ALTERATIONS IN MODULATION OF ACETYLCHOLINE-RELEASE FOLLOWING LESION OF HIPPOCAMPAL CHOLINERGIC NEURONS WITH THE NEUROTOXIN AF64A

Accumulation of acetylcholine (ACh) following administration of physos tigmine or tetrahydroaminoacridine (THA) normally inhibits further evo ked release of ACh through presynaptic muscarinic receptors. However, in cerebral cortical slices from patients with Alzheimer's disease, AC h release is enhanced by THA, an effect mediated via nicotinic recepto rs. In this study, the effects of THA and physostigmine were examined in hippocampal slices from rats in which cholinergic neurons were lesi oned with the neurotoxin ethylcholine mustard aziridinium (AF64A). Phy sostigmine and THA did not reduce the evoked release of ACh in lesione d tissues as they did in controls, and THA significantly increased rel ease. The enhancement of release by THA was blocked by the nicotinic a ntagonist mecamylamine, suggesting that it was mediated through nicoti nic receptors. Direct stimulation of muscarinic receptors with oxotrem orine significantly reduced ACh release in control tissues, but had no effect in lesioned slices, indicating that presynaptic muscarinic rec eptors were no longer operative. These results suggest that adaptive c hanges in nicotinic and muscarinic receptors occur in AF64A-treated ra ts which are similar to those reported in Alzheimer's disease.