Influence of antipsychotics on presynaptic receptors modulating the release of dopamine in synaptosomes of the nucleus accumbens of rats.

The release of preloaded [3H]dopamine (DA) from superfused synaptosomes stimulated by 30 mM K+ was investigated in the nucleus accumbens of rats. Under conditions preventing the uptake of DA (presence of 40 microM cocaine) release of [3H]DA was inhibited by DA and apomorphine in a concentration-dependent manner (IC50s 0.65 and 0.3 microM, respectively). The maximal inhibitory effects of DA, as well as of apomorphine, were about 50% of the controls. The DA-induced inhibition was antagonized by antipsychotics completely; the rank order of antagonistic potencies was haloperidol greater than clozapine greater than sulpiride; methiothepine was ineffective. Furthermore, the K+-stimulated release of [3H]DA was inhibited by serotonin in a concentration-dependent manner (IC50 = 0.9 microM). This inhibitory effect was antagonized by methiothepine with a high efficiency, by clozapine and methysergide with moderate efficiencies; haloperidol and sulpiride were ineffective. The experimental system demonstrated appears to be suitable for characterizing the DA- and serotonin-antagonistic potencies of antipsychotics and other drugs on presynaptic autoreceptors as well as receptors modulating release of DA in the nucleus accumbens.