192IGG-SAPORIN-INDUCED IMMUNOTOXIC LESIONS OF CHOLINERGIC BASAL FOREBRAIN SYSTEM DIFFERENTIALLY AFFECT GLUTAMATERGIC AND GABAERGIC MARKERS IN CORTICAL RAT-BRAIN REGIONS

To study the effect of reduced cortical cholinergic activity on GPLBAe rgic and glutamatergic mechanisms in cholinoceptive cortical target re gions a novel cholinergic immunotoxin (conjugate of the monoclonal ant ibody 192IgG against the low-affinity nerve growth factor receptor wit h the cytotoxic protein saporin) was applied, which specifically and s electively destroys cholinergic cells in rat basal forebrain nuclei. T o correlate the responses to cholinergic immunolesion in cholinoceptiv e cortical target regions with cholinergic hypoactivity, quantitative receptor autoradiography to measure NMDA, AMPA and kainate glutamate r eceptor subtypes, GABA, and benzodiazepine receptors as well as cholin e uptake sites, and histochemistry to estimate acetylcholinesterase ac tivity were performed in adjacent brain sections. One week. after a si ngle intraventricular injection of 4 mu g of 199IgG-saporin, NMDA rece ptor binding was markedly reduced in cortical regions displaying a red uced activity of acetylcholinesterase and high-affinity choline uptake sites as a consequence of cholinergic lesion, whereas AMPA and kainat e binding sites were significantly increased in these regions. Muscimo l binding to GABA, receptors was increased in the caudal portions of f rontal and parietal cortices as well as occipital and temporal cortex as compared to the corresponding brain regions fi om vehicle-injected control rats. Binding levels of benzodiazepine receptors were not affe cted by the lesion in any of the cortical regions studied. The differe ntial changes in glutamate and GABA receptor subtypes following cholin ergic immunolesion might be regarded as the consequence of a cortical reorganization compensating for the reduced cholinergic presynaptic in put. The data further suggest that presynaptic cortical cholinergic de ficits might affect both glutamatergic and GABAergic functions with di fferent intensity and different directions.