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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

    816.03: Inhibition of mTORC1 in the nucleus accumbens ‘protects’ against drug-seeking behavior and is associated with reductions in addiction-relevant synaptic plasticity proteins

    Location: Halls B-H

    Sch. of Biomed. Sci. and Pharm., Univ. of Newcastle, Callaghan, Australia

    Abstract Body: Introduction: The mammalian target of rapamycin (mTOR) is a serine threonine protein kinase that is necessary for synaptic plasticity through effects on the translation of synaptic proteins, such as Ca2+/Calmodulin- dependent kinase II alpha (CAMKIIα) and AMPA receptor subunits (GluRs). A recent study showed that intra-nucleus accumbens (NAC) infusion of the mTORC1 inhibitor rapamycin, reduced cue-induced cocaine-seeking, but had no effect on cocaine self-administration under low-effort, fixed ratio one conditions. In the present study, we investigated the effect of systemic rapamycin on cocaine taking under high effort, progressive ratio (PR) conditions. We also examined the effect of repeated intra-NAC infusions of rapamycin on the expression of addiction-relevant behaviours, including ‘relapse’. Methods: In Experiment 1, animals received either intra-cerebroventricular (i.c.v.; 12.5µg/side) or systemic (intra-peritoneal; i.p., 10mg/kg) rapamycin prior to PR testing over three consecutive days. In Experiment 2, animals received intra-NAC shell (NACsh) infusions of rapamycin (2.5µg/side, once/day; 5 days) during self-administration training. We then tracked the expression of addiction-relevant behaviours, including cue-induced reinstatement - a gauge of relapse-like behavior. In both experiments, brains were collected following the final testing session for protein analyses. Results: In Experiment 1, rapamycin attenuated PR break points, an effect associated with reduced phospho-p70s6k (mTORC1 activity), GluR1 AMPAR and CAMKIIα levels in the NACsh and core. In Experiment 2, rapamycin reduced compulsive drug-seeking, PR responding, and cue-induced reinstatement. These behavioural changes were associated with reduced phospho-p70s6k (mTORC1 activity), total CAMKIIα and GluR1 AMPAR levels in the NACsh. Conclusions: Together, these data highlight a role for mTORC1 in the neural processes that control the expression and maintenance of drug reward, including protracted relapse vulnerability. These effects appear to involve a role for mTORC1 in the regulation of GluR1 AMPARs and CAMKIIα in the NACsh.

    Lay Language Summary: Our studies show that a drug called rapamycin, which is commonly used to prevent transplant rejection, can protect against cocaine taking and ‘relapse’ behavior in rats.
    Addiction to cocaine (and other drugs) continues to produce significant health costs in many countries, including the United States. Cocaine is a very addictive drug and it is extremely difficult to quit and remain abstinent from taking this drug for any significant period of time. Indeed, up to 90% of cocaine addicts relapse withinone year. Despite this striking figure, there are no FDA-approved pharmacotherapies to assist in the treatment of psychostimulant addiction. This is due, at least in part, to an incomplete understanding of the processes in the brain that contribute to cocaine addiction.
    Previous work has indicated that drug taking may alter the activity of a protein complex called mTORC1, particularly within areas of the brain that control normal reward seeking behaviors, such as eating. Rapamycin is an FDA-approved drug that inhibits mTORC1, however its effects on addictive behaviors are yet to be fully explored. Specifically, it was not known whether treatment with rapamycin during drug taking and before abstinence could have a lasting protective effect against cocaine taking and relapse following withdrawal.
    To address this question we trained rats to press a lever to receive intravenous infusions of cocaine. Rats were then tested for a number of addiction-relevant behaviours, including a task where the number of lever presses required to earn a cocaine injection was made progressively more difficult. We also tested rats for ‘relapse’ behavior. In this test, animals remained abstinent for 3 weeks before being re-exposed to a cue that previously signaled the availability of cocaine.
    Our data showed that when animals were treated with rapamycin, rats were less willing to lever press for cocaine when high levels of effort were required. Strikingly, rapamycin-injected rats also exhibited lower levels of relapse-like behavior up to one month after treatment. Further, rapamycin treatment was associated with a reduction of several proteins known to be critical for drug seeking in key areas of the brain reward system.
    These findings suggest that treatment with rapamycin, even before cocaine use has ceased, can produce long-lasting changes in the brain reward circuitry that may help to promote abstinence.
    Ongoing experiments in our laboratory are focused on understanding exactly when in the addiction cycle mTORC1 expression is altered and how these changes can best be treated with rapamycin or related drugs.