Binge alcoholism is a growing problem worldwide. Young adults (16-24 years of age) are particularly prone to the adverse effects of alcoholic binging, which is often consumed with secondary drugs of abuse including marijuana. Previous research has suggested that alcohol may share pharmacological effects with cannabinoid agonists such as D9-tetrahydrocannabinol (THC), the primary psychoactive substituent of marijuana. Further, previous work has found that these effects may be modulated by alcohol's effects on the endocannabinoid system. Although much of the preclinical work on both alcohol and cannabinoids has been conducted in male rodents, results of sparse studies in female rodents have suggested sex-selective differences, with females often exhibiting enhanced sensitivity to the pharmacological effects of ethanol as well as THC. In the parent grant, our goals are to characterize some of these differences for THC and to investigate potential mechanisms. In this supplement, we propose to incorporate examination of ethanol/ cannabinoid co-abuse into our overall research strategy. As with the parent grant, integrated in vivo and in vitro measures will be used. To take advantage of local expertise on the hepatic effects of alcohol, we have expanded the dual brain and behavior focus present in the parent grant to incorporate research on the effects of alcohol and THC on the liver. In the proposed project, we will investigate sex differences in the acute in vivo pharmacological effects of alcoho and THC co-administration, as well as their rewarding / aversive effects following repeated intermittent co-administration (Aim 1). These behavioral effects will be correlated with in vitro measures of endocannabinoid system functioning in the brain and the liver and with determination of the extent of liver injury induced by co-abuse of both substances (Aim 2). Understanding the sex-selective effects of co-abuse of alcohol and marijuana is particularly critical at this time since the recent loosening of legal restrictions on marijuana use in the U.S. will likely be associated with increased rates of alcohol-marijuana co-abuse in both sexes.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Special Emphasis Panel (ZDA1-SXC-E (16))
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Lynch, Minda
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Research Triangle Institute
Research Triangle
United States
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Barrus, Daniel G; Lefever, Timothy W; Wiley, Jenny L (2018) Evaluation of reinforcing and aversive effects of voluntary ?9-tetrahydrocannabinol ingestion in rats. Neuropharmacology 137:133-140
Craft, Rebecca M; Greene, Nicholas Z; Wakley, Alexa A (2018) Antinociceptive effects of JWH015 in female and male rats. Behav Pharmacol 29:280-289
Lefever, Timothy W; Lee, Youn O K; Kovach, Alexander L et al. (2017) Delivery of nicotine aerosol to mice via a modified electronic cigarette device. Drug Alcohol Depend 172:80-87
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Britch, Stevie C; Wiley, Jenny L; Yu, Zhihao et al. (2017) Cannabidiol-?9-tetrahydrocannabinol interactions on acute pain and locomotor activity. Drug Alcohol Depend 175:187-197
Craft, R M; Haas, A E; Wiley, J L et al. (2017) Gonadal hormone modulation of ?9-tetrahydrocannabinol-induced antinociception and metabolism in female versus male rats. Pharmacol Biochem Behav 152:36-43
Marusich, Julie A; Craft, Rebecca M; Lefever, Timothy W et al. (2015) The impact of gonadal hormones on cannabinoid dependence. Exp Clin Psychopharmacol 23:206-16
Wakley, Alexa A; Wiley, Jenny L; Craft, Rebecca M (2015) Gonadal hormones do not alter the development of antinociceptive tolerance to delta-9-tetrahydrocannabinol in adult rats. Pharmacol Biochem Behav 133:111-21
Marusich, Julie A; Lefever, Timothy W; Antonazzo, Kateland R et al. (2014) Evaluation of sex differences in cannabinoid dependence. Drug Alcohol Depend 137:20-8
Wakley, Alexa A; Wiley, Jenny L; Craft, Rebecca M (2014) Sex differences in antinociceptive tolerance to delta-9-tetrahydrocannabinol in the rat. Drug Alcohol Depend 143:22-8

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