Decreased pallidal GABA following reverse microdialysis with clozapine, but not haloperidol

Changes in striatopallidal GABA are believed to play a significant role in the motor side effects produced by antipsychotic drugs (APDs). In the current study, we measured extracellular GABA in the globus pallidus (GP) of rats. GABA release was partially impulse- and Ca2+-dependent, as evidenced by decreased efflux following tetrodotoxin (TTX) or removal of Ca2+. In addition, GABA release was significantly increased by high K+ (100 mM KCl) stimulation. Reverse dialysis of the atypical APD, clozapine (1-100 microM), produced a concentration dependent decrease in extracellular GABA. In contrast, the typical APD, haloperidol (1-100 microM), had no significant effect on GABA levels. These results suggest that clozapine has direct actions within the GP, while the effects of haloperidol are most likely mediated through its effects in the striatum. The clozapine-induced decrease in pallidal GABA may account for its low motor side effect liability.