Trans-synaptic stimulation of cortical acetylcholine release after partial 192 IgG-saporin-induced loss of cortical cholinergic afferents.

Environmental and pharmacological stimulation of cortical acetylcholine (ACh) efflux was determined in rats sustaining partial deafferentation of cortical cholinergic inputs. Rats were bilaterally infused with the selective cholinotoxin 192 IgG-saporin (0.005 microgram/0.5 microliter/site) into the frontoparietal cortex. In the first experiment, animals were pretrained to associate the onset of darkness with presentation of a palatable 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 determined in lesioned and sham-lesioned rats. Intracortical infusions of 192 IgG-saporin reduced basal cortical ACh efflux by 47% of sham-lesioned values, consistent with reductions in the density of AChE-positive fibers. In spite of this deafferentation, ZK 93,426 produced a transient potentiation of the cortical ACh efflux induced by the darkness/cereal stimulus similar to that observed in control animals. In the second experiment, the ability of the more efficacious BZR partial inverse agonist FG 7142 (8.0 mg/kg, i.p.) to enhance basal cortical ACh efflux was compared in lesioned and sham-lesioned rats. Again, lesioned rats exhibited an increase comparable to control animals after FG 7142. This drug-induced stimulation of cortical ACh efflux was comparably and completely blocked in both groups by co-perfusion with tetrodotoxin (1.0 microM). These results suggest similarities in the modulation of cortical ACh efflux in intact and partially deafferented rats and indicate the potential of BZR inverse agonists for restoring transmission in animals with partial loss of cortical cholinergic inputs.