The 5-HT3 antagonist zacopride attenuates cocaine-induced increases in extracellular dopamine in rat nucleus accumbens

Pretreatment with the serotonin-3 (5-HT3) antagonist racemic (+/-)-Zacopride hydrochloride (ZAC, 0.1 mg/kg, IP) has been previously found to completely abolish the locomotor activity induced by cocaine (10 mg/kg, IP). To determine if this effect was mediated by fluctuations in the extracellular levels of forebrain dopamine (DA), we examined the ability of ZAC to attenuate cocaine-induced increases in extracellular DA levels. Microdialysis samples were collected from the nucleus accumbens region (NAS) of awake, male, Sprague-Dawley rats. ZAC treatment alone (0.1 mg/kg, IP) did not alter DA levels relative to baseline. However, this dose of ZAC given 1 h prior to cocaine challenge (10 mg/kg, IP) caused a 27% reduction in the peak level of extracellular DA produced by cocaine, relative to saline-pretreated control animals. These results suggest that the ability of ZAC to attenuate cocaine-induced increases in extracellular DA levels may contribute to ZAC's ability to suppress cocaine-induced locomotor activity in the rat. However, additional neurochemical mechanisms are likely to be important in mediating the robust behavioral effects previously reported.