Cannabinoid Dependence Resubmission

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DESCRIPTION (provided by applicant): Marijuana is the most commonly used illicit drug in the US, and the emergence of high efficacy synthetic cannabinoid (CB) drugs JWH-018 and JWH073 (sold as "Spice" and "K2") as popularly abused drugs indicate the gravity of the public health challenge posed by CB abuse-related disorders. Cannabis dependence is the third most prevalent substance abuse disorder, after nicotine and alcohol, and 30- 70% of chronic marijuana smokers experience symptoms of CB withdrawal. Despite this, relatively few studies have examined effects of chronically administered CBs in animals. To address this critical gap, we propose to develop robust animal models of CB dependence that can be used to better understand pharmacological and behavioral aspects of CB dependence. A hurdle to modeling CB dependence in animals has been the failure to observe an evident spontaneous withdrawal syndrome; symptoms often are mild and emerge over days. The CB antagonist, rimonabant, has been used to precipitate 'withdrawal', yet it remains unclear whether the effects of rimonabant reflect physical dependence or are the expression of other intrinsic effects of rimonabant. In preliminary studies in mice injected daily with a high efficacy CB1 agonist, AM2389, we found that rimonabant increased paw tremors and disrupted other behaviors; importantly, qualitatively similar results were obtained when the daily agonist injections were interrupted for 24-72 hrs. These data represent the first evidence of spontaneous CB withdrawal in mice and we will systematically extend these studies by delineating the experimental parameters necessary to maximize the expression of CB dependence using radiotelemetry, observation techniques, and operant responding endpoints to measure effects of both spontaneous and precipitated withdrawal. Our first aim is pharmacological, i.e., we will study mice treated chronically with the CB full agonist AM2389, with which we have obtained encouraging preliminary data. Studies will continue in mice treated chronically with the illicit drugs ¿9-tetrahydrocannabinol (THC), or the newly scheduled CBs JWH-018 and JWH-073, anticipating that the intrinsic activity and duration of action for each agonist will determine the magnitude of the observed effects. Our second aim is to identify the role of contextual influences on the development and expression of CB dependence. The importance of contextual cues in maintaining drug- seeking behavior is well-established for other abused substances but has received scant attention in the CB literature. We propose to specifically pair particular environments with injection of rimonabant, and determine if conditioned cues can also 'precipitate' CB withdrawal. Our immediate goals are to identify the pharmacological and behavioral mechanisms underlying the development of CB dependence. The direct impact of these studies will be an increased understanding of consequences of chronic exposure to marijuana and other abused CBs. Our long term goal is to develop a research program in which these models will be used to identify potential new therapies and management strategies for the treatment of cannabis addiction.