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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    816—Cocaine Reinforcement, Seeking, and Reinstatement II

    Wednesday, November 13, 2013, 1:00 pm - 5:00 pm

    816.04: Intra-VTA administration of the glucagon-like peptide-1 receptor agonist exendin-4 attenuates cocaine taking and seeking in rats

    Location: Halls B-H

    *H. D. SCHMIDT, E. G. MIETLICKI-BAASE, K. IGE, L. A. GUERCIO, M. WIMMER, C. PIERCE, M. R. HAYES;
    Dept Psychiatry, Univ. of Pennsylvania Sch. of Med., PHILADELPHIA, PA

    Abstract Body: Glucagon-like peptide 1 receptor (GLP-1R) signaling in the brain is physiologically relevant for the control of food intake. Administration of the GLP-1R agonist exendin-4 directly into the ventral tegmental area (VTA) selectively reduces intake of palatable food and food self-administration maintained on a progressive ratio schedule of reinforcement. Since the reinforcing properties of both food and cocaine are mediated, in part, by the mesolimbic dopamine system, it is plausible that GLP-1R signaling in the VTA control for appetitive behaviors that extend beyond food intake and include cocaine taking and seeking. However, the role of GLP-1R signaling in cocaine addiction is unclear. The goal of these experiments was to determine the role of VTA GLP-1R signaling in cocaine self-administration and the reinstatement of cocaine seeking, an animal model of relapse. Initially, rats were trained to press a lever for cocaine (0.254 mg/59 µl, i.v.) using a progressive ratio schedule of reinforcement. Exendin-4 (0, 0.005 and 0.05 μg/100nl) was microinjected directly into the VTA immediately prior to a cocaine self-administration session. A separate cohort of rats was trained to self-administer cocaine on a fixed-ratio 5 schedule of reinforcement. After 21 days of cocaine self-administration, drug taking was extinguished by replacing cocaine with saline. Once rats had extinguished their cocaine self-administration behavior, reinstatement of cocaine seeking was elicited by an acute priming injection of cocaine (10 mg/kg, i.p.). Exendin-4 (0, 0.005 and 0.05 μg/100nl) was microinjected directly into the VTA immediately prior to a reinstatement test session. Intra-VTA administration of exendin-4 dose-dependently attenuated cocaine self-administration and cocaine priming-induced reinstatement of drug seeking. This is the first study demonstrating a role for VTA GLP-1R signaling in cocaine taking and seeking. Collectively, these findings support the hypothesis that GLP-1R signaling in the VTA, in addition to regulating food intake, plays a critical role in cocaine-induced behavioral plasticity.
    This work is support by K01 DA030445 (H.D.S), R01 DK096139 (M.R.H.), T32-GM07517 (L.A.G), R01 DA15214, K02 DA18678, and R01 DA22339 (R.C.P.).

    Lay Language Summary: Our findings identify a novel neuroendocrine circuit that can be activated to reduce cocaine consumption in rats. Specifically, stimulation of a select population of glucagon-like peptide 1 receptors (GLP-1R) in the ventral tegmental area (VTA) of the brain reduces cocaine self-administration in rats. Activation of VTA GLP-1Rs was sufficient to attenuate voluntary cocaine taking and the reinstatement of cocaine seeking, an animal model of drug craving and relapse.
    Cocaine addiction is a major public health concern in the United States. Illicit drug use costs the United States hundreds of billions of dollars in increased health care costs, crime and lost productivity. Therefore, there is a critical need to develop drugs to treat cocaine addiction. The ultimate goal of these experiments is to identify novel targets for the development of new pharmacotherapies for cocaine craving and addiction. Using an animal model of cocaine craving, our preliminary data reveal that GLP-1R agonists may be appropriate candidates for the treatment of cocaine addiction. These novel findings are provocative and suggest that drugs targeting brain GLP-1Rs may be efficacious therapies for treating cocaine craving and relapse.
    Cocaine and other drugs of abuse exert their reinforcing properties by hijacking the same neurocircuits in the brain that mediate natural rewards including food. GLP-1Rs in the ventral tegmental area have been shown previously to regulate food intake. Thus, it is possible that GLP-1R signaling in this brain region also mediates cocaine craving and taking. To test this hypothesis and model voluntary cocaine taking and seeking in human addicts, rats were trained to self-administer intravenous infusions of cocaine. In order to determine the role of GLP-1Rs in cocaine consumption, the GLP-1R agonist exendin-4 was injected directly into the VTA prior to a cocaine self-administration session. Interestingly, this infusion of extendin-4 was sufficient to attenuate cocaine taking in rats. In order to determine whether intra-VTA administration of exendin-4 blocks cocaine craving, cocaine-experienced rats underwent forced drug abstinence, analogous to detoxification in human addicts. Subsequently, an acute priming injection of cocaine was used to promote cocaine craving and seeking during abstinence. Administration of exendin-4 directly into the VTA prior to the priming cocaine injection was sufficient to block drug craving and seeking in this animal model of cocaine relapse.
    Interestingly, the doses of exendin-4 required to attenuate cocaine taking and seeking are much lower than doses shown to interfere with normal food consumption. Thus, these results suggest that low doses of GLP-1R agonists may selectively prevent cocaine craving and relapse without interfering with normal reinforced behaviors including feeding behaviors.