Antipsychotic drug administration differentially affects [3H]muscimol and [3H]flunitrazepam GABA(A) receptor binding sites.
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.
Skilbeck
Kelly J
KJ
Department of Pharmacology, Blackburn D06, The University of Sydney, NSW 2006, Australia.
O'Reilly
Jennifer N
JN
Johnston
Graham A R
GA
Hinton
Tina
T
D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001345:Autoradiography; D001569:Benzodiazepines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003720:Densitometry; D005445:Flunitrazepam / Q000378:metabolism*; D006220:Haloperidol / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006624:Hippocampus / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D009118:Muscimol / Q000378:metabolism*; D000077152:Olanzapine; D017397:Prefrontal Cortex / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism*; D011877:Radionuclide Imaging; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism; D013788:Thalamus / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D014018:Tissue Distribution / Q000187:drug effects; D014316:Tritium / Q000378:metabolism
D014150:Antipsychotic Agents; D011963:Receptors, GABA-A; D014316:Tritium; D001569:Benzodiazepines; D009118:Muscimol; D005445:Flunitrazepam; D006220:Haloperidol; D000077152:Olanzapine