TRANSSYNAPTIC STIMULATION OF CORTICAL ACETYLCHOLINE-RELEASE AFTER PARTIAL 192-IGG-SAPORIN-INDUCED LOSS OF CORTICAL CHOLINERGIC AFFERENTS

Environmental and pharmacological stimulation of cortical acetylcholin e (ACh) efflux was determined in rats sustaining partial deafferentati on of cortical cholinergic inputs. Rats were bilaterally infused with the selective cholinotoxin 192 IgG-saporin (0.005 mu g/0.5 mu l/site) into the frontoparietal cortex. In the first experiment, animals were pretrained to associate the onset of darkness with presentation of a p alatable fruit cereal reward. The ability of this stimulus to enhance frontoparietal ACh efflux alone, and with the benzodiazepine receptor (BZR) weak inverse agonist ZK 93,426 (1.0 or 5.0 mg/kg, i.p.), was det ermined in lesioned and sham-lesioned rats. Intracortical infusions of 192 IgG-saporin reduced basal cortical ACh efflux by 47% of sham-lesi oned values, consistent with reductions in the density of AChE-positiv e fibers. In spite of this deafferentation, ZK 93,426 produced a trans ient potentiation of the cortical ACh efflux induced by the darkness/c ereal stimulus similar to that observed in control animals. In the sec ond experiment, the ability of the more efficacious BZR partial invers e agonist FG 7142 (8.0 mg/kg, i.p.) to enhance basal cortical ACh effl ux was compared in lesioned and sham-lesioned rats. Again, lesioned ra ts exhibited an increase comparable to control animals after FG 7142. This drug-induced stimulation of cortical ACh efflux was comparably an d completely blocked in both groups by co-perfusion with tetrodotoxin (1.0 mu M). These results suggest similarities in the modulation of co rtical ACh efflux in intact and partially deafferented rats and indica te the potential of BZR inverse agonists for restoring transmission in animals with partial loss of cortical cholinergic inputs.