Matthew W. Buczynski - US grants

DESCRIPTION (provided by applicant): 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.

DESCRIPTION (provided by applicant): 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.

DESCRIPTION (provided by applicant): Nicotine addiction is a complex behavioral phenomenon, characterized by alterations in synaptic transmission which contribute to a progression of addiction-related processes including reward, dependence, and relapse. The motivational and addictive properties of nicotine are critically reliant on activation of the mesolimbic dopamine (DA) circuitry, and most therapeutic approaches for smoking cessation have focused on this system. Endocannabinoid-related lipids (ERL) including oleoylethanolamide (OEA) modulate this circuitry by exerting a stimulus-dependent influence at these synapses, and drugs targeting OEA signaling have been proposed as an alternative therapeutic strategy for treating nicotine addiction. Both the OEA degradation pathway, mediated by fatty acid amide hydrolase (FAAH), as well as the presumptive OEA receptor peroxisome proliferator- activated receptor alpha (PPAR?) has been heavily pursued as pharmacological targets for treating nicotine addiction, yet comparatively little is known about the mechanisms of OEA production. Activation of PPAR? induces plasticity of cholinergic and glutamatergic transmission, which are both dysregulated following long- term nicotine self-administration. We propose that OEA-driven fluctuations between cholinergic plasticity (during depressed PPAR? influence) and glutamatergic plasticity (during active PPARalpha signaling) create a negative spiral that plays an functional role in facilitating nicotine addictio. The role of NAPE-PLD in VTA cholinergic and glutamatergic plasticity will be functionally studied using electrophysiology techniques acquired in my K99 training phase in combination with in vivo micro dialysis. Having developed these techniques, we will then study the functional and behavioral role of NAPE-PLD following long-term nicotine self-administration the independent R00 phase of the project. This work will provide important insight into the mechanisms leading to reward dysfunction and nicotine dependence, and provide another avenue for pharmacotherapeutic development.