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)

Pigeon cerebrospinal fluid was assayed for 5-HT (5-hydroxytryptamine) and catecholamine metabolites after systemic drug injection. The 5-HT1-like receptor agonists 8-hydroxy-(di-n-propylamino)tetralin (8-OH-DPAT), 5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)1H indole (RU 24969), 1-(m-trifluoromethylphenyl)piperazine (TFMPP), and 1-(3-chlorphenyl)piperazine (mCPP) decreased levels of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) without altering other metabolites. 5-HIAA decreases occurred at doses of 8-OH-DPAT and RU 24969 that have anti-conflict effects in pigeons, whereas TFMPP and mCPP decreased 5-HIAA only at behaviorally disruptive doses. The novel compound 1-(2-methoxyphenyl)-1-(4-(2-phthalimido)butyl)piperazine (NAN-190), a putative 5-HT1A receptor antagonist, did not affect 5-HIAA, but attenuated the decreases produced by the agonists. NAN-190 and the alpha 1-adrenoceptor antagonist prazosin increased levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylethylene glycol and had additive effects when co-administered. The rank order of potency in inhibiting [3H]8-OH-DPAT binding in pigeon cerebrum was 8-OH-DPAT = RU 24969 > NAN-190 >> mCPP > TFMPP. The results support suggestions that decreased 5-HT neurotransmission underlies the anxiolytic-like effects of 5-HT1A receptor agonists in pigeons.
Eur J Pharmacol 1992 Dec 15
PMID:Neurochemical effects of 5-HT1 receptor ligands in pigeons. 128 73

The effects on nociception of intrathecal (i.th.) administration of selective 5-HT1A and 5-HT1B agonists were studied in rats. Nociception was evaluated using the tail-flick test with adjustments for tail-skin temperature, the increasing temperature hot-plate test and the scoring of biting and scratching behaviour after i.th. N-methyl-D-aspartate (NMDA). Activation of the spinal 5-HT1A receptor induced an antinociceptive effect in the increasing temperature hot-plate test and produced a dose dependent decrease in NMDA-receptor mediated behaviour. No significant change in nociception measured by either of the nociceptive tests was found after administration of the 5-HT1B agonist. These results support the hypothesis that spinal 5-HT1A receptor activation has an antinociceptive effect, and indicate a possible interaction between the serotonergic and glutaminergic transmitter systems.
Neuroreport 1992 Dec
PMID:The role of 5-HT1A and 5-HT1B receptors in spinal nociceptive transmission and in the modulation of NMDA induced behaviour. 133 83

We have used receptor autoradiography to investigate the distribution and pharmacological profile of non 5-HT1A/5-HT1C[3H]5-hydroxytryptamine binding sites in the brain of rabbits, hamsters and opossums. These data were compared to those found under similar conditions in the brain of rats and guinea pigs, species which are known to possess 5-HT1B and 5-HT1D receptors, respectively. In the presence of 100 nM 8-OH-DPAT and mesulergine, the regional distribution of [3H]5-hydroxytryptamine binding sites was very similar in the brain of all species investigated; densest labelling was observed in the globus pallidus, substantia nigra and superior colliculus. In all species, 5-carboxamidotryptamine competed for the labelled sites in a biphasic manner and metergoline displayed a subnanomolar affinity. In contrast, the beta-adrenoceptor blocking agents (-)propranolol, (-)pindolol, and (+/-)SDZ 21009 were potent displacers only in the rat, hamster and opossum brains. These data indicate that non 5-HT1A/5-HT1C[3H]5-HT binding sites display a high affinity for these agents in a particular rodent suborder as well as in opossum, a phylogenetically unrelated species.
Synapse 1992 Dec
PMID:Non 5-HT1A/5-HT1C [3H]5-HT binding sites in the hamster, opossum, and rabbit brain show similar regional distribution but different sensitivity to beta-adrenoceptor antagonists. 136 Dec 46

