Differential effects of long-term treatment with clozapine or haloperidol on GABA A receptor binding and GAD 67 expression

Abstract

One of the most consistent findings in postmortem studies of schizophrenia is increased GABA A receptor binding and reduced glutamic acid decarboxylase (GAD 67) expression. Due to long-term antipsychotic treatment before death, these findings may reflect not only the consequences of schizophrenia but also medication effects. To differentiate between these options, we used an animal model and evaluated long-term effects of typical (haloperidol) and atypical (clozapine) antipsychotic drugs on the GABAergic system. A total of 33 adult male rats were treated in three cohorts over a period of 6 months. One cohort of 11 animals received clozapine (45 mg/kg/day), another one received haloperidol (1.5 mg/kg/day) and a third one received pH-adapted minimal concentrations of HCl in the drinking water. Receptor autoradiography of the GABA A receptor ([ 3H]-muscimol binding) and in situ hybridization in adjacent sections with 35S-labeled cRNA probes of the γ-aminobutyric acid (GABA)-producing enzyme, GAD 67, was performed. While haloperidol increased GABA A receptor binding in striatum and nucleus accumbens (NA), it suppressed GABA A receptor binding in temporal (TEMPC) and parietal (PARC) cortex. Clozapine induced GABA A receptor binding in infralimbic cortex (ILC) and similar like haloperidol in anterior cingulate cortex (ACC), two regions of the limbic cortex. In addition, either drug increased gene expression of GAD 67. It is concluded that antipsychotic drugs differentially alter the GABAergic system, strongly suggesting that drug effects are partially responsible for the up-regulation of GABA A receptor binding in certain brain regions as observed in postmortem brains of schizophrenic patients. However, the reduced GAD 67 expression seen in postmortem brains does not appear to reflect drug effects, since our animal model demonstrated increased gene expression.