Epidemiological studies have consistently shown that the incidence of Parkinson's disease (PD) is reduced in smokers. However, the mechanism by which smoking acts to reduce the incidence of PD remains unknown. Our earlier studies have demonstrated that dopamine (DA) blockade promotes increased activity of the inhibitory, indirect pathway leading to learned inhibition of movement, a phenomenon that we term 'aberrant motor learning.' In this application, we aim to test the hypothesis that chronic nicotine by desensitizing ?2-containing nAChRs, prevents such aberrant learning and lessens PD symptoms. Specific Aim 1 will dissociate whether ?2 deactivation on DA neurons is sufficient to block aberrant motor learning and whether the specific deletion of this population of ?2-containing nAChRs prevents the initial acquisition of aberrant learning during DA receptor blockade or facilitates the acquisition of new learning once DA signaling is restored. Specific Aim 2 will delineate the mechanism by which chronic nicotine, acting via ?2-containing nAChRs, blocks aberrant learning. Given that nicotine administered over a period of time significantly alters DA release, we will test the hypothesis that such adaptive changes have protective effects against aberrant synaptic plasticity induced by DA blockade.

R21NS083383

2013-04-01

2015-03-31