Treatment with haloperidol and diazepam alters GABAA receptor density in the rat brain

A significant body of data suggests that GABAA receptors are altered in the CNS of subjects with schizophrenia. However, subjects with schizophrenia are treated with antipsychotic drugs and, in some cases, antipsychotic drugs and benzodiazepines. It has therefore been suggested that the changes in GABAA receptors in the CNS of subjects with schizophrenia are due to such drug treatments. Surprisingly, there appear to be no studies to determine the effect of a combined antipsychotic-benzodiazepine treatment on GABAA receptors. We therefore measured both the GABA binding site ([3H]muscimol) and the benzodiazepine binding site ([3H]flumazenil) in the CNS of rats treated with either haloperidol, diazepam or a combination of the two drugs. The main findings of our study are that treatment with diazepam or the combination of diazepam and haloperidol results in regionally selective increases GABA binding sites but treatment with haloperidol alone decreases the GABA binding site in the thalamus but increases these sites in the hypothalamus. By contrast, treatment with diazepam, haloperidol and a combination of the two drugs resulted in widespread decreases in the number of benzodiazepine binding sites in the rat CNS. The notable exception to this outcome was increased numbers of benzodiazepine binding sites in the frontal cortex of rats that had received diazepam. Our data suggests that there are complex changes in the GABAA receptor following treatment with haloperidol, diazepam or a combination of these drugs. This outcome may be relevant to the therapeutic benefits of using both drugs in conjunction early in the treatment of a psychotic episode.