Antipsychotic drug administration differentially affects [ 3H]muscimol and [ 3H]flunitrazepam GABA A receptor binding sites

Abstract

Post-mortem studies of the human brain indicate that certain GABA A receptor subtypes may be differentially altered in schizophrenia. Increased binding to the total population of GABA A receptors using [ 3H]muscimol is observed in the post-mortem schizophrenic brain, yet a proportion of these receptors which bind benzodiazepines and are labelled with [ 3H]flunitrazepam, show decreased or unaltered expression. Data from animal studies suggest that antipsychotic drugs alter GABA A receptor expression in a subtype selective manner, but in the opposite direction to that observed in schizophrenia. To broaden our understanding of the effects of antipsychotic drugs on GABA A receptors, we examined the saturation binding maximum ( B max) and binding affinity ( K D) of [ 3H]muscimol and [ 3H]flunitrazepam in the prefrontal cortex (PFC), hippocampus and thalamus of male SD rats that received a sucrose solution containing either haloperidol (1.5 mg/kg), olanzapine (6.5 mg/kg) or no drug daily for up to 28 days using quantitative receptor autoradiography. [ 3H]Muscimol binding density was increased most prominently in the PFC after 7 days, with larger and more prolonged effects being induced by the atypical antipsychotic drug olanzapine in subcortical regions. While no changes were observed in [ 3H]muscimol binding in any region after 28 days of drug administration, [ 3H]flunitrazepam binding density ( B max) was increased for both antipsychotic treatments in the PFC only. These findings confirm that the subset of GABA A receptors sensitive to benzodiazepines are regulated differently from other GABA A receptor subtypes following antipsychotic drug administration, in a time- and region-dependent manner.