This project focuses on N-methyl-D-aspartate (NMDA-R) and nicotinic cholinergic receptor (nAChR), which are ligand-gated ion channels. NMDA-Rs mediate the psychotropic actions of phencyclidine, and play a role in opioid tolerance and dependence; nAChRs are the primary site of action of nicotine.
One research aim i s to clarify mechanisms by which polyamines (PAs) modulate function of NMDA-R and other neuro-transmitter receptors or transporters. NMDA recognition sites in brain occur in two affinity states, and PAs (as well as mono- and divalent cations) convert these sites from a low- to a high-affinity conformation. PAs also enhance binding of [H-3]dizocilpine (DZ), even at saturating glutamate and glycine concentrations. Furthermore, arcaine, a PA antagonist, which inhibits the facilitation by PAs of DZ binding at saturating concentrations of glutamate, does not affect conversion between affinity states. Arcaine-sensitive modulation may involve enhancement in the efficiency of transduction between NMDA-R activation and channel opening, or it may involve an action of PAs to increase affinity of NMDA-R for DZ. Studies of dopamine and serotonin transporters (DAT, ST, respectively) show that spermine (SP) inhibits binding of [H-3]CFT and [H-3]mazindol to DAT, but has no effect on binding of [H-3]paroxetine to ST. The effect of SP on binding to DAT involves a decrease in the density of binding sites. The results suggest that PAs can alter the rewarding effects of cocaine, which are mediated through interactions with DAT, and they have implications for treatment of cocaine abuse. After demonstrating that ascorbic acid (AA) protects neurons in culture from NMDA toxicity, we examined potential neuroprotective effects of AA against toxicity produced by nitric oxide (NO), generated from the breakdown of sodium nitroprusside (SNP). Although AA protects against NMDA toxicity, it enhances toxicity produced by SNP. The data support a model in which the redox state of NO determines whether the free radical produces neuroprotection or neurotoxicity. Epibatidine, an alkaloid from frog skin, has a high affinity for nAChR. Studies show substantial uptake of radiolabeled epibatidine into brain, a distribution in the CNS consistent with nAChR, and its selective displacement by nicotinic ligands suggest that labeled epibatidine analogues are promising ligands for labeling nAChR in vivo using noninvasive imaging procedures.
