Alteration of GABA receptors in rat substantia nigra after chronic treatment with antischizophrenic drugs

Abstract

Antischizophrenic drugs cause activation of striatal tyrosine hydroxylase (TH) when acutely injected. This effect on TH was blocked when GABA receptors in substantia nigra (SN) were stimulated by microinjection of muscimol. After chronic administration, there was a decline in the ability of haloperidol or chlorpromazine to activate TH; this apparent tolerance could be detected for at least two weeks after cessation of drug treatment. Since GABA receptors in SN appeared to participate in the acute action of these drugs, it was possible that the tolerance to TH activation might reflect alterations in GABA receptors. This possibility was investigated by measuring ( 3H)GABA binding in SN of rats that had received chronic (8 week) drug treatment. Chronic chlorpromazine (20 mg/kg/day) and haloperidol (1.0 mg/kg/day), but not clozapine (20 mg/kg/day), caused a significant increase (35%) in specific ( 3H)GABA binding in SN; the amount of binding sites (B max) increased without a change in the apparent affinity (K D) of the receptors for GABA. Under the same conditions, no change was seen in GABA binding in striatum. The increase in GABA binding sites in the SN may be a compensatory response to a chronic decrease in nigral GABAergic transmission occurring as an indirect result of striatal dopamine receptor blockade. While the change in GABA receptors in SN may participate in the decline of the effect of these drugs on striatal TH, it may also alter the activity of nigral efferents which are not dopaminergic. It was found that after complete transection of pathways between SN and forebrain, GABA receptors in SN remained intact, as indicated by binding studies and the ability of muscimol microinjection to induce contralateral turning behavior. Thus, GABA receptors located on projections descending from the SN may be important for motor control. Alteration of these receptors may mediate some of the time-dependent behavioral changes—tolerance to catalepsy and akinesia, enhancement of responsiveness to dopamine-agonists, emergence of tardive-dyskinesias—resulting from chronic antischizophrenic drug treatment.