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Item The Effects of Long-Term Varenicline Administration on Ethanol and Sucrose Seeking and Self-Administration in Male P Rats(Wiley, 2018) Czachowski, Cristine L.; Froehlich, Janice C.; DeLory, Michael; Psychology, School of ScienceBackground Varenicline, a partial agonist at α4β2 and full agonist at α7 nicotinic cholinergic receptors, is FDA-approved for treatment of smoking cessation and has been found to reduce alcohol craving in clinical populations. In rodents, varenicline decreases free-choice ethanol (EtOH) intake with somewhat mixed findings in operant paradigms that utilize a combined appetitive/consummatory response. Methods The present experiment utilized an operant paradigm that procedurally separates appetitive from consummatory responding and a “reward-blocking” approach (i.e., rats were able to consume EtOH during treatment) to better understand the efficacy of varenicline as a treatment for EtOH self-administration and subsequent EtOH seeking. Separate groups of EtOH- and sucrose-reinforced alcohol-preferring, male P rats experienced alternating cycles of vehicle (2-week cycles) and varenicline (0.3, 1.0, and 2.0 mg/kg self-administered in a gelatin preparation) treatment (3-week cycles) prior to daily sessions where a single lever press resulted in 20 minutes of reinforcer access. At the end of each cycle, a single extinction session assessed the seeking response in the absence of drug pretreatment. Results Varenicline dose dependently decreased EtOH intake. Sucrose intake was largely unaffected, with no overall treatment effects and only sporadic days where the medium and high dose differed from vehicle. Neither sucrose nor EtOH seeking was significantly decreased by varenicline, and there were no treatment effects on either lick or lever-press latency. Overall effect sizes were much greater for both drinking and seeking in the EtOH group as compared to the sucrose group. Conclusions Varenicline effectively attenuates EtOH self-administration during treatment, but the experience with EtOH consumption while varenicline is “on board” is not sufficient to alter subsequent EtOH seeking. The overall pattern of findings indicates that varenicline blocks the rewarding properties of EtOH while not substituting for EtOH, that the nonspecific effects on an alternate reinforcer are negligible, and that blood levels of varenicline need to be maintained in order for treatment to remain effective.Item Therapeutic challenges for concurrent ethanol and nicotine consumption: naltrexone and varenicline fail to alter simultaneous ethanol and nicotine intake by female alcohol-preferring (P) rats(Springer, 2019-02-13) Waeiss, Robert A.; Knight, Christopher P.; Hauser, Sheketha R.; Pratt, Lauren A.; McBride, William J.; Rodd, Zachary A.; Psychiatry, School of MedicineRationale and Objectives: Simultaneous alcohol and nicotine consumption occurs in the majority of individuals with alcohol use disorder (AUD) and nicotine dependence. Varenicline (Var) is used to assist in the cessation of nicotine use, while naltrexone (Nal) is the standard treatment for AUD. Despite evidence that ethanol (EtOH) and nicotine (NIC) co-use produces unique neuroadaptations, preclinical research has focused on the effects of pharmacotherapeutics on a single reinforcer. The current experiments examined the effects of Var and Nal on EtOH, NIC, or EtOH+NIC intake. Methods: Animals were randomly assigned to 1 of 4 drinking conditions of 24-hour access to a 3-bottle choice paradigm, one of which always contained water. Drinking conditions were water only, 0.07 and 0.14 mg/mL NIC (NIC only), 15% and 30% EtOH (EtOH only), or 15% and 30% EtOH with 0.14 mg/mL NIC (EtOH+NIC). The effects of Var (0, 1, or 2 mg/kg) or Nal (0, 1, or 10 mg/kg) injections on maintenance and relapse consumption were determined during 4 consecutive days. Results: Var reduced maintenance and relapse NIC intake but had no effect on EtOH or EtOH+NIC drinking. Conversely, Nal reduced EtOH maintenance and relapse drinking, but had no effect on NIC or EtOH+NIC drinking. Discussion: The results indicate the standard pharmacological treatments for nicotine dependence and AUD were effective at reducing consumption of the targeted reinforcer but neither reduced EtOH+NIC couse/abuse. These findings suggest that co-abuse may promote unique neuroadaptations that require models of polysubstance abuse to develop pharmacotherapeutics to treat AUD and nicotine dependence.