RT Journal Article SR Electronic T1 Tolerance to ethanol or nicotine results in increased ethanol self-administration and long term depression in the dorsolateral striatum JF eneuro JO eneuro FD Society for Neuroscience SP ENEURO.0112-15.2016 DO 10.1523/ENEURO.0112-15.2016 A1 Chandrika Abburi A1 Shannon L. Wolfman A1 Ryan A. E. Metz A1 Rinya Kamber A1 Daniel S. McGehee A1 John McDaid YR 2016 UL http://www.eneuro.org/content/early/2016/07/18/ENEURO.0112-15.2016.abstract AB Ethanol (EtOH) and nicotine are the most widely co-abused drugs. Tolerance to EtOH intoxication, including motor impairment, results in greater EtOH consumption and may result in a greater likelihood of addiction. Previous studies suggest that cross-tolerance between EtOH and nicotine may contribute to the abuse potential of these drugs. Here we demonstrate that repeated intermittent administration of either EtOH or nicotine in adult male Sprague-Dawley rats results in tolerance to EtOH-induced motor impairment and increased EtOH self-administration. These findings suggest that nicotine and EtOH cross-tolerance results in decreased aversive and enhanced rewarding effects of EtOH. Endocannabinoid signaling in the dorsolateral striatum (DLS) has been implicated in both EtOH tolerance and reward, so we investigated whether nicotine or EtOH pre-treatment might modulate endocannabinoid signaling in this region. Using similar EtOH and nicotine pre-treatment methods resulted in increased paired-pulse ratios of evoked EPSCs in enkephalin-positive medium spiny neurons in DLS slices. Thus, EtOH and nicotine pre-treatment may modulate glutamatergic synapses in the DLS presynaptically. Bath application of the CB1 receptor agonist Win 55,2-212 increased the paired-pulse ratio of evoked EPSCs in control slices, while Win 55,2-212 had no effect on paired pulse ratio in slices from either EtOH or nicotine pre-treated rats. Consistent with these effects, nicotine pretreatment occluded LTD induction by high frequency stimulation of the corticostriatal inputs to the dorsolateral striatum. These results suggest that nicotine and EtOH pre-treatment modulates striatal synapses to induce tolerance to the motor impairing effects of EtOH, which may contribute to nicotine and EtOH co-abuse.Significance Statement: This study demonstrates that repeated intermittent nicotine or ethanol pre-exposure results in lower levels of ethanol-induced motor impairment and higher levels of ethanol self-administration. These effects of pretreatment suggest cross-tolerance between these drugs, which may contribute to the development of dependence. These studies identify cellular mechanisms underlying the development of ethanol tolerance that may lead to novel treatments for alcohol and nicotine dependence.