Drugs that have abuse liability in humans typically serve as positive reinforcers to maintain and strengthen behavior leading to their administration in animals and serve as discriminative stimuli controlling two-lever choice behavior. Experiments are being conducted to assess neurobiological and behavioral mechanisms underlying drug self-administration behavior and behavior controlled by drugs as discriminative stimuli in rats and monkeys and the ability of pharmacological or behavioral manipulations to modify such behavior. Tobacco dependence is the leading preventable cause of mortality in the world and nicotine appears to be the main critical psychoactive component in establishing and maintaining tobacco dependence. Marked inter-individual differences in vulnerability to nicotine dependence exist, but factors underlying such differences are not well understood. The midbrain alpha4_beta2* subtype of nicotinic acetylcholine receptors (nAChRs) has been implicated in mediation of the reinforcing effects of nicotine responsible for dependence. However, no study has been performed evaluating the impact of inter-individual differences in midbrain nAChR levels on motivation to self-administer nicotine. We measured baseline levels of alpha 4 beta 2 nAChRs using 2-18Ffluoro-A-85380 and positron emission tomography (PET) in squirrel monkeys. Motivation to self-administer nicotine (number of lever presses) was subsequently measured using a progressive-ratio schedule of reinforcement. Greater motivation to self-administer nicotine was associated with lower levels of midbrain alpha4-beta2 nAChRs. Thus, baseline expression of alpha4-beta2 nAChRs predicts motivation to self-administer nicotine. Emerging evidence suggests that the rewarding, abuse-related effects of nicotine are modulated by the endocannabinoid system of the brain. For example, pharmacological blockade or genetic deletion of cannabinoid CB1 receptors reduces or eliminates many abuse-related behavioral and neurochemical effects of nicotine. Furthermore, doses of the natural cannabinoid delta-9-tetrahydrocannabinol and nicotine that are ineffective when given alone can induce conditioned place preferences when given together. These previous studies have used systemically administered CB1 receptor agonists and antagonists and gene deletion techniques, which affect cannabinoid CB1 receptors throughout the brain. A more functionally selective way to alter endocannabinoid activity is to inhibit fatty acid amide hydrolase (FAAH), thereby magnifying and prolonging the effects of the endocannabinoid anandamide only when and where it is synthesized and released on demand. Here, we combined behavioral and neurochemical approaches to evaluate whether the FAAH inhibitor URB597 could alter the abuse-related effects of nicotine in rats. We found that URB597, at a dose that had no behavioral effects by itself, prevented development of nicotine-induced conditioned place preference (CPP) and acquisition of nicotine self-administration. URB597 also reduced nicotine-induced reinstatement in both CPP and self-administration models of relapse. Furthermore, in vivo electrophysiology experiments showed that URB597 blocked the activation of dopamine neurons in the ventral tegmental area by nicotine and in vivo microdialysis experiments showed that URB597 reduced nicotine-induced dopamine elevations in the nucleus accumbens shell, the two main areas of the brain's mesolimbic reward system. These findings suggest that FAAH inhibition can counteract the addictive properties of nicotine and that FAAH may serve as a new target for development of medications for treatment of tobacco dependence. Nicotine stimulates the activity of mesolimbic dopamine neurons, and this is believed to mediate the rewarding and addictive properties of tobacco use. We have investigated the modulation of nicotine effects by the endocannabinoid system on dopamine neurons in the ventral tegmental area of rats with electrophysiological techniques both in vivo and in vitro. We discovered that pharmacological inhibition of FAAH, the enzyme that catabolizes fatty acid ethanolamides, among which the endocannabinoid anandamide is the best known, suppressed nicotine-induced excitation of dopamine cells. Importantly, this effect was mimicked by the administration of the FAAH substrates oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), but not methanandamide, the hydrolysis resistant analog of AEA. OEA and PEA are naturally occurring lipid signaling molecules structurally related to anandamide, but devoid of affinity for cannabinoid receptors. They blocked the effects of nicotine by activation of the peroxisome proliferator-activated receptor- alpha (PPAR alpha), a nuclear receptor transcription factor involved in several aspects of lipid metabolism and energy balance. Activation of PPAR- alpha triggered a nongenomic stimulation of tyrosine kinases, which might lead to phosphorylation and negative regulation of neuronal nicotinic acetylcholine receptors. These data indicate for the first time that the anorexic lipids OEA and PEA possess neuromodulatory properties as endogenous ligands of PPAR-alpha in the brain and provide a potential new target for the treatment of nicotine addiction.

Project Start
Project End
Budget Start
Budget End
Support Year
26
Fiscal Year
2010
Total Cost
$1,196,392
Indirect Cost
Name
National Institute on Drug Abuse
Department
Type
DUNS #
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Lamb, Richard J; Ginsburg, Brett C; Schindler, Charles W (2017) Conditioned Stimulus Form Does Not Explain Failures to See Pavlovian-Instrumental-Transfer With Ethanol-Paired Conditioned Stimuli. Alcohol Clin Exp Res 41:1063-1071
Secci, Maria E; Auber, Alessia; Panlilio, Leigh V et al. (2017) Attenuating Nicotine Reinforcement and Relapse by Enhancing Endogenous Brain Levels of Kynurenic Acid in Rats and Squirrel Monkeys. Neuropsychopharmacology 42:1619-1629
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Lamb, R J; Schindler, Charles W; Pinkston, Jonathan W (2016) Conditioned stimuli's role in relapse: preclinical research on Pavlovian-Instrumental-Transfer. Psychopharmacology (Berl) 233:1933-44
Schindler, Charles W; Scherma, Maria; Redhi, Godfrey H et al. (2016) Self-administration of the anandamide transport inhibitor AM404 by squirrel monkeys. Psychopharmacology (Berl) 233:1867-77
Justinova, Zuzana; Le Foll, Bernard; Redhi, Godfrey H et al. (2016) Differential effects of the metabotropic glutamate 2/3 receptor agonist LY379268 on nicotine versus cocaine self-administration and relapse in squirrel monkeys. Psychopharmacology (Berl) 233:1791-800
Scherma, Maria; Dessì, Christian; Muntoni, Anna Lisa et al. (2016) Adolescent ?(9)-Tetrahydrocannabinol Exposure Alters WIN55,212-2 Self-Administration in Adult Rats. Neuropsychopharmacology 41:1416-26
Secci, Maria E; Factor, Julie A; Schindler, Charles W et al. (2016) Choice between delayed food and immediate oxycodone in rats. Psychopharmacology (Berl) 233:3977-3989
Schindler, Charles W; Redhi, Godfrey H; Vemuri, Kiran et al. (2016) Blockade of Nicotine and Cannabinoid Reinforcement and Relapse by a Cannabinoid CB1-Receptor Neutral Antagonist AM4113 and Inverse Agonist Rimonabant in Squirrel Monkeys. Neuropsychopharmacology 41:2283-93
Lamb, R J; Ginsburg, Brett C; Schindler, Charles W (2016) Effects of an ethanol-paired CS on responding for ethanol and food: Comparisons with a stimulus in a Truly-Random-Control group and to a food-paired CS on responding for food. Alcohol 57:15-27

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