fluvoxamine and ipsapirone

Twelve homing pigeons were trained to discriminate the 5-HT1A receptor agonist flesinoxan (0.25 mg/kg p.o.) from its vehicle in a fixed ratio (FR) 30 two-key operant drug discrimination procedure. Tests for generalization and antagonism showed that compounds with agonistic action at the 5-HT1A receptor, such as 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), buspirone and ipsapirone all substituted for the flesinoxan cue. Compounds with mixed agonistic action at the 5-HT(1A/1B) receptor fully (eltoprazine) or partially (RU24969 (5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl-1H-indole)) substituted for flesinoxan. TFMPP (1-(3-trifluoromethylphenyl)piperazine) and mCPP (1-(3-chlorophenyl)piperazine), both acting at the 5-HT(1B/2C) receptor, did not substitute for flesinoxan, neither did the selective 5-HT re-uptake inhibitor fluvoxamine. The results of the antagonism tests showed that the 5-HT1A receptor antagonists NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine), WAY 100635 ((N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclo-he xane-carboxamide) and the newly developed DU125530 (2-[4-[4-(7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-1-piperazinyl ]butyl]-1,2-benzisothiazol-3(2H)-one-1,1-dioxide) fully (more than 80%) blocked the flesinoxan cue without having substantial effects when given alone. WAY100135 (N-tert-butyl-3-(4-(2-methoxyphenyl)piperazine-1-yl)-2-phenylpropanamide ), (+/-)-pindolol and (S)-UH-301 ((S)-5-fluoro-8-hydroxy-2-(dipropylamino)-tetralin) all partially antagonized the flesinoxan cue. However, both WAY100135 as well as (+/-)-pindolol also partially substituted for flesinoxan in generalization tests. NAN190, (S)-UH-301, WAY100635 and DU125530 were without any activity in the generalization test at the doses tested. The putative 5-HT1A receptor antagonist S15535 (4-benzodioxan-5-yl) 1-(indan-2-yl)piperazine) was identified as a full agonist in the present procedure. Taken together these results suggest that the flesinoxan cue in pigeons is mediated by the 5-HT1A receptor and that DU125530 acts as a full antagonist on the 5-HT1A receptor.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Buspirone; Columbidae; Discrimination Learning; Fluvoxamine; Indoles; Pindolol; Piperazines; Pyridines; Pyrimidines; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Serotonin Antagonists; Serotonin Receptor Agonists; Thiazoles

Effects of fluvoxamine, a relatively selective 5-HT uptake inhibitor, and ipsapirone, a relatively selective 5-HT1A agonist, were studied on the initiation and/or maintenance of the voluntary intake of alcohol, morphine, cocaine, and/or nicotine in rats using the two-bottle free-choice method. Fluvoxamine (30 mg/kg/day in the drinking fluid) when given during existing morphine consumption increased the intake of this drug (1 +/- 1 vs. 3 +/- 1 mg/kg/day) but had no effect on alcohol (2 +/- 2 vs. 2 +/- 2 g/kg/day) or cocaine (10 +/- 10 vs. 13 +/- 10 mg/kg/day) intake. Ipsapirone (10 mg/kg/day in the drinking fluid) when given during existing alcohol or morphine consumption decreased the intake of the first (2 +/- 2 vs. 1 +/- 1 g/kg/day) and increased the intake of the second drug (2 +/- 1 vs. 4 +/- 1 mg/kg/day), but had no effect on nicotine (1 +/- 1 vs. 1 +/- 1 mg/kg/day) or cocaine (7 +/- 8 vs. 7 +/- 6 mg/kg/day) intake. Ipsapirone when given before exposure to the above drugs reduced subsequent alcohol (2 +/- 1 vs. 1 +/- 1 g/kg/day) and increased subsequent morphine intake (2 +/- 2 vs. 4 +/- 1 mg/kg/day), but had no effect on the voluntary consumption of cocaine (8 +/- 7 vs. 10 +/- 6 mg/kg/day) and nicotine (1 +/- 1 vs. 1 +/- 1 mg/kg/day). These results suggest: (1) selective stimulation of 5-HT1A receptors reduces alcohol preference, (2) stimulation of all 5-HT receptors has no effect on alcohol intake, indicating the presence of inhibitory receptors, (3) stimulation of the serotonergic system in general stimulates morphine preference, (4) the serotonin system does not affect nicotine or cocaine preference and (5) the serotonergic system is not involved in the voluntary consumption of all, but-only of some drugs/chemicals of abuse. Recognition of these drug/chemical-specific sites in the brain might lead to a better understanding of differences in drug abuse patterns among humans and help in the development of specific drugs for the treatment of selective drug addictions.

Topics: Alcohol Drinking; Animals; Choice Behavior; Cocaine; Fluvoxamine; Male; Morphine; Narcotics; Nicotine; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Selective Serotonin Reuptake Inhibitors; Serotonin Receptor Agonists

Topics: Analysis of Variance; Animals; Antidepressive Agents; Clomipramine; Clorgyline; Fluvoxamine; Frontal Lobe; Hydroxyindoleacetic Acid; Imipramine; Microdialysis; Monoamine Oxidase Inhibitors; Piperidines; Pyrimidines; Raphe Nuclei; Rats; Serotonin; Stereotaxic Techniques; Tranylcypromine; Tryptophan