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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA019666-06A1
Application #
8236691
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Volman, Susan
Project Start
2005-04-01
Project End
2017-02-28
Budget Start
2012-03-15
Budget End
2013-02-28
Support Year
6
Fiscal Year
2012
Total Cost
$298,853
Indirect Cost
$98,853
Name
University of Minnesota Twin Cities
Department
Neurosciences
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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
Ingebretson, Anna E; Hearing, Matthew C; Huffington, Ethan D et al. (2018) Endogenous dopamine and endocannabinoid signaling mediate cocaine-induced reversal of AMPAR synaptic potentiation in the nucleus accumbens shell. Neuropharmacology 131:154-165
Sweis, Brian M; Abram, Samantha V; Schmidt, Brandy J et al. (2018) Sensitivity to ""sunk costs"" in mice, rats, and humans. Science 361:178-181
Sweis, Brian M; Larson, Erin B; Redish, A David et al. (2018) Altering gain of the infralimbic-to-accumbens shell circuit alters economically dissociable decision-making algorithms. Proc Natl Acad Sci U S A 115:E6347-E6355
Hearing, Matthew; Graziane, Nicholas; Dong, Yan et al. (2018) Opioid and Psychostimulant Plasticity: Targeting Overlap in Nucleus Accumbens Glutamate Signaling. Trends Pharmