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 receptor antagonism are components in the action of some of the recently developed antipsychotic drugs, e.g., clozapine and ziprasidone. However, studies of the role of 5-HT1A receptor agonism in the ability of these drugs to modulate dopamine (DA) release in the nucleus accumbens (NAC), which may be relevant 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 release in the NAC compared to the striatum (STR). Ipsapirone produced a biphasic 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 release may be due td 5-HT1A receptor antagonism, as is the case with S(-)-pindolol. The mechanism and clinical significance of these results for developing antipsychotic drugs is discussed. (C) 1999 Elsevier Science B.V. All rights reserved.