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 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.