Chronic nicotine increases alcohol self-administration in adult male Wistar rats.

RATIONALE: Alcohol and nicotine co-dependence is common in humans, and nicotine increases alcohol drinking in humans without alcohol use disorder (AUD). Nevertheless, there is little basic research on the interactions between the reinforcing effects of these two drugs. OBJECTIVES: The aim of this study was to investigate the effects of chronic nicotine injections on oral alcohol self-administration in alcohol non-dependent rats. METHODS: After stable alcohol self-administration was reached (baseline) and a period without alcohol access, adult male rats were treated with chronic nicotine or saline injections for 105 days during which time they were tested intermittently for alcohol self-administration. There were 3 experimental groups: (1) saline, rats treated with saline for 105 days; (2) early nicotine, rats treated with nicotine for 70 days, and then with saline for 35 days; and (3) late nicotine: rats treated with saline for 35 days, and then with nicotine for 70 days. RESULTS: Our results indicate that (1) chronic nicotine increases alcohol consumption regardless of whether exposure to alcohol was interrupted (early nicotine) or not (late nicotine) before the start of nicotine treatment, (2) the number of alcohol reinforcements correlates to blood-alcohol levels, and (3) alcohol self-administration rapidly decreases when nicotine is no longer available (early nicotine). CONCLUSIONS: These discoveries may have clinical implications in social drinkers that use nicotine products, in that chronic nicotine can escalate alcohol drinking and cessation of nicotine exposure may decrease alcohol use.

Attenuating Nicotine Reinforcement and Relapse by Enhancing Endogenous Brain Levels of Kynurenic Acid in Rats and Squirrel Monkeys.

The currently available antismoking medications have limited efficacy and often fail to prevent relapse. Thus, there is a pressing need for newer, more effective treatment strategies. Recently, we demonstrated that enhancing endogenous levels of kynurenic acid (KYNA, a neuroinhibitory product of tryptophan metabolism) counteracts the rewarding effects of cannabinoids by acting as a negative allosteric modulator of α7 nicotinic receptors (α7nAChRs). As the effects of KYNA on cannabinoid reward involve nicotinic receptors, in the present study we used rat and squirrel monkey models of reward and relapse to examine the possibility that enhancing KYNA can counteract the effects of nicotine. To assess specificity, we also examined models of cocaine reward and relapse in monkeys. KYNA levels were enhanced by administering the kynurenine 3-monooxygenase (KMO) inhibitor, Ro 61-8048. Treatment with Ro 61-8048 decreased nicotine self-administration in rats and monkeys, but did not affect cocaine self-administration. In rats, Ro 61-8048 reduced the ability of nicotine to induce dopamine release in the nucleus accumbens shell, a brain area believed to underlie nicotine reward. Perhaps most importantly, Ro 61-8048 prevented relapse-like behavior when abstinent rats or monkeys were reexposed to nicotine and/or cues that had previously been associated with nicotine. Ro 61-8048 was also effective in monkey models of cocaine relapse. All of these effects of Ro 61-8048 in monkeys, but not in rats, were reversed by pretreatment with a positive allosteric modulator of α7nAChRs. These findings suggest that KMO inhibition may be a promising new approach for the treatment of nicotine addiction.

The Novel Metabotropic Glutamate Receptor 2 Positive Allosteric Modulator, AZD8529, Decreases Nicotine Self-Administration and Relapse in Squirrel Monkeys.

BACKGROUND: Based on rodent studies, group II metabotropic glutamate receptors (mGluR2 and mGluR3) were suggested as targets for addiction treatment. However, LY379268 and other group II agonists do not discriminate between the mainly presynaptic inhibitory mGluR2 (the proposed treatment target) and mGluR3. These agonists also produce tolerance over repeated administration and are no longer considered for addiction treatment. Here, we determined the effects of AZD8529, a selective positive allosteric modulator of mGluR2, on abuse-related effects of nicotine in squirrel monkeys and rats. METHODS: We first assessed modulation of mGluR2 function by AZD8529 using functional in vitro assays in membranes prepared from a cell line expressing human mGluR2 and in primate brain slices. We then determined AZD8529 (.03-10 mg/kg, intramuscular injection) effects on intravenous nicotine self-administration and reinstatement of nicotine seeking induced by nicotine priming or nicotine-associated cues. We also determined AZD8529 effects on food self-administration in monkeys and nicotine-induced dopamine release in accumbens shell in rats. RESULTS: AZD8529 potentiated agonist-induced activation of mGluR2 in the membrane-binding assay and in primate cortex, hippocampus, and striatum. In monkeys, AZD8529 decreased nicotine self-administration at doses (.3-3 mg/kg) that did not affect food self-administration. AZD8529 also reduced nicotine priming- and cue-induced reinstatement of nicotine seeking after extinction of the drug-reinforced responding. In rats, AZD8529 decreased nicotine-induced accumbens dopamine release. CONCLUSIONS: These results provide evidence for efficacy of positive allosteric modulators of mGluR2 in nonhuman primate models of nicotine reinforcement and relapse. This drug class should be considered for nicotine addiction treatment.

Effects of Fatty Acid Amide Hydrolase (FAAH) Inhibitors in Non-Human Primate Models of Nicotine Reward and Relapse.

Inhibition of the enzyme fatty acid amide hydrolase (FAAH) counteracts reward-related effects of nicotine in rats, but it has not been tested for this purpose in non-human primates. Therefore, we studied the effects of the first- and second-generation O-arylcarbamate-based FAAH inhibitors, URB597 (cyclohexyl carbamic acid 3'-carbamoyl-3-yl ester) and URB694 (6-hydroxy-[1,1'-biphenyl]-3-yl-cyclohexylcarbamate), in squirrel monkeys. Both FAAH inhibitors: (1) blocked FAAH activity in brain and liver, increasing levels of endogenous ligands for cannabinoid and α-type peroxisome proliferator-activated (PPAR-α) receptors; (2) shifted nicotine self-administration dose-response functions in a manner consistent with reduced nicotine reward; (3) blocked reinstatement of nicotine seeking induced by reexposure to either nicotine priming or nicotine-associated cues; and (4) had no effect on cocaine or food self-administration. The effects of FAAH inhibition on nicotine self-administration and nicotine priming-induced reinstatement were reversed by the PPAR-α antagonist, MK886. Unlike URB597, which was not self-administered by monkeys in an earlier study, URB694 was self-administered at a moderate rate. URB694 self-administration was blocked by pretreatment with an antagonist for either PPAR-α (MK886) or cannabinoid CB1 receptors (rimonabant). In additional experiments in rats, URB694 was devoid of THC-like or nicotine-like interoceptive effects under drug-discrimination procedures, and neither of the FAAH inhibitors induced dopamine release in the nucleus accumbens shell--consistent with their lack of robust reinforcing effects in monkeys. Overall, both URB597 and URB694 show promise for the initialization and maintenance of smoking cessation because of their ability to block the rewarding effects of nicotine and prevent nicotine priming-induced and cue-induced reinstatement.