ROLE OF MAGL INHIBITION IN NICOTINE WITHDRAWAL AND REWARD. A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University. by Pretal Ishvarlal Patel Muldoon Director: M. Imad Damaj, PhD Professor, Department of Pharmacology and Toxicology Tobacco use is one of the leading causes of preventable deaths worldwide. Nicotine, the main psychoactive component of tobacco, sustains and initiates tobacco addiction. Cessation of nicotine induces a dependence withdrawal syndrome. Recent in vivo studies indicate that the endocannabinoid (EC) system modulates both nicotine reward and withdrawal. The purpose of this proposal is to investigate the role of enhancing endogenous 2-arachidonoylglycerol (2-AG) and by blocking its degradative enzyme, monoacylglycerol lipase (MAGL) enzyme, in nicotine reward and dependence. The selective MAGL inhibitor JZL184 dose-dependently reduced both precipitated and spontaneous somatic and aversive withdrawal signs in mice. These effects were blocked by rimonabant indicating a CB1 receptor mechanism. Furthermore, repeated administration of JZL184 for 6 days did not produce tolerance to the alleviation of withdrawal and the treatment did not induce alterations in CB1 receptor levels or receptor-mediated G-protein activity in various brain regions. In addition, a decrease in 2-AG levels was found in the nucleus accumbens in nicotine-dependent mice undergoing precipitated withdrawal, suggesting that a dysregulation of this EC signaling system occurs during nicotine withdrawal. Lastly, we tested the effectiveness of a combination of low-dose JZL184 and high dose of the FAAH inhibitor PF-3845 on spontaneous nicotine withdrawal. Indeed, the combination of low-dose JZL184 and PF-3845 significantly attenuated nicotine spontaneous withdrawal signs. MAGL inhibition by JZL184 dose-dependently caused a significant blockade of nicotine reward as measured in the mouse conditioned place preference (CPP). In contrast to withdrawal, JZL184’s effect on nicotine CPP was not CB1 mediated. In addition, JZL184 treatment did not cause significant alterations in CB1 receptor levels or receptor-mediated G-protein activity in several brain regions involved in nicotine reward. The effects of JZL184 on nicotine CPP was selective since the drug failed to alter food-induced CPP and LiCl-induced conditioned place aversion in the mouse. Interestingly, active doses of JZL184 did not only cause an increases in 2-AG levels but also induced a concomitant decrease in arachidonic acid (AA) levels in various brain regions suggesting an AA cascade dependent-mechanism. In line of these changes, a cox-2 inhibitor, valdecoxib, dose-dependently blocked nicotine preference.
| Identifer | oai:union.ndltd.org:vcu.edu/oai:scholarscompass.vcu.edu:etd-1436 |
| Date | 16 November 2012 |
| Creators | Muldoon, Pretal |
| Publisher | VCU Scholars Compass |
| Source Sets | Virginia Commonwealth University |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Theses and Dissertations |
| Rights | © The Author |
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