The use of tobacco products is one of leading causes of preventable death worldwide. The psychoactive effects of tobacco have been attributed primarily to its content of the bioactive substance nicotine. Current therapies decrease the withdrawal symptoms that occur in addicted individuals upon cessation of nicotine intake. However, this approach has had only moderate success rates in reducing relapse in addicted individuals and does not reverse the biochemical changes that occur in the central nervous system after repeated nicotine use. Endocannabinoid (eCB) signaling has been implicated in modulating the induction and expression of reward-related behaviors for nicotine and nearly all other known drugs of abuse, yet our understanding of the roles of specific eCBs that are involved in nicotine reward remains unclear. Interestingly, combined inhibition of monoacylglycerol lipase (MAGL) and fatty acid acyl hydrolase (FAAH), which degrade distinct sets of eCBs, can mimic the classic cannabinoid behaviors caused by tetrahydrocannabinol (THC), whereas inhibiting each pathway alone only causes a unique partial THC-like response. Thus, individual eCBs likely underlie distinct behavioral phenomena, and modulating these pathways may have different therapeutic outcomes. This project will focus on elucidating the specific eCB signaling mechanisms that reinforce nicotine self-administration in rats, as well as the therapeutic potential of FAAH and MAGL inhibition.
Aim 1 will evaluate the effect of selective FAAH and MAGL inhibitors on nicotine self-administration.
Aim 2 will characterize eCB changes induced by nicotine self-administration. Using this information, Aim 3 will investigate the receptor mechanisms through which eCBs modulate nicotine self-administration. The overall goal of the experiments described here is to characterize eCB-receptor mechanisms reinforcing nicotine behavior, as well as the effects of eCB clearance inhibition (FAAH and MAGL) on nicotine self- administration behavior. A better understanding of these processes should lead to innovative therapies that have direct impact and clinical relevance for reducing nicotine use in addicted individuals.

Public Health Relevance

The use of tobacco products, driven by the psychoactive effects of nicotine, is one of leading causes of preventable death worldwide. Current treatment options diminish the nicotine withdrawal symptoms that occur in addicted individuals, but do not address the biochemical changes that arise in the brain after chronic nicotine use. The goal of this study is to elucidate the role of endocannabinoids and related bioactive lipids that are affected by chronic nicotine intake to facilitate the development of new therapeutic targets for treating nicotine abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DA029994-03
Application #
8476208
Study Section
Special Emphasis Panel (ZRG1-F02A-J (20))
Program Officer
Babecki, Beth
Project Start
2011-06-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
3
Fiscal Year
2013
Total Cost
$55,670
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Buczynski, Matthew W; Herman, Melissa A; Hsu, Ku-Lung et al. (2016) Diacylglycerol lipase disinhibits VTA dopamine neurons during chronic nicotine exposure. Proc Natl Acad Sci U S A 113:1086-91
Buczynski, Matthew W; Polis, Ilham Y; Parsons, Loren H (2013) The volitional nature of nicotine exposure alters anandamide and oleoylethanolamide levels in the ventral tegmental area. Neuropsychopharmacology 38:574-84
Niphakis, Micah J; Cognetta 3rd, Armand B; Chang, Jae Won et al. (2013) Evaluation of NHS carbamates as a potent and selective class of endocannabinoid hydrolase inhibitors. ACS Chem Neurosci 4:1322-32
Wright Jr, M Jerry; Angrish, Deepshikha; Aarde, Shawn M et al. (2012) Effect of ambient temperature on the thermoregulatory and locomotor stimulant effects of 4-methylmethcathinone in Wistar and Sprague-Dawley rats. PLoS One 7:e44652
Natividad, Luis A; Buczynski, Matthew W; Parsons, Loren H et al. (2012) Adolescent rats are resistant to adaptations in excitatory and inhibitory mechanisms that modulate mesolimbic dopamine during nicotine withdrawal. J Neurochem 123:578-88