Correlation of the amnestic effects of nicotinic antagonists with inhibition of regional brain acetylcholine synthesis in rats.

Acetylcholine (ACh) is considered to play a primary role in normal mnemonic functioning. Although most research has centered on the central muscarinic cholinergic system, of recent interest in normal and pathologic cognitive processing is the role of the nicotinic cholinergic system. The purpose of this research was to further characterize the role of the nicotinic system in learning and memory processing in a classical passive avoidance task by rats. The centrally acting nicotinic antagonist mecamylamine produced a dose-dependent impairment of performance in the passive avoidance task, however, the peripherally acting nicotinic antagonist hexamethonium was ineffective in this test. To elucidate the potential neurochemical mechanisms underlying mecamylamine's amnestic effect, we examined the ability of the drug to alter specific dynamic components of rat brain cholinergic systems in five brain regions. Mecamylamine produced a dose-dependent inhibition of the synthesis of [3H]ACh from pulse-injected [3H]choline in all regions examined, but was without effect on endogenous, steady-state levels of ACh. As with the behavioral study, administration of hexamethonium was without effect on [3H]ACh synthesis. Calculation of the turnover rates of ACh allowed a correlation between the inhibition of the behavioral task and the inhibition of central cholinergic function. The high degree of correlation obtained (as well as earlier studies in nonhuman primates) underlined the possibility that presynaptically located nicotinic receptors on brain cholinergic neurons are tonically active and mediate a positive feedback mechanism for controlling cholinergic neuronal activity. These receptors may be the neurochemical substrate which underlie the behavioral changes after administration of nicotinic agonists and antagonists.