The effects of antipsychotic drugs on GABAA receptor binding depend on period of drug treatment and binding site examined

Changes in GABAA receptors are observed in schizophrenia, with benzodiazepine-sensitive GABAA receptor subtypes being affected differently to other subtypes. However, long-term antipsychotic drug use in schizophrenia may underlie these changes. To test this, we examined the effects of administering a typical (haloperidol) and an atypical (olanzapine) antipsychotic drug on the GABAA receptor agonist (orthosteric) and benzodiazepine (allosteric) binding sites in rat prefrontal cortex. As antipsychotic drugs have delayed maximal therapeutic effects we also examined different drug treatment periods. Male SD rats received a sucrose solution containing either haloperidol (1.5 mg/kg), olanzapine (6.5 mg/kg) or no drug daily for either 7, 14 or 28 days. Sections of rat brain were then labelled with [3H]muscimol, which labels the total population of GABAA receptors, or the benzodiazepine site ligand [3H]flunitrazepam in separate saturation binding experiments using quantitative receptor autoradiography. [3H]Muscimol binding was enhanced in the prefrontal cortex after 7 days but no differences were observed after longer periods of drug administration. In contrast there was a delayed increase in density of benzodiazepine-sensitive GABAA receptors in the PFC, suggesting that antipsychotic drugs have different effects on different GABAA receptor subtypes. These changes in the properties of GABAA receptor binding following antipsychotic drug administration are not consistent with those observed in schizophrenia and suggest a ‘reshuffling’ in GABAA receptor subtypes over time.