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

    733—Cocaine Reinforcement, Seeking, and Reinstatement I

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

    733.03: Role of projections from ventral medial prefrontal cortex to nucleus accumbens shell in context-induced reinstatement of cocaine seeking

    Location: Halls B-H

    *F. C. CRUZ, K. R. BABIN, R. M. LEAO, J. M. BOSSERT, Y. SHAHAM, B. T. HOPE;
    Natl. Inst. on Drug Abuse - NIDA, NIH, Baltimore, MD

    Abstract Body: In human addicts and rat models, contexts associated with previous drug use can provoke relapse to drug seeking. In rats, this effect is attenuated by inactivation of nucleus accumbens or medial prefrontal cortex (mPFC). We are currently examining whether context-induced reinstatement of cocaine seeking is mediated by projections from ventral mPFC to nucleus accumbens shell. We used an optogenetic approach, in which male rats received bilateral ventral mPFC microinjections of AAV constructs coding for either light-sensitive eNpHR3.0-eYFP or control eYFP protein with optical fibers implanted into accumbens shell. Rats were then trained to self-administer cocaine (1 and 0.5 mg/kg/infusion) for 12 days; drug infusions were paired with a discrete tone-light cue. Lever pressing was subsequently extinguished in a nondrug-associated context in the presence of the discrete cue. Rats were then tested for reinstatement in the cocaine-associated context under extinction conditions. We performed two counterbalanced tests in which either light or no light was delivered bilaterally into accumbens shell. Optically-induced inhibition of accumbens shell attenuated context-induced reinstatement of cocaine seeking in rats injected with eNpHR3.0, but not eYFP into ventral mPFC. These results demonstrate that activation of the projection from ventral mPFC to accumbens shell is involved in context-induced reinstatement of cocaine seeking

    Lay Language Summary: Environmental cues or contexts previously associated with cocaine-taking induce cocaine craving that is mediated by inputs from the ventromedial prefrontal cortex to neuronal ensembles in the nucleus accumbens shell region.
    The context 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. In the current study, rats were trained to press a lever for intravenous injections of cocaine for 10 days in a context A that the rats learn to associate with taking cocaine. 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. Rats were then tested for reinstatement of cocaine seeking by re-exposing them to either the drug-associated context A or the extinction-associated B contexts for 90 min. We observed robust context-induced reinstatement of cocaine seeking in the context A but not in context B.
    We previously demonstrated that cocaine-associated context A activates specific patterns of sparsely distributed neurons called neuronal ensembles in the nucleus accumbens shell that mediate context-induced reinstatement of cocaine seeking. In the first part of our current study, we used Fos immunohistochemistry to identify neurons that were activated by the cocaine-associated context A in brain areas known to convey information to the nucleus accumbens shell. Fos is a commonly used protein marker of strongly activated neurons. Fos expression was increased in a small proportion of sparsely distributed neurons in ventromedial prefrontal cortex, ventral hippocampus, and basolateral amygdala.
    We then used an optogenetic approach to investigate whether context-induced reinstatement of cocaine seeking could be mediated by activation of synaptic connections from the ventromedial prefrontal cortex to neuronal ensembles in the nucleus accumbens shell. Adeno-associated virus (AAV) expressing either the light-sensitive halorhodopsin+yellow fluorescent protein (YFP) or the control YFP protein alone was injected bilaterally into the ventromedial prefrontal cortex of male rats along with optical fibers implanted into accumbens shell. Light-induced activation of halorhodopsin inhibits ventromedial prefrontal cortex terminals in the accumbens shell. Rats were trained as described above to self-administer cocaine in context A and extinguish lever-pressing in context B. Rats were then tested for reinstatement of drug seeking in cocaine-associated context A with or without bilateral delivery of light into the nucleus accumbens shell. Light-induced activation of halorhodopsin inhibits ventromedial prefrontal cortex terminals in the accumbens shell. Light-induced inhibition of these terminals in accumbens shell attenuated context-induced reinstatement of cocaine seeking in rats injected with halorhodopsin+YFP but not in control rats with YFP alone. We conclude that ventromedial prefrontal cortex inputs activate neuronal ensembles in the nucleus accumbens shell to play a causal role in context-induced reinstatement of cocaine seeking. We are now investigating unique molecular alterations within these synaptic terminals to identify mechanisms that mediate the learned association between context and cocaine taking behavior.