cgs-12066b and vanoxerine

Modulation of striatal dopamine (DA) release by serotonin (5HT) and its antagonists was studied utilizing in vitro perfusion techniques. In isolated striatal tissue, 5HT (10 microM) increased the fractional basal release of labeled DA. The 5HT(2/1c) antagonist ketanserin (5 microM) also stimulated the basal release. These two effects were mediated by different mechanisms as cocaine (10 microM) greatly inhibited the 5HT-mediated response, but slightly increased the ketanserin-mediated response. 6-Nitroquipazine maleate (10 microM, 5HT uptake inhibitor) partially inhibited both responses. Inhibition by GBR 12909 (DA uptake inhibitor) at 1 microM of the 5HT-mediated DA release was similar to that of cocaine, but at 10 microM it increased release before addition of 5HT, and maintained elevated DA release while present in the incubation medium. At 1 microM GBR 12909, ketanserin-mediated DA release was stimulated and a much greater release was seen at 10 microM, but the prolonged release was not observed as after 5HT-mediated release. Among other antagonists methiothepin (5HT(1,2,6) antagonist) also enhanced DA release, whereas oxymetazoline (5HT(1A,1B,1D) agonist) had no effect. RS2359-190 (5HT(4) antagonist) had a small effect (slight stimulation) on 5HT-mediated DA release, and no effect on ketanserin-mediated DA release. CGS 12066A (5HT(1B) agonist) inhibited 5HT-mediated DA release. The glutamate antagonist MK-801 and the GABA(A) antagonist bicuculline had no affect on either response. These results indicate that 5HT-mediated DA release occurs via reversal of the DA transporter and that inhibitory presynaptic 5HT heteroreceptors and both inhibitory and stimulatory somato-dendritic 5HT receptors regulate release. In addition to the reversal of the transporter, an inhibitory 5HT(2) component was identified.

Topics: Animals; Bicuculline; Cocaine; Corpus Striatum; Dizocilpine Maleate; Dopamine; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; GABA Antagonists; Ketanserin; Male; Methiothepin; Mice; Mice, Inbred C57BL; Oxymetazoline; Piperazines; Quinoxalines; Quipazine; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists

The effect of 5-HT1B receptor stimulation on dopamine-mediated reinforcement in rats was investigated using intravenous self-administration of the selective dopamine uptake inhibitor GBR-12909 on an FR5 schedule of reinforcement. Pretreatment with the 5-HT1A/1B receptor agonist CGS-12066B (1-10 mg/kg, IP) dose-dependently reduced the self-administration of GBR-12909 (83 micrograms/injection) by increasing the interval between drug injections, consistent with a enhancement of the reinforcing effects of GBR-12909. Additionally, CGS-12066B pretreatment (3 mg/kg, IP) shifted the dose-effect function for GBR-12909 self-administration to the left. Pretreatment with the selective 5-HT1A receptor agonist 8-OH-DPAT (0.03-1.0 mg/kg, SC) had no significant effect on GBR-12909 self-administration (83 micrograms/injection), indicating that the effect of CGS-12066B is not mediated by the 5-HT1A receptor. Finally, CGS-12066B pretreatment (1-10 mg/kg, IP) did not alter the self-administration of cocaine (0.03-0.5 mg/injection), suggesting that the simultaneous stimulation of multiple 5-HT receptor subtypes by the indirect 5-HT agonist properties of cocaine may mask the effect of 5-HT1B receptor stimulation on DA-mediated reinforcement.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Cocaine; Conditioning, Operant; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Narcotics; Piperazines; Quinoxalines; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT1B; Receptors, Serotonin; Self Administration; Serotonin Receptor Agonists

Serotonin (5-HT) and dopamine (DA) are established neurotransmitters in the brain. This study examined whether, in conscious, free-moving rats, increased concentrations of endogenous 5-HT in extracellular fluid of the corpus striatum affect local release of endogenous DA. Administration of the 5-HT reuptake blocker alaproclate via a microdialysis probe increased striatal dialysate levels of DA and its metabolites dihydroxyphenylacetic acid and homovanillic acid as well as levels of 5-HT and the 5-HT metabolite 5-hydroxyindoleacetic acid. Whereas DA reuptake blockade with GBR-12909 did not prevent these effects of alaproclate, serotonergic ablation by i.c.v. administration of 5,7-dihydroxytryptamine markedly decreased basal levels of 5-HT and 5-hydroxyindoleacetic acid and abolished the effects of alaproclate on dialysate levels of DA, 5-HT and their metabolites. The results are consistent with a stimulatory action of endogenous 5-HT on striatal DA release in conscious animals.

Topics: 5,7-Dihydroxytryptamine; Alanine; Animals; Chromatography, High Pressure Liquid; Corpus Striatum; Dopamine; Dopamine Uptake Inhibitors; Male; Microdialysis; Perfusion; Piperazines; Quinoxalines; Rats; Rats, Sprague-Dawley; Selective Serotonin Reuptake Inhibitors; Serotonin; Serotonin Receptor Agonists