PD 118717 (7-[3-[4-(2-pyrimidinyl)-1-piperazinyl]-propoxy]-2H-1- benzopyran-2-one sulfate) proved to be a dopamine (DA) D-2 autoreceptor agonist in biochemical and electrophysiological studies in rats and to exhibit an antipsychotic-like profile in behavioral tests in rodents and monkeys. In vitro binding studies indicated that PD 118717 bound selectively to DA D-2 vs. D-1 receptors and exhibited agonist binding properties (biphasic inhibitory curves and GTP shift) similar to DA. It also had significant affinity for serotonin-(5-HT)1A but not 5-HT1B and 5-HT2 receptors. PD 118717 was active in antagonizing the tau-butyrolactone-induced accumulation of dopa in rat striatum and mesolimbic regions. PD 118717 also depressed the firing of DA neurons in substantia nigra pars compacta of rats. In both of the latter tests the effects of PD 118717 were reversed by haloperidol. PD 118717 decreased brain DA metabolism, decreased DA utilization, decreased accumulation of dopa after inhibition of L-aromatic amino acid decarboxylase, stimulated serum corticosterone and inhibited stimulated serum prolactin levels. PD 118717 did not alter striatal acetylcholine levels; nor did it induce locomotor stimulation or stereotypy in normal animals, suggesting a lack of postsynaptic DA stimulation of normosensitive DA receptors. In tests designed to reveal even weak postsynaptic DA agonist effects, PD 118717 stimulated locomotor activity in 6-hydroxydopamine-lesioned animals and relatively higher doses induced a low degree of stereotyped behavior when combined with the DA D-1 agonist SKF 38393. PD 118717 decreased the accumulation of 5-hydroxytryptophan in brain, an effect probably due to an agonist action at 5-HT1A receptors. PD 118717 decreased spontaneous locomotor activity in rodents, antagonized amphetamine-stimulated hyperactivity in mice and inhibited Sidman avoidance in monkeys, effects seen with antipsychotic agents. Unlike DA antagonist antipsychotics, PD 118717 did not induce extrapyramidal dysfunction in monkeys. PD 118717 displayed behavioral activity after p.o. dosing and its effects did not show tolerance on repeated dosing. In conclusion, PD 118717 has the profile of a DA autoreceptor agonist in neurochemical and neurophysiological tests and produces effects suggestive of antipsychotic efficacy without neurological side effect liability in preclinical behavioral tests.
J Pharmacol Exp Ther 1992 Dec
PMID:Pharmacological characterization of PD 118717, a putative piperazinyl benzopyranone dopamine autoreceptor agonist. 136 70

Previous studies have shown that activation of the 5-HT1A receptor subtype enhances rat plasma ACTH concentration. Such receptors have been suggested to be located on CRH neuronal cell bodies in the paraventricular nuclei of the hypothalamus (PVN). In this report, microinjection of 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a selective 5-HT1A agonist, into the PVN increased rat plasma ACTH concentration in a dose-related manner. Similar responses were observed when two other 5-HT1A agonists, busipirone and gepirone, were used. (+/-)-Pindolol, known to have 5-HT1A antagonist properties, blocked the effect induced by an optimal dose of 8-OH-DPAT after injection into the PVN. This same dose of 8-OH-DPAT also induced a decrease of hypothalamic CRH concentration, which was completely antagonized as well by pretreatment injection of (+/-)-pindolol into the PVN. A significant inverse correlation was found between hypothalamic CRH and plasma ACTH levels. These results confirm that elevation of the plasma ACTH concentration induced by 5-HT1A receptor subtype activation is mediated by the release of CRH from the paraventricular nuclei of the hypothalamus in rats, but do not exclude other mechanisms.
Neuroendocrinology 1992 Dec
PMID:Activation of 5-HT1A receptor subtype in the paraventricular nuclei of the hypothalamus induces CRH and ACTH release in the rat. 136 87

Quantitative autoradiography was used to evaluate the time course and reversibility of corticosterone (CORT)-induced decreases in binding at 5-HT1A receptors in the dorsal hippocampus, cortex and septum of the male rat. Continuous exposure to high levels of CORT decreased binding of [3H]8-hydroxy-2-(di-n-propylamino)tetralin at 5-HT1A receptors in the dentate gyrus and in the oriens and lacunosum moleculare layers of CA4 after 16 to 48 h. CORT-induced decreases in binding were also observed in the dorsal lateral septum after 2-4 days, and in the intermediate lateral septum after 4-8 days of exposure to high levels of CORT. When CORT pellets that had remained in rats for 8 days were removed 3 weeks prior to sacrifice, binding at 5-HT1A receptors increased in comparison to control values in the oriens and lacunosum moleculare layers of CA2, and in layers 4-6 of the parietal/temporal cortex. These increases in binding were associated with very low serum CORT levels, and resembled increases previously observed in those areas in ADX rats. Although removal of CORT reversed the decreases in binding in the septum, no significant increases above control values were observed. Thus, there appear to be differences in the degree of sensitivity in the various brain regions to low and high levels of circulating adrenal steroids.
Neuroendocrinology 1992 Dec
PMID:Quantitative autoradiographic analyses of the time course and reversibility of corticosterone-induced decreases in binding at 5-HT1A receptors in rat forebrain. 136 98

1. The effects of intracerebroventricular injections to the right lateral ventricle (i.c.v.) of 5-hydroxytryptamine (5-HT, 40 and 120 nmol kg-1), N,N-di-n-propyl-5-carboxamidotryptamine (DP-5-CT; 3 nmol kg-1), 5-carboxamidotryptamine (5-CT; 3 nmol kg-1), 8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT; 3, 40 and 120 nmol kg-1) and 1-(2,5-di-methoxy-4-iodophenyl)-2-aminopropane (DOI; 40 and 120 nmol kg-1) on renal sympathetic nerve activity, blood pressure, heart rate and phrenic nerve activity were investigated in normotensive rats anaesthetized with alpha-chloralose. 2. 5-HT caused a long lasting pressor response which was associated with an initial bradycardia and renal sympathoinhibition followed by a tachycardia and renal sympathoexcitation. Pretreatment with the 5-HT2/5-HT1C receptor antagonists, cinanserin (300 nmol kg-1, i.c.v.) or LY 53857 (300 nmol kg-1, i.c.v.) reversed the initial bradycardia and sympathoinhibition to tachycardia and sympathoexcitation. Combined pretreatment with LY 53857 (300 nmol kg-1, i.c.v.) and the 5-HT1A antagonist, spiroxatrine (300 nmol kg-1, i.c.v.), blocked the effects of 5-HT on all the above variables. 3. Pretreatment with the vasopressin V1-receptor antagonist, beta-mercapto-beta,beta-cyclopentamethylene-propionyl1, O-Me-Tyr2, Arg8-vasopressin [(d(CH2)5Tyr(Me)AVP, 10 micrograms kg-1, i.v.] did not affect the magnitude but reduced the duration of the pressor response produced by i.c.v. 5-HT and reversed the initial bradycardia and renal sympathoinhibition to tachycardia and sympathoexcitation. 4. 1-(2,5-Di-methoxy-4-iodophenyl)-2-aminopropane (DOI) caused a pressor effect which was associated with a bradycardia and sympathoinhibition. These effects were blocked by pretreatment with BWSOlC67 (0.1 mg kg-', i.v.), a peripherally acting 5-HT2/5-HTc receptor antagonist. However,BWSOlC67 (0.1 mg kg-', i.v.) failed to block the effects of i.c.v. 5-HT.5. DP-5-CT, 5-CT and 8-OH-DPAT (3 nmol kg-', i.c.v.) caused sympathoexcitation, tachycardia and a rise in blood pressure. Pretreatment with methiothepin (1 mg kg-', i.v.) or spiroxatrine (300 nmol kg-',i.c.v.) attenuated the response to i.c.v. DP-5-CT.6. It is concluded that i.c.v. administration of 5-HT activates 5-HTlA receptors to cause sympathoexcitation and 5-HT2 or 5-HT1c receptors to cause the release of vasopressin.
Br J Pharmacol 1992 Dec
PMID:Central administration of 5-HT activates 5-HT1A receptors to cause sympathoexcitation and 5-HT2/5-HT1C receptors to release vasopressin in anaesthetized rats. 146 25

The effect of trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]-benzene-acetamide methane sulfonate (U-50,488H), a kappa-opiate agonist-induced tolerance and abstinence on 5-HT1A receptors was determined in regions of the brain and spinal cord of the rat. The administration of U-50,488H (25 mg/kg, i.p., twice daily) to male Sprague-Dawley rats for 4 days resulted in the development of almost complete tolerance to its analgesic and hypothermic effects. On day 5, the animals were divided into tolerant and abstinent groups and sacrificed. The brain and spinal cord were excised from all groups of rats and the brain was dissected into 6 regions, namely, amygdala, hypothalamus, striatum, midbrain, pons+medulla and cortex. The 5-HT1A receptors were characterized by using [3H]8-hydroxy-2-(di-n-propylamino)tetralin ([3H]DPAT) as the ligand. The binding constants (Bmax and Kd values) of [3H]DPAT in regions of the brain and spinal cord of rats tolerant to U-50,488H and vehicle did not differ. However, the Bmax value of [3H]DPAT in the hypothalamus of U-50,488H-abstinent rats was decreased but the Kd value did not change. In the other regions of the brain and spinal cord of U-50,488H-abstinent rats, the Bmax and Kd values of [3H]DPAT were unaffected. Subcutaneous administration of DPAT produced hypothermic response in vehicle- and U-50,488H-treated rats. The intensity of this effect was more marked in U-50,488H-abstinent group. It is concluded that 5-HT1A receptors are down-regulated in the hypothalamus of U-50,488H-abstinent rats but the hypothermic response to 5-HT1A agonist is intensified.
Neuropharmacology 1992 Dec
PMID:Abstinence from U-50,488H, a kappa-opiate receptor agonist, decreases the binding of [3H]DPAT to 5-HT1A receptors in the hypothalamus of the rat. 147 Mar

The present paper compares the effects of different serotonergic agonists and antagonists with benzodiazepine derivatives in two animal models of anxiety; the Vogel's and the open-field tests. In the Vogel's conflict test, both diazepam and midazolam produced an anti-punishment action. The drugs 8-OH-DPAT (0.025 and 0.05 mg/kg), buspirone (0.62 mg/kg), gepirone and ipsapirone (0.3 and 0.62 mg/kg, respectively) increased punished intake of water. Ritanserin disinhibited the behaviour of rats at the doses of 2.5 and 5.0 mg/kg and ICS 205-930 (0.001 and 0.01 mg/kg) exerted a marked increase in punished drinking, while ondansetron was active only after the largest dose (1.5 mg/kg). In the open-field test, all drugs increased the number of entries into the central area, as well as the time spent in the central sector of the open-field. The present data indicate similar but not identical spectra of pharmacological sensitivity of both ethologically-oriented and conflict tests, for various classes of anxiolytic drugs. The 5-HT1A receptor agonists and 5-HT2 receptor antagonist have been shown to have similar anxiolytic-like profile to the benzodiazepines but in a narrower dose-range. The 5-HT3 receptor antagonists appeared to be unique in respect to their very strong anti-emotional activity (ICS 205-930), devoid of any clear-cut general inhibitory properties upon locomotion.
Neuropharmacology 1992 Dec
PMID:The comparison of benzodiazepine derivatives and serotonergic agonists and antagonists in two animal models of anxiety. 147 Mar 1

A variety of evidence has led to suggestions that brain serotonin (5-HT) and norepinephrine (NE) interact within the medial hypothalamus to control food intake. To test the possibility that chronic decrements in 5-HT might enhance NE-induced feeding, adult male rats were prepared with permanently indwelling cannulae aimed at the paraventricular nucleus (PVN), then received either intracisternal (IC) or PVN injections of the 5-HT neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT) vs. its vehicle, 1% ascorbic acid. Over a 4-week period, IC-5,7-DHT rats showed no signs of enhanced daily feeding or drinking. However, in 40-min intake tests, feeding but not drinking was enhanced by injecting 20 nmol NE into the PVN commencing 2 weeks after neurotoxin treatment. Terminal monoamine assays confirmed that IC-5,7-DHT produced large (80-90%) depletions of brain regional 5-HT. A functional index of 5-HT terminal damage was also implied by the impaired short-term feeding responses IC-5,7-DHT rats showed to the systemic administration of the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) when tested between 3 and 4 weeks after IC treatment. Over a comparable 4-week period, PVN-5,7-DHT rats also showed no tendencies to overeat or overdrink on a daily basis. However, in contrast to IC-5,7-DHT rats, they also showed no differences in their feeding or drinking responses to NE injections into the PVN. This was so despite reliable depletions of 5-HT in the hypothalamus (-28%) and hippocampus (-71%). These results support earlier work showing that neither widespread nor localized hypothalamic damage to brain 5-HT neurons produce chronic overeating. However, the data suggest that phasic enhancements of PVN NE activity may trigger enhanced feeding when there is widespread damage to brain 5-HT neurons, although the PVN does not appear to be the brain site mediating this effect.
Brain Res 1992 Dec 04
PMID:Effects of intracisternal vs. intrahypothalamic 5,7-DHT on feeding elicited by hypothalamic infusion of NE. 147 2


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