Epidemiological studies have shown that women and men differ in their patterns of substance abuse and dependence. Sex differences in the effects of D9-tetrahydrocannabinol (THC), the primary psychoactive substituent of marijuana, have been reported in humans and in rodent models;however, the mechanisms responsible for these differences are unclear and are the focus of the proposed research.
Aims 1 and 2 will determine whether sex differences in the antinociceptive and dependence-related effects of THC, respectively, are modulated by gonadal hormones, estradiol, and progesterone in females and testosterone in males. Emphasis will be on the effects of repeated THC administration on behavior, as substance abuse, by definition, requires chronic use. Dependence-related behaviors include precipitated withdrawal (somatic and affective signs), THC discrimination (a rodent model of marijuana intoxication), and conditioned place preference/aversion (CPP/CPA), a rodent model to assess the degree to which drug effects are associated with pleasure or aversion. Sex differences in tolerance to the antinociceptive effects of THC, one of the potential therapeutic indications of cannabinoid-based medications, will also be evaluated.
Aim 3 will characterize the pharmacokinetics of THC and will identify regional alterations in central CB1 and CB2 receptor densities and functioning and endocannabinoid levels that are associated with behavioral changes. Understanding these basic mechanisms underlying sex differences in antinociceptive and dependence-related effects of cannabinoids will facilitate development of sex-specific approaches to treat marijuana dependence and to use cannabinoid-based medications therapeutically, specifically in the treatment of pain and spasticity. In addition, increasing scientific knowledge of endocrinological mechanisms that affect endocannabinoid system functioning could enhance understanding and treatment of a wide variety of disorders, in which dysregulation of the endocannabinoid system has been implicated, including substance abuse, psychiatric disorders, obesity, and various neurological disorders.

Public Health Relevance

The proposed research will use integrated behavioral, neurochemical, and pharmacokinetic approaches to determine how gonadal steroid hormones modulate cannabinoid pharmacology related to D9- tetrahydrocannabinol (THC)-induced analgesia and dependence. This comprehensive approach will reveal the mechanisms underlying sex differences in cannabinoid pharmacology, ultimately leading to the development of more effective sex-specific treatments for pain and for cannabinoid dependence. Results are also likely to uncover mechanisms of hormonal modulation of the brain endocannabinoid system (endogenous ligands and receptors), a key mediator of cannabinoid behavioral effects.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
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Lynch, Minda
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Research Triangle Institute
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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; Craft, Rebecca M; Lefever, Timothy W et al. (2015) The impact of gonadal hormones on cannabinoid dependence. Exp Clin Psychopharmacol 23:206-16
Wiley, Jenny L; Burston, James J (2014) Sex differences in Δ(9)-tetrahydrocannabinol metabolism and in vivo pharmacology following acute and repeated dosing in adolescent rats. Neurosci Lett 576:51-5
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
Craft, Rebecca M; Marusich, Julie A; Wiley, Jenny L (2012) Sex differences in cannabinoid pharmacology: A reflection of differences in the endocannabinoid system? Life Sci :
Marusich, Julie A; Wiley, Jenny L (2012) Rimonabant abolishes sensitivity to workload changes in a progressive ratio procedure. Pharmacol Biochem Behav 101:575-80
Wiley, Jenny L; Evans, Rhys L; Grainger, Darren B et al. (2011) Locomotor activity changes in female adolescent and adult rats during repeated treatment with a cannabinoid or club drug. Pharmacol Rep 63:1085-92
Wiley, Jenny L; Jones, Amanda R; Wright Jr, M Jerry (2011) Exposure to a high-fat diet decreases sensitivity to Δ9-tetrahydrocannabinol-induced motor effects in female rats. Neuropharmacology 60:274-83
Burston, James J; Wiley, Jenny L; Craig, Abimbola A et al. (2010) Regional enhancement of cannabinoid CB₁ receptor desensitization in female adolescent rats following repeated Delta-tetrahydrocannabinol exposure. Br J Pharmacol 161:103-12

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