Behavioral and neurochemical consequences of the administration of nicotinic cholinergic agents to rodents and non-human primates

Abstract

Acetyl~holine (Ach) is known as a primary neurotransmitter in normal mnemonic functioning. While most research has been directed at the central muscarinic cholinergic subsystem, of recent interest in normal and pathologic cognitive processing is. the role of the nicotinic cholinergic subsystem. The purpose of my research was to further characterize~ behaviorally and neurobiochemically, the role of this system in animal models of learning and memory by: establishing a working model of cognitive impairment in the rat using a classical behavioral paradigm and muscarinic'cholinergic amnestic agent; exploring in depth the influence.of classical nicotinic cholinergic agents on performance by rats of the same and other models of learning and memory; examining the ability of these nicotinic agents to alter performance of a complex cognitive task by non-human primates; examining the ;influence of these agents on neurochemistry of the rat brain cholinergic system in an attempt-to correlate drug~induced behavioral and biochemical alterations. The classical muscarinic antagonist scopolamine significantly disrupted learning of 2 ·passive avoidance tasks by rats. The nicotinic agonist nicotine afforded significant memory enhancement in monkeys performing a· delayed matching-to-sample task. The centrally-acting nicotinic antagonist mecamylamine, but not the peripherally-acting nicotinic antagonist hexamethonium, produced significant impairment of the ability of rats to. learn a passive avoidance task and the ability of monkeys to perform a delayed matching-to-sample task. Mecamylamine failed to exert a centrally~selective effect on performance of an active. avoidance or radial arm maze task by rats. Biochemical analyses revealed dr~atic drug-induced changes in neurochemical markers of the rat brain cholinergic syst.em. Sigriificant decreases in synthesis of Ach and ra:te of.Ach.turnover were measured in the hippocampus arid parietal cortex of rats receiving the dose of mecamylamine· affording cognitive-impairment in rats. Lower, beha,viorally-ineffective doses of mecamylamine, or hex.amethonium was not associated with significant changes in the same markers. These results provide ruther support for a role of the central nicotinic system in mnemonic processing and insight into biochemical mechanisms potentially ~derlying the observed behavioral consequences of pharmacological manipulation of the central nicotinic cholinergic system.