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The Journal of Neuroscience, August 15, 2007, 27(33):8771-8778; doi:10.1523/JNEUROSCI.2017-06.2007
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Behavioral/Systems/Cognitive
Enhanced Nicotinic Receptor Function and Drug Abuse Vulnerability
Zara M. Fagen,1 Robert Mitchum,1 Paul Vezina,1,2 andDaniel S. McGehee1,3 1Committee on Neurobiology and 2Departments of Psychiatry and 3Anesthesia and Critical Care, University of Chicago, Chicago, Illinois 60637
Correspondence should be addressed to Daniel S. McGehee, University of Chicago, Department of Anesthesia and Critical Care, 5841 South Maryland Avenue, MC 4028, Chicago, IL 60637. Email: dmcgehee{at}midway.uchicago.edu
In animals and humans, vulnerability to drug abuse varies among individuals. Animals that display high activity levels in a novel environment are more likely to self-administer psychostimulant drugs, including nicotine, cocaine, amphetamine, and morphine. Recent reports from behavioral studies indicate that nicotinic acetylcholine receptor (nAChR) activity contributes to the rewarding effects of several different addictive drugs. Thus, we hypothesized that differences in nAChR activity may contribute to the predisposition to drug self-administration. After screening of adult rats (>60 d postnatal) for the behavioral response to a novel environment, electrophysiological measures of nAChR function were conducted in brain slices that included the mesoaccumbens dopamine neurons of the ventral tegmental area (VTA). We found a positive correlation between the response to novelty and nAChR function in each assay conducted, including nAChR modulation of glutamatergic and GABAergic synaptic inputs to VTA dopamine neurons, as well as somatic nAChR responses of VTA neurons. The response to novelty and sensitivity to addictive drugs are positively correlated with the hormonal response to stress. Consistent with this observation, we found enhanced nAChR responses in vitro after a 48 h corticosterone treatment and in vivo after 48 h of repeated stress. Each of these effects was inhibited by RU486 (11ß-[p-(dimethylamino)phenyl]-17ß-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one) pretreatment, suggesting a steroid hormone receptor-dependent process. These findings suggest that differences in nAChR function within the mesoaccumbens dopamine system may contribute to individual differences in drug abuse vulnerability and that these are likely attributable to differences in stress hormone levels.
Key words: nicotinic acetylcholine receptor; glucocorticoid; stress; corticosterone; drug abuse; addiction; acetylcholine; dopamine
Received May 11, 2006; revised June 20, 2007; accepted June 28, 2007.
Correspondence should be addressed to Daniel S. McGehee, University of Chicago, Department of Anesthesia and Critical Care, 5841 South Maryland Avenue, MC 4028, Chicago, IL 60637. Email: dmcgehee{at}midway.uchicago.edu
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