Acute and Chronic Changes in the Nigrostriatal Loop After Treatment with Antipsychotic Drugs

Abstract

The allosteric change in tyrosine hydroxylase (TH) in nigrostriatal dopamine (DA) terminals was used to monitor the response of this system to antipsychotic drugs. The activation of striatal TH induced by haloperidol was blocked by: 1) intranigral application of agents that stimulate GABA receptors or elevate GABA in SN, or 2) intrastriatal application of agents that block GABA receptors or decrease striatal GABA. Since blockade of striatal GABA receptors increased the turnover rate of GABA in SN, it appears that striatal GABAergic interneurons may inhibit the striatonigral GABA projections. Additional evidence for a reciprocal relationship between striatal and nigral GABA transmission derives from studies of the effects of chronic antipsychotic treatment or lesions of nigrostriatal DA neurons: 1) GABA turnover in striatum was enhanced, 2) GABA turnover in SN was reduced and 3) GABA receptors in SN became supersensitive. The data suggest that actions of DA in striatum are expressed via changes in striatonigral GABA transmission; by blocking striatal DA transmission, antipsychotic drugs increase GABA activity in striatum and reduce GABA utilization in SN. The increase in GABA receptors in SN resulting from chronic exposure to antipsychotics may account for the decline of the effect of these drugs on striatal TH; it may also alter the response of non-DA nigral efferents that are important for motor control. Alteration of striatonigral GABA function may therefore mediate some of the time-dependent behavioral changes produced by long-term antipsychotic drug treatment.