496. Nicotine, mecamylamine, and movement disorders in smokers with schizophrenia

Abstract

The significantly greater prevalence of cigarette smoking among persons with schizophrenia compared to the general population suggests a neurobiological correlate between the pathophysiology of this disorder and nicotine dependence. In animal models, dopamine (DA) activity in the dorsal striatum is affected by nicotine administration. It might then be expected that cigarette smoking would influence motor function referable to the dorsal striatum, namely dyskinesias and neuroleptic-induced Parkinsonism (NIP). Clinical studies suggest that cigarette smoking ameliorates NIP and exacerbates dyskinesias. In the present study, we are endeavoring to characterize the role of CNS nicotinic acetylcholine receptor (nAChR) antagonism and the effect of smoking on movement disorders in smokers with schizophrenia. We hypothesized that blockade of nAChRs by the non-competitive antagonist, mecamylamine, and activation of these receptors by nicotine would have opposite effects on dyskinesias and NIP. This study has a randomized, double blind, placebo-controlled, crossover, counterbalanced design. Over the course of 4 day-long visits, each 1 week apart, every subject is administered each of the following 4 conditions: (1) mecamylamine pill (10 mg)/active nicotine transdermal skin patch (21 mg/day); (2) mecamylamine pill/placebo patch; (3) placebo pill/active patch; (4) placebo pill/placebo patch. At the end of each day, clinical rating scales and instrumental measures are used to quantify changes in movement disorder severity. Data collection is ongoing. An interim analysis of the first 6 subjects shows trends towards increase in dyskinesias (p < 0.08) and NIP (p < 0.10) in association with mecamylamine, and an increase in NIP (p < 0.10) in association with increased nicotine levels. This may be a manifestation of similar effects of nAChR antagonism (mecamylamine) vs. nAChR desensitization (elevated nicotine levels) on motor function. This study aims to advance our understanding of nicotinic modulation of DA function in the dorsal striatum in schizophrenia.