The aim of the study was to obtain supporting evidence, using a behavioral paradigm, of the hypothesis that chromogranin A attenuates transmitter release in the CNS. We studied the effects of chromogranin A injected into the nucleus accumbens on locomotor activity triggered by application of picrotoxin into the ventral tegmental area of rats. Injection of picrotoxin into the ventral tegmental area, which is known to disinhibit dopaminergic mesolimbic neurons, caused a significant increase in horizontal activity. Distance covered during locomotion and movement time increased more than twofold, whereas stereotypy time and number, indices of nonlocomotor behavior, were not significantly affected by picrotoxin. Pressure injection of chromogranin A into the nucleus accumbens prior to injection of picrotoxin into the ventral tegmental area prevented these locomotor effects and had little or no effect on nonlocomotor behavior. Similarly, the picrotoxin-induced activity was prevented by injecting cobalt chloride into the nucleus accumbens. The results show that chromogranin A has an attenuating effect, either directly or indirectly, on dopaminergic neurotransmission in the nucleus accumbens that can be exemplified by inhibiting picrotoxin-induced locomotor activity. Further studies are needed to determine the mechanism of chromogranin A action in the nucleus accumbens.