This project focuses on modulatory mechanisms that govern functions of the N-methyl-D-aspartate receptor (NMDA-R) and the nicotinic cholinergic receptor (nAChR). NMDA-R is studied because: 1) phencyclidine interacts with sites inside the ion channel of NMDA-R; and 2) NMDA-R is implicated in opioid tolerance and dependence (see project report """"""""Physiological Effects of Opioids""""""""). Substance abuse may be determined, in part, by persistent biochemical changes, which may ensue from drug administration or from experiences associated with drug abuse. ongoing studies ask whether behavioral experiences per se could alter parameters of NMDA-R binding. Hippocampi from Fischer-344 rats, trained in a complex learning task, were assayed for NMDA-R binding using [H-3]CGS 19755. Trained rats have more binding than naive rate, supporting a role of NMDA-R in learning and memory, and the view that NMDA-R changes accompany long-term potentiation in the hippocampus. We have also identified and characterized polyamine binding sites, some of which are localized to NMDA-R. The sites may provide a template for the design of new therapeutic agents directed at NMDA-R function. Nitric oxide (NO), a free radical, is an intercellular messenger produced by NMDA-R activation. It is formed in the brain, in a reaction that is catalyzed by nitric oxide synthase (NOS). On the basis of studies which implicated nitric oxide in NMDA-R-mediated cytotoxicity, a role of NO in AIDS is proposed. Effects of endogenously produced NO may be exacerbated by the use of organic nitrite inhalants as NO is a by-product of the breakdown of these compounds. Endogenous mechanisms regulating nAChR function are studied. [H-3]Mecamylamine (MEC) is being used as a probe for the nAChR channel. Nucleotides, in particular ATP, appear to modulate binding at acetylcholine recognition sites and at sites thought within the nAChR channel, suggesting that they modulate opening of the channel. At concentrations near those at which they occur in brain, polyamines exert an uncompetitive inhibition of the binding of MEC, suggesting that these substances are endogenous modulators of nAChR.
