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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

    816.21: Determining a critical window for optogenetic inhibition of cocaine seeking

    Location: Halls B-H

    ">*M. T. STEFANIK1, P. W. KALIVAS2;
    1Dept. of Neurosciences, 2Neurosciences, Med. Univ. of South Carolina, Charleston, SC

    Abstract Body: The vulnerability to relapse has been linked to enduring adaptations in the structure and function of the brain’s reward circuitry, which may be important mediators of addictive behavior. Recent data from our laboratory indicate that these changes play a role in cocaine seeking in rats. It is not known, however, how or if these dynamic changes in cellular plasticity contribute to functional behavioral outcomes. Recent advances in optogenetics provide opportunities for novel insights into the roles of the brain circuits that contribute to relapse. Previously, we demonstrated that optogenetic inhibition of the nucleus accumbens (NAc) or its afferents from the prefrontal cortex, basolateral amygdala or ventral tegmental area for the entire 2-hour reinstatement session attenuated reinstated cocaine seeking. Other recent data from our laboratory shows dynamic changes in measures of NAc plasticity during the first 15 minutes of a reinstatement session, changes that parallel behavior. The data presented assess the functional (behavior) and structural (spine morphology) implications of optogenetic inhibition of the NAc or its afferents during cue-induced reinstatement of cocaine seeking. Male Sprague-Dawley rats underwent surgeries for viral microinjections of adeno-associated virus containing coding for the proton pump archaerhodopsin (ArchT) (CAG promoter), implantation of bilateral guide fiber optics, and implantation of intra-jugular venous catheters. Animals then went through 12 days of cocaine self-administration followed by extinction training (2 hr/day). Following extinction, animals underwent cue-primed reinstatement of lever pressing along with the presence/absence of optical inhibition. Preliminary results show a functional inhibition of cocaine seeking during the first 15 minutes of the reinstatement session, followed by the return of seeking behavior following the termination of light delivery. Identifying structures contributing to cocaine seeking and when these structures are active is critical to advance our understanding of addiction and provides insight into possibilities for therapeutic intervention.

    Lay Language Summary: An increased susceptibility to relapse, or make decisions to seek out drug in spite of the potential for negative consequences, is a defining feature of drug addiction. Chronic exposure to addictive substances biases behavior towards relapse by producing long-lasting maladaptive changes in how the brain processes and responds to reward. Determining when, where, and how these changes are necessary is imperative to design effective treatments that curb relapse to drug use.
    In the current study, we show a critical window for intervention that can stop relapse in an animal model. In this model, rats are allowed to self-administer cocaine daily, and each time a cocaine injection is made, a light/tone cue comes on. The rat learns to associate the light/tone cue with cocaine delivery, allowing us to induce relapse-like drug-seeking behavior by presenting the conditioned light/tone cue. We then use an optogenetic strategy (light activated channels and transporters used to manipulate neural activity) to selectively “turn off” critical regions within the brain’s reward circuitry and subsequently stop drug seeking.
    Previous efforts to learn about the neural structures that are changed during the relapse to drug seeking have relied upon technologies that inactivate structures for an indeterminate amount of time. However, some drug-induced pathological changes are manifested in a temporally dynamic manner, necessitating a treatment that can reversibly intervene at different periods during the course of the behavior. With the invention of optogenetics, we now have a tool that can selectively turn on and off portions of the brain with the desired temporal precision.
    By optically inhibiting neurons in the nucleus accumbens, a brain structure central to reward processing, during a key 15 minute time period when the animal is exposed to cocaine-conditioned cues, we successfully inhibit reinstated cocaine seeking. However, when light delivery stopped, rats began responding again. In contrast, if we optically inhibited the projections into the nucleus accumbens from the prefrontal cortex for 15 minutes, we significantly reduced drug seeking while light was being delivered, but did not observe a rebound in drug seeking when the laser was turned off. Current work is underway to see if these changes in behavior parallel changes in measures of brain plasticity.
    The implications for this work are twofold: first, this work is a first step in unraveling the sequence of events that leads to relapse to cocaine seeking, and second, it suggests that future strategies for treating relapse might best focus on cortical projections that initiate and regulate drug seeking behaviors controlled by the nucleus accumbens.