Functional Validation of Candidate Genes Deriving from Convergent Analysis of Gene Expression Profiling in Nicotine Self-Administering Animals and Genome Wide Association Studies in Smokers
Final Report Abstract
In the current nicotine project, we have identified several novel targets associated with nicotine reinforcement that have important clinical implications and are currently undergoing further evaluation in our laboratory. For example, we report here that rodents lacking Ras GEFs (Ras-GRP1, Ras-GRF1 and Ras-GRF2) show deficits in nicotine reinforcement. Ras plays a key role in signal transduction, and has primarily been targeted in cancer research. Only a handful of studies have examined the role of Ras GEFs and Ras in terms of drug reinforcement. Our studies of Ras GEFs suggest for the first time a prominent role of these molecules, and potentially their downstream target, Ras, in the mediation of nicotine reward. These findings provide an important consideration for future studies examining mechanistic alterations related to nicotine addiction, as well as the pharmacological development of therapies to treat nicotine addiction. We also report here a genotype x sex mediation of nicotine reward in the OPRM1 study. As outlined above, previous studies of the role of the OPRM1 A118G polymorphism, the most common functional variation at the OPRM1 locus, have been inconsistent. Our demonstration of greater sensitivity to the rewarding effects of nicotine in male mice carrying the human G allele of the A118G polymorphism and male study participants carrying the OPRM1 118G allele is the first of its kind to demonstrate converging evidence of the role of the polymorphism in nicotine reinforcement. Thus, our findings have important implications for the development of treatment strategies for smoking addiction, as our findings suggest that responses to opioid pharmacotherapies, currently approved for alcohol addiction, may also be appropriate for nicotine addiction, using an individualized approach. We also report that the CaV1.2 subunit of L-type calcium channels is critically involved in nicotine reinforcement. Previous work has identified the role of calcium channels in nicotine reward and withdrawal. However, the contribution of calcium channel subunits has not previously been identified in terms of nicotine-related behaviors. Our identification and isolation of the CaV1.2 subunit as mediating nicotine reinforcement improves our understanding of the role of calcium channels in nicotine reward and provides for the development of more precise and efficient calcium channel pharmacotherapies that may have potential in the treatment of nicotine addiction. Finally, we have developed three new models for assessing the role of genetic alterations and pharmacological treatments on nicotine reward. Although nicotine self-administration is critical to providing translational valuation of genetic and pharmacological manipulations, these new models allow for high throughput screening of potential treatments, and in some cases can predict future responses to nicotine based on easily-identifiable behaviors. Although not a complete surprise, per se, our intriguing finding of the G allele increasing sensitivity to nicotine reward in male, but not females, in both mice and humans, has immediate clinical implications, and is currently the subject of a grant in progress to identify the mechanism underlying these genotype and gender differences.
Publications
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(2013). The ClockΔ19 mutation in mice fails to alter the primary and secondary reinforcing properties of nicotine. Drug and Alcohol Dependence, 133, Issue 2, 733-739
Bernardi, R.E., Spanagel, R.
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(2014). A two-injection protocol for nicotine sensitization.Behavioural Brain Research, 275C, 11-14
Bernardi, R.E., Spanagel, R.
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(2014). Basal activity Level in mice predicts the initial and sensitized locomotor response to nicotine only in high responders. Behavioural Brain Research, 264, 143-150
Bernardi, R.E., Spanagel, R.
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(2014). The transcriptional regulation of L-type calcium channel subtypes Cav1.2 and Cav1.3 by nicotine and their potential role in nicotine sensitization. Nicotine and Tobacco Research, 16, 774-785
Bernardi, R.E., Uhrig, S., Spanagel, R., Hansson, A.C.
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A gene-by-sex interaction for nicotine reward: evidence from humanized mice and epidemiology. Translational Psychiatry volume 6, page e861 (2016)
Bernardi, R.E., Zohsel, K., Hirth, N., J Treutlein, M Heilig, M Laucht, Spanagel, R., Sommer, W.H.
