Addiction is a chronic relapsing disorder. Despite extended abstinence, addicts may experience intense craving in response to drug re-exposure, cues or stress. How do strong cravings re-emerge and what are the neurobiological triggers? Nucleus accumbens (NAc) is a key target of addictive drugs in the mammalian brain. Animal models implicate NAc in enduring vulnerability to reinstatement of drug seeking. Although reinstatement involves plasticity in NAc AMPA-type glutamate receptors (AMPARs), the identity of this plasticity is unclear. Combining rodent reinstatement models with NAc whole-cell recordings in an ex vivo preparation, we identified a putative neural substrate for relapse. During cocaine abstinence, a cocaine prime, in vivo or in vitro, induces AMPAR long-term depression (""""""""re-exposure LTD""""""""), indicating that NAc AMPAR plasticity in response to environmental stimuli during abstinence is highly dynamic. We hypothesize that re- exposure LTD provides a synaptic gateway for reinstatement. To test this, we will directly measure and manipulate NAc AMPAR plasticity in drug-, cue- and stress-primed reinstatement and incubation models. In addition, """"""""priming in a dish"""""""" gives us a tractable model system to study molecular mechanisms of reinstatement-linked plasticity. We hypothesize that """"""""propping up"""""""" NAc AMPAR function during abstinence may be a useful tool in combating relapse.

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Using a combination of rodent behavioral models and advanced cellular electrophysiological techniques, we will investigate the relationship between synaptic plasticity and drug relapse. We have identified a putative neurobiological relapse trigger in the nucleus accumbens-a region of the mesolimbic dopamine circuit that is critical in addiction. We expect our studies to inform new strategies for relapse prevention and treatment.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Volman, Susan
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University of Minnesota Twin Cities
Schools of Medicine
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Sweis, Brian M; Redish, A David; Thomas, Mark J (2018) Prolonged abstinence from cocaine or morphine disrupts separable valuations during decision conflict. Nat Commun 9:2521
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