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.

Public Health Relevance

Chronic nicotine is protective against Parkinson's disease symptoms. We will test the hypothesis that chronic nicotine mitigates aberrant corticostriatal plasticity and aberrant motor learning induced by dopamine denervation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS083383-01
Application #
8532580
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Sieber, Beth-Anne
Project Start
2013-04-01
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$191,932
Indirect Cost
$66,932
Name
University of Chicago
Department
Biology
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Augustin, Shana M; Beeler, Jeff A; McGehee, Daniel S et al. (2014) Cyclic AMP and afferent activity govern bidirectional synaptic plasticity in striatopallidal neurons. J Neurosci 34:6692-9
Koranda, Jessica L; Cone, Jackson J; McGehee, Daniel S et al. (2014) Nicotinic receptors regulate the dynamic range of dopamine release in vivo. J Neurophysiol 111:103-11