The effect of ipsapirone and S(-)-pindolol on dopamine release in rat striatum and nucleus accumbens

Serotonin (5-hydroxytryptamine, 5-HT)(1A) receptor agonism and 5-HT2A recep tor antagonism are components in the action of some of the recently develop ed antipsychotic drugs, e.g., clozapine and ziprasidone. However, studies o f the role of 5-HT1A receptor agonism in the ability of these drugs to modu late dopamine (DA) release in the nucleus accumbens (NAC), which may be rel evant to antipsychotic action, are lacking. Thus, we examined the effect of clinically available agents, ipsapirone, a 5-HT1A receptor partial agonist , and the mixed 5-HT1A/(1B)/beta receptor antagonist S(-)-pindolol, on DA r elease in the NAC compared to the striatum (STR). Ipsapirone produced a bip hasic effect; low dose (0.1 mg/kg) decreased, high dose (3 mg/kg) increased and intermediate doses (0.1 and 1 mg/kg) did not change DA release in the NAG, respectively. However, ipsapirone, at all doses (0.3, 1, 3, but not 0. 1 mg/kg) increased striatal DA release. S(-)-pindolol (3, 10, but not 1 mg/ kg) produced a comparable increase in DA release in the NAC and STR. These results suggest that the ability of lower dose of ipsapirone to decrease DA release in the NAC is more likely to be due to 5-HT1A receptor agonism. On the other hand, the effect of higher dose of ipsapirone on striatal DA rel ease may be due td 5-HT1A receptor antagonism, as is the case with S(-)-pin dolol. The mechanism and clinical significance of these results for develop ing antipsychotic drugs is discussed. (C) 1999 Elsevier Science B.V. All ri ghts reserved.