LESION WITH THE NEUROTOXIN AF64A ALTERS HIPPOCAMPAL CHOLINERGIC RECEPTOR FUNCTION

The effect of selective lesion of cholinergic inputs to the hippocampu s on the function of hippocampal cholinergic receptors was examined. H ippocampal cholinergic neurons were lesioned in the rat by administrat ion of the selective cholinergic neurotoxin AF64A (ethylcholine mustar d aziridinium). Cholinergic receptor function was examined by assessin g the ability of cholinergic agonists and antagonists to modulate the evoked release of radiolabelled acetylcholine (ACh) from hippocampal s lices. Nicotine enhanced release, with a bell-shaped dose-response cur ve. The dose-response curve and EC(50) for nicotine was shifted 10-fol d to the left in lesioned rats, suggesting an increased sensitivity to nicotine. However, there were no differences in either the number or affinity of nicotinic receptors as determined with binding studies. Th e muscarinic agonist oxotremorine inhibited the evoked release of ACh in control tissues, but had much less effect in AF64A-lesioned tissues . Binding to the M1 receptor subtype was not changed. However, the K-d for binding to the high affinity subtype of the M2 receptor was incre ased 10-fold, suggesting that the receptor has become less sensitive t o stimulation. Loss of M2 function may allow an increase in the effect of stimulating nicotinic receptors that modulate ACh release.