
  • Addiction, Drugs

    733—Cocaine Reinforcement, Seeking, and Reinstatement I

    Wednesday, November 13, 2013, 8:00 am - 12:00 noon

    733.17: Accumbens shell neuronal ensembles in context-induced reinstatement of cocaine seeking

    Location: Halls B-H

    Natl. Inst. On Drug Abuse, Baltimore, MD

    Abstract Body: In human addicts and rat models, contexts associated with previous drug use can provoke drug relapse. We recently proposed that specific patterns of sparsely distributed neurons, called neuronal ensembles, encode learned associations between drug-associated contexts and drug effects. Here, we trained rats to self-administer cocaine in context A and extinguished lever pressing in a distinct context B. On test day, re-exposure to context A, but not context B, reinstated cocaine seeking and increased expression of the neural activity marker Fos in ~4% of accumbens shell neurons. To assess a causal role for these activated neurons in context-induced reinstatement, we used c-fos-lacZ transgenic rats that co-express the lacZ protein product β-galactosidase in the same neurons that express Fos. We trained these rats to self-administer cocaine in context A and extinguished the rats’ lever pressing in context B. On induction day, groups of rats were exposed to either the cocaine context A or a distinct novel context C for 30 minutes. Sixty minutes later, we injected the inert prodrug Daun02 or vehicle into accumbens shell. β-galactosidase found only in activated neurons catalyzes Daun02 to the active product daunorubicin that lesions neurons. Three days later on test day, context-induced reinstatement and Fos induction were attenuated in rats previously injected with Daun02 in the cocaine context but not in the novel context. We conclude that activation of ensembles in the accumbens shell that encode learned associations between cocaine effects and the drug-associated context is critical for context-induced reinstatement of cocaine seeking.

    Lay Language Summary: The learned association between cocaine seeking and drug-related environmental cues is attenuated by selectively ablating a neuronal ensemble that encodes this memory in rat nucleus accumbens.
    Environmental cues associated with drug use can provoke relapse in drug addicts long after the last drug use. We model relapse behavior in rats using a procedure called context-induced reinstatement. Rats learn to press a lever for an intravenous injection of cocaine in the presence of one set of environmental cues that we call context A and learn to associate this context with drug taking. Next, rats are allowed to press the lever in the presence of a different set of environmental cues that we call context B but no longer receive cocaine infusions. Rats gradually stop pressing the active lever and learn to associate context B with extinction of lever pressing. Upon re-exposure to the original context A, rats immediately return to pressing the active lever despite no drug being available_this latter stage is called context-induced reinstatement and thought to model drug craving during relapse.
    The nucleus accumbens brain area is important for drug seeking and hypothesized to encode learned associations between drug-taking and environmental cues. We hypothesized that sparsely distributed patterns of neurons called neuronal ensembles are selectively activated by the environmental cues in context A during cocaine taking and gradually altered during training to encode the learned association. Different ensembles are activated in context B to encode extinction. Following re-exposure of rats to context A and expression of reinstatement behavior, we used Fos immunohistochemistry to identify a sparsely distributed set of neurons that comprised only 3.3% of all neurons in the nucleus accumbens. Fos is a commonly used protein marker of strongly activated neurons.
    We hypothesized that this specific patterns of Fos-expressing neurons form a neuronal ensemble necessary for context-induced reinstatement in rats. To demonstrate a causal role for these neurons in context-induced reinstatement, we used a pharmacogenetic method called Daun02 inactivation in cfos-lacZ transgenic rats to selectively lesion only those neurons that were activated during reinstatement in context A (versus neurons that were activated by exposure to a novel context C). The protein beta-galactosidase is induced only in strongly activated Fos-expressing neurons of these rats. Following activation of neurons in context A or the control context C, the inactive prodrug Daun02 was injected into the nucleus accumbens where it was catalyzed into the toxin daunorubicin by beta-galactosidase induced only in the behaviorally activated neurons. Three days later, on test day, we re-exposed these rats to context A to assess reinstatement of cocaine-seeking behavior. Context-induced reinstatement was attenuated only in rats that previously received Daun02 injections in context A, but not in rats that received Daun02 in the control context C. We conclude that distinct ensembles are activated in nucleus accumbens by exposure to different contexts and that these ensembles mediate context-induced reinstatement of cocaine seeking.