Nerve cells which synthesize and release acetylcholine (ACh) play a crucial role in cognitive processes, motor coordination and numerous other functions of the central nervous system (CNS). The relationship between impaired CNS cholinergic neurotransmission and various deficits in learning and memory has received widespread attention in view of the amnestic properties of centrally-active muscarinic cholinergic receptor (mChR) antagonists as well as the significant correlation between forebrain cholinergic neurodegeneration and the severity of cognitive deficits in people with Alzheimer's type dementia (AD). While much attention is currently focused upon the clinical efficacy of cholinergic agonist replacement therapy for AD and related dementias, the significant clinical improvements produced by indirect acting cholinomimetics (e.g. physostigmine and tetrahydroaminoacridine) underscores the potential importance of drugs which can facilitate neurotransmission in non-degenerated cholinergic neurons. The general objective of this study is to characterize and delineate the role of mAChR and nicotinic cholinergic receptors (nAChR) which modulate presynaptic activity of CNS cholinergic neurons. Within this general framework, experiments will be carried out in laboratory rats to accomplish the following specific goals: (1) pharmacologically characterize mAChR and nAChR which regulate ACh release from CNS cholinergic nerve terminals and delineate the biochemical processes (second messengers, ionic dependencies) which underlie these effects; (2) characterize bothmA ChR- and nAChR-mediated effects in several major forebrain cholinergic systems during development and aging; (3) characterize and compare the compensatory changes (if any) which accompany chronic treatment with selective or non-selective cholinergic agents; and (4) confirm results from in vitro measures of cholinergic neurotransmission with direct determinations of ACh release in vivo using brain microdialysis and other indirect measures. If the goals of this project are achieved, these results should provide a better understanding of the functional importance of autoregulatory mechanisms in CNS cholinergic neurons and help clarify the potential utility of novel pharmaceutical agents which facilitate cholinergic neurotransmission and ameliorate cognitive deficits that are associated with AD or related CNS disease processes.
