Stress is a risk factor for drug relapse in humans and it has been suggested that stress-induced neural adaptations alter the threshold for reward. Recent work indicates that the endocannabinoids (ECs), acting via the CB1 cannabinoid receptor, also sensitize the brain to reward; while the CB1 receptor antagonist, SR141716, produces the opposite effect, i.e. reduces the sensitivity of the brain to reward. Our preliminary data show that the concentrations of the EC, N-arachidonylethanolamine (AEA) is reduced in the limbic forebrain both by the dopamine uptake inhibitor GBR129092 and by acute restraint stress. Based upon these data, we hypothesize that the elevation of mesolimbic (ML) dopamine that occurs during stress results in a decrease in the concentration of mesolimbic AEA and that the resulting underactivity of CB1 receptors results in a counterbalancing reduction in the sensitivity of the reward pathway. We predict that manipulations that increase EC concentrations or CB1 receptor activity would enhance the stress-induced sensitization of the reward pathway while removal of CB1 receptors or their inhibition would reduce the sensitization. Mouse models will be used to complete the following specific aims: (1) To determine the relationship between mesolimbic dopamine and mesolimbic AEA; (2) To determine the effects of acute and chronic (predictable and unpredictable) stress on regional EC concentrations, CB1 receptor number and transduction, and FAAH activity; and (3) To determine the role of endogenous activation of the CB1 receptor in the adaptation of the reward circuit to chronic stress. In summary, we will use a combination of techniques to explore the relationships between cannabinergic tone and chronic stress with a focus on the possible role of the CB1 receptor in the modulation of reward sensitivity. The successful completion of these studies will enhance our understanding of the processes involved in the adaptation of the brain to chronic stress.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
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Special Emphasis Panel (ZDA1-RXL-E (14))
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Lin, Yu
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Medical College of Wisconsin
Schools of Medicine
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Hill, M N; Miller, G E; Ho, W-S V et al. (2008) Serum endocannabinoid content is altered in females with depressive disorders: a preliminary report. Pharmacopsychiatry 41:48-53
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Carrier, Erica J; Auchampach, John A; Hillard, Cecilia J (2006) Inhibition of an equilibrative nucleoside transporter by cannabidiol: a mechanism of cannabinoid immunosuppression. Proc Natl Acad Sci U S A 103:7895-900

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