cgs-12066b and 1-(3-chlorophenyl)piperazine

1. In the present study, we analysed the effect of different doses of 5-hydroxytryptamine (5-HT; intravenous infusions of 0.001-40 microg/kg per min) in the autoperfused hindquarters of the rat subjected to electrical stimulation (frequencies of 0.5-20 Hz) of the lumbar chains, investigating the relationship between the adrenergic and serotonergic systems in this vascular bed. 2. Because we observed that 5-HT inhibited the increases in perfusion pressure induced by electrical stimulation of the lumbar chains, we used different agonists and antagonists to analyse the mechanism of action of 5-HT. 3. The effect of 5-HT was inhibited by methiothepin (a non-specific 5-HT receptor antagonist), but not by ritanserin (a selective 5-HT2 receptor antagonist). The effects of 5-HT were mimicked by 5-carboxamidotryptamine (a 5-HT1 receptor agonist) and L-694 247 (a selective 5-HT1D receptor agonist), but not by 8-hydroxy-2-dipropylaminotetralin (a 5-HT1A receptor agonist), CGS-12066B (a 5-HT1B receptor agonist), alpha-methyl-5-HT (a 5-HT2 receptor agonist), 1-(3-chlorophenyl) piperazine (a 5-HT2C receptor agonist) or 1-phenylbiguanide (a 5-HT3 receptor agonist). The selective 5-HT1D/1B receptor antagonist BRL 15572 inhibited the effect of the agonist L-694 247. 4. Our data suggest that 5-HT inhibits the increases in perfusion pressure induced by the electrical stimulation of the lumbar chains, acting on presynaptic 5-HT1D receptors and decreasing the release of noradrenaline from the sympathetic nerves in the hindquarter vascular bed of the rat.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Biguanides; Biphenyl Compounds; Dose-Response Relationship, Drug; Electric Stimulation; Hindlimb; In Vitro Techniques; Infusions, Intravenous; Male; Methiothepin; Oxadiazoles; Perfusion; Piperazines; Pressure; Quinoxalines; Rats; Rats, Wistar; Ritanserin; Serotonin; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT3 Receptor Agonists; Serotonin Agents; Serotonin Antagonists; Serotonin Receptor Agonists; Tryptamines; Vasoconstriction

The changes in the latency for tail withdrawal in response to noxious heating of the skin induced by microinjection of opioid or serotonergic agonists into the anterior pretectal nucleus (APtN) was studied in rats. The mu-opioid agonist DAMGO (78 and 156 picomol), but not the delta-opioid agonist DADLE (70 and 140 pmol), the kappa-opioid agonist bremazocine (0.24 and 0.48 nanomol) or the sigma-opioid agonist N-allylnormetazocine (0.54 nanomol), produced a dose-dependent antinociceptive effect. The 5-HT1 agonist 5-carboxamidotryptamine (19 and 38 nanomol) and the 5-HT1B agonist, CGS 12066B (1.12 and 2.24 nanomol), but not the non-selective 5-HT agonist m-CPP (41 to 164 nanomol), 5-HT2 agonist alpha-methylserotonin (36 and 72 nanomol) and 5-HT3 agonist 2-methylserotonin (36 and 72 nanomol), produced a dose-dependent antinociceptive effect. These results indicate that the antinociceptive effects of opioid or serotonergic agonists microinjected into the APtN depend on drug interaction with local mu or 5-HT1B receptors, respectively.

Topics: Analgesics; Animals; Benzomorphans; Brain; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Leucine-2-Alanine; Enkephalins; Male; Microinjections; Pain; Phenazocine; Piperazines; Quinoxalines; Rats; Rats, Wistar; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Serotonin; Serotonin Receptor Agonists

The present study examined functional supersensitivity to 5-hydroxytryptamine (5-HT) and 5-HT ligands selective for 5-HT1, 5-HT2 and 5-HT3 receptors in two tests for nociception following the spinal administration of 5,7-dihydroxytryptamine (5,7-DHT). Intrathecal pretreatment with 5,7-DHT 30-100 micrograms (following desipramine) produced a selective depletion of spinal cord 5-HT levels of > 80% and augmented the antinociceptive action of 5-HT in the tail flick and hot plate tests. The tail flick test was the more sensitive test for expression of this action. Supersensitivity was observed with the 5-HT1 receptor ligands CGS 12066B (7-trifluoromethyl-4-(4-methyl-1-piperazinyl-pyrrolo[1,2-a] quinoxalinedimaleate), RU 24969 (5-methoxy-3-(1,2,4,6-tetrahydro-4-pyridinyl)1H indole succinate), TFMPP (m-trifluoromethylphenyl-piperazine HCl), mCPP (1-(3-chlorophenyl)piperazine dihydrochloride) and 5-Me-ODMT (5-methoxy-N,N-dimethyltryptamine hydrogen oxalate) but not with the 5-HT2 receptor ligand DOI ((+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane HCl) or the 5-HT3 receptor ligand 2-Me-5-HT (2-methyl-5-hydroxytryptamine maleate) in the tail flick test. In the hot plate test, supersensitivity was observed only with 5-Me-ODMT. Intrathecal pretreatment with fluoxetine, a 5-HT uptake inhibitor, potentiated the action of 5-HT but not any of the other 5-HT1 receptor ligands examined. These results indicate that supersensitivity occurs with 5-HT and 5-HT1 receptor ligands but not with 5-HT2 or 5-HT3 receptor ligands. Both the loss of uptake sites and receptor upregulation may contribute to enhanced activity of 5-HT, but for other ligands, only the latter mechanism appears to occur.

Topics: 5,7-Dihydroxytryptamine; Amphetamines; Analgesia; Analgesics; Analysis of Variance; Animals; Binding Sites; Indoles; Injections, Spinal; Male; Pain; Piperazines; Quinoxalines; Radioligand Assay; Rats; Rats, Sprague-Dawley; Serotonin Receptor Agonists; Up-Regulation

The effect of the serotonergic receptor agonist 1-(m-trifluoromethylphenyl)piperazine (TFMPP) was studied on the K(+)-evoked [3H]acetylcholine [( 3H]ACh) release from guinea pig hippocampal synaptosomes loaded with [3H]choline. TFMPP (5-1,000 microM) inhibited the evoked ACh release in a dose-dependent manner (IC50 = 81.8 microM). The inhibitory effect of TFMPP was mimicked by CGS-12066B (10, 30, and 100 microM), a 5-hydroxytryptamine1B (5-HT1B)/5-HT1D receptor agonist; 1-(m-chlorophenyl)piperazine (100 microM), a 5-HT1C/5-HT1B receptor agonist; and 5-carboxamidotryptamine (10 microM), a nonselective 5-HT1 receptor agonist. 8-Hydroxy-2-(di-n-propylamino)tetralin (10 and 100 microM), a 5-HT1A receptor agonist, and quipazine (10 and 100 microM), a 5-HT2 receptor agonist, did not have any significant effect. Serotonergic antagonists, such as dihydroergotamine (0.1 and 1 microM), metergoline (0.1 microM), methysergide (0.5 and 1 microM), or yohimbine (1 and 10 microM), blocked the TFMPP effect dose-dependently. In contrast, methiotepine (0.3 and 1 microM), propranolol (1 microM), ketanserin (0.1 microM), mesulergine (0.1 microM), ICS 205930 (0.1 and 1 microM), and spiroperidol (1 and 7 microM) did not affect the TFMPP-induced inhibition of the evoked ACh release. These data suggest that, in guinea pig hippocampus, the K(+)-evoked ACh release is modulated by a 5-HT1 receptor distinct from the 5-HT1A, 5-HT1B, and 5-HT1C subtypes.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Acetylcholine; Animals; Guinea Pigs; Hippocampus; Male; Piperazines; Potassium; Quinoxalines; Quipazine; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Synaptosomes; Tetrahydronaphthalenes

Although the serotonergic system has been implicated in the modulation of anxiety states, the specific receptor subtypes that mediate these states require clarification. The effects of drugs that act preferentially at 5-HT1B receptors were evaluated on the behavior elicited in the elevated plus-maze, an animal model of anxiety. Variations in the intensity of light affected mouse behavior in the plus-maze; lower light intensity increased the entries to and time spent on the open arm in a manner similar to that seen with stress-attenuating circumstances. Opposite effects were observed in high light-intensity, similar to effects seen under elevated stress conditions. Chlordiazepoxide produced increased entries and time spent on the open arm, whereas pentylenetetrazol (PTZ) produced opposite effects. The preferential 5-HT1B agents TFMPP and mCPP exhibited a profile similar to PTZ. The effects of TFMPP in the plus-maze were reversed by chlordiazepoxide, but not by the benzodiazepine receptor antagonist flumazenil, which suggests that this effect is not directly mediated by benzodiazepine receptors. The decreased entries and time spent on the open arm of the maze following TFMPP or mCPP administration was possibly mediated by an antagonistic action at 5-HT1B receptors, since this effect was reversed by the selective 5-HT1B agonist CGS 12066B. The present study further demonstrates the utility of mouse behavior in the elevated plus-maze as a model for identifying anxio-modulatory substances.

Topics: Animals; Anti-Anxiety Agents; Anxiety Disorders; Chlordiazepoxide; Male; Mice; Mice, Inbred Strains; Models, Psychological; Pentylenetetrazole; Piperazines; Quinoxalines; Serotonin

Previously, it has been shown that, in small doses, putative 5-HT1A receptor agonists selectively increase ingestion of hypertonic saline without affecting either water or isotonic saline intake. Evidence was obtained in the present series of experiments for selective reduction in hypertonic saline following the administration of a variety of serotonergic directly- and indirectly-acting agonists. Water, isotonic saline (0.9%), or hypertonic saline (1.8%) were made available to separate groups of water-deprived rats. The results indicated some selectivity with the 5-HT-uptake inhibitor and releaser d-fenfluramine and the 5-HT uptake inhibitor fluoxetine, and with the 5-HT agonists mCPP [1-3-chlorophenyl)piperazine] and MK 212 [6-chloro-2-(1-piperazinyl)pyrazine]. In each case, hypertonic intake was significantly suppressed. Distinct from these compounds were TFMPP [1-(3-(trifluoromethyl)phenyl)piperazine], RU 24969 [5-methoxy-3-(1,2,3,6-tetrahydropyridinyl)1H-indole], and quipazine. This second group either reduced fluid intake indiscriminately or reduced water and isotonic saline drinking. Selective reduction in the intake of hypertonic saline did not occur. Finally, peripheral-administration of 5-HT or the 5-HT1B agonist CGS 12066B [7-trifluoromethyl-4(4-methyl-1-piperazinyl-pyrolo) (1,2-a) 1:2 maleate], had no significant effect on fluid intake in any fluid condition. The results are discussed in terms of a possible serotonergic mechanism which may underlie inhibition of hypertonic salt drinking, and which involves mediation through a subtype of the 5-HT1 receptor.

Topics: Animals; Dose-Response Relationship, Drug; Drinking Behavior; Fenfluramine; Fluoxetine; Hypertonic Solutions; Indoles; Male; Piperazines; Pyrazines; Quinoxalines; Quipazine; Rats; Receptors, Serotonin; Serotonin