Additivities of Compounds that Increase the Numbers of High Affinity [3H]Muscimol Binding Sites by Different Amounts Define More than 9 GABAA Receptor Complexes in Rat Forebrain: Implications for Schizophrenia and Clozapine Research

摘要: Background The numbers of [3H]MUS binding sites were reported to be elevated in layers II and III, but not V or VI, cingulate cortex schizophrenic brains post mortem. These increases are probably due compensatory up-regulation GABAA receptors on pyramidal cells as a consequence selective loss GABAergic interneurons layer cortex. number [3H]flunitrazepam was reduced cortex, this may directly reflect the interneurons. Chronic administration clozapine rats significantly reduce temporal hippocampus which blockade that make synaptic contact with cells. Basket well other can also generate both theta gamma oscillations. Clozapine power EEG. Schizophrenic patients show EEG at 40 Hz (gamma frequency) lower frequencies during auditory stimulation. receptor blocker bicuculline 10 nM, μM, increase amplitude slow oscillations (≤1 Hz) rat hippocampal slices. It therefore seems possible clozapine, by selectively blocking another receptor, could Findings Twenty-six compounds inhibit [35S]TBPS ways reversible nM R-5135 found membranes prepared from whole forebrain. In almost all cases little effect affinity (Kd) for [3H]MUS. Concentration-response curves revealed maximum (Esat) ranging 140% (for meclizine) 313% control honokiol. Additivity experiments showed propofol (44% above control) diflunisal (50% entirely additive, there small, significant overlap, suggesting existence three groups defined diflunisal. Meclizine additive diflunisal, indicating fourth site. Alphaxalone is completely meclizine, has an Esat value larger than + fifth mefenamate greater alphaxalone, sixth magnolol then mefenamate, honokiol magnolol, suggesting, proving, seventh eighth group sites. alone, without enhancers represent ninth heterogeneous indicated very low pseudo Hill coefficients strychnine displacing enhancer. Altogether, our results suggest more 9 different weak overall displacer (IC50 = 280 μM). However, 5 μM 6% (P < 0.0001, n 10) enhanced (∼14%) clotrimazole (∼17%) 17 tested. Tentative conclusions absence bind preferentially less cerebral Conversely, (allosterically) appears block small fraction (10–20%) IC50 micromolar range. This located certain (basket cells?) these would expected firing rate release GABA onto Such generation basket Some appear destroyed selectively, second trimester gestation non-paralytic polio virus, individuals who will later become schizophrenic. Since oscillations, destruction power, observed schizophrenics.