Abstract

The effects of antipsychotic drugs (APDs) on brain dopamine receptors in the striatum are ultimately expressed through efferent projections which primarily use amino acid transmitters, including gamma-aminobutyric acid and glutamate. The present study examined the effects of APDs on extracellular amino acid levels in the rat ventral pallidum (VP) and globus pallidus (GP), areas that receive projections from distinct striatal subregions. Clozapine, an APD with low motor side effect liability, and metoclopramide, a low-potency APD with high motor side effect liability, were compared with haloperidol, a widely used APD with high motor side effect liability. Drugs were administered subcutaneously and amino acid levels were monitored concurrently in the VP and GP by intracranial microdialysis. High doses of haloperidol and metoclopramide increased and clozapine decreased extracellular gamma-aminobutyric acid levels in the GP but not the VP. Low, but not high, doses of the three drugs tended to increase extracellular glutamate levels in both pallidal regions. Clozapine, but not the other two drugs, decreased extracellular threonine in the GP and glycine and threonine in the VP. Results indicate a correlation between increased gamma-aminobutyric acid levels in the GP and the propensity of the APDs tested to induce motor side effects. The novel effects of clozapine on extracellular glycine and threonine further distinguish this drug as a unique antipsychotic compound.