 mg/kg). Cotreatment of guinea pigs with 8-OH-DPAT (3 mg/kg s.c.) and SKF 99101H (30 mg/kg i.p.), which were inactive when given alone, gave a marked myoclonic jerk response. Conversely, the myoclonic jerk response to higher doses of 5-HTP (150 mg/kg i.p.) was dose dependently blocked by the 5-HT1D receptor antagonist GR 127935 (N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1 ,2,4-oxadiazol-3-yl)[1,1'-biphenyl]4-carboxamide oxalate) (ED50 0.32 mg/kg i.p.) and the selective 5-HT1A receptor antagonist WAY 100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride) (ED50 0.33 mg/kg i.p.). The response to 5-HTP (150 mg/kg i.p.) was also blocked by ritanserin (0.01-0.3 mg/kg i.p.). Our data therefore confirm previous reports concerning the effects of 5-HT2A/2C receptor blockade on 5-HTP induced myoclonic jerks and suggest that both 5-HT1D and 5-HT1A receptors play an important role in mediating this behavioural response.
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PMID:The role of 5-HT1D and 5-HT1A receptors in mediating 5-hydroxytryptophan induced myoclonic jerks in guinea pigs. 875 Jul 41

Whole cell patch-clamp recordings were obtained from projection neurons and interneurons of the rat basolateral amygdala (BLA) to understand local network interactions in morphologically identified neurons and their modulation by serotonin. Projection neurons and interneurons were characterized morphologically and electrophysiologically according to their intrinsic membrane properties and synaptic characteristics. Synaptic activity in projection neurons was dominated by spontaneous inhibitory postsynaptic currents (IPSCs) that were multiphasic, reached 181 +/- 38 pA in amplitude, lasted 296 +/- 27 mS, and were blocked by the GABAA receptor antagonist, bicuculline methiodide (30 microM). In interneurons, spontaneous synaptic activity was characterized by a burst-firing discharge patterns (200 +/- 40 Hz) that correlated with the occurrence of 6-cyano-7-nitroquinoxaline-2,3-dione-sensitive, high-amplitude (260 +/- 42 pA), long-duration (139 +/- 19 mS) inward excitatory postsynaptic currents (EPSCs). The interevent interval of 831 +/- 344 mS for compound inhibitory postsynaptic potentials (IPSPs), and 916 +/- 270 mS for EPSC bursts, suggested that spontaneous IPSP/Cs in projection neurons are driven by burst of action potentials in interneurons. Hence, BLA interneurons may regulate the excitability of projection neurons and thus determine the degree of synchrony within ensembles of BLA neurons. In interneurons 5-hydroxytryptamine oxalate (5-HT) evoked a direct, dose-dependent, membrane depolarization mediated by a 45 +/- 6.9 pA inward current, which had a reversal potential of -90 mV. The effect of 5-HT was mimicked by the 5-HT2 receptor agonist, alpha-methyl-5-hydroxytryptamine (alpha-methyl-5-HT), but not by the 5-HT1A receptor agonist, (+/-) 8-hydroxydipropylaminotetralin hydrobromide (8-OH-DPAT), or the 5-HT1B agonist, CGS 12066A. In projection neurons, 5-HT evoked an indirect membrane hyperpolarization ( approximately 2 mV) that was associated with a 75 +/- 42 pA outward current and had a reversal potential of -70 mV. The response was independent of 5-HT concentration, blocked by TTX, mimicked by alpha-methyl-5-HT but not by 8-OH-DPAT. In interneurons, 5-HT reduced the amplitude of the evoked EPSC and in the presence of TTX (0.6 microM) reduced the frequency of miniature EPSCs but not their quantal content. In projection neurons, 5-HT also caused a dose-dependent reduction in the amplitude of stimulus evoked EPSCs and IPSCs. These results suggest that acute serotonin release would directly activate GABAergic interneurons of the BLA, via an activation of 5-HT2 receptors, and increase the frequency of inhibitory synaptic events in projection neurons. Chronic serotonin release, or high levels of serotonin, would reduce the excitatory drive onto interneurons and may act as a feedback mechanism to prevent excess inhibition within the nucleus.
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PMID:Serotonergic modulation of neurotransmission in the rat basolateral amygdala. 1040 Sep 36