Serotonin-mediated striatal dopamine release involves the dopamine uptake site and the serotonin receptor

Modulation of striatal dopamine (DA) release by serotonin (5HT) and its ant agonists was studied utilizing in vitro perfusion techniques. In isolated s triatal tissue, 5HT (10 muM) increased the fractional basal release of labe led DA. The 5HT(2/1c) antagonist ketanserin (5 muM) also stimulated the bas al release. These two effects were mediated by different mechanisms as coca ine (10 muM) greatly inhibited the 5HT-mediated response, but slightly incr eased the ketanserin-mediated response. 6-Nitroquipazine maleate (10 muM, 5 HT uptake inhibitor) partially inhibited both responses. Inhibition by GBR 12909 (DA uptake inhibitor) at 1 muM of the 5HT-mediated DA release was sim ilar to that of cocaine, but at 10 muM it increased release before addition of 5HT, and maintained elevated DA release while present in the incubation medium. At 1 muM GBR 12909, ketanserin-mediated DA release was stimulated and a much greater release was seen at 10 muM, but the prolonged release wa s not observed as after BHT-mediated release. Among other antagonists methi othepin (5HT(1,2,6) antagonist) also enhanced DA release, whereas oxymetazo line (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) inhi bited 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 transpo rter and that inhibitory presynaptic 5HT heteroreceptors and both inhibitor y and stimulatory somato-dendritic 5HT receptors regulate release. In addit ion to the reversal of the transporter, an inhibitory 5HT(2) component was identified. (C) 2000 Elsevier Science Inc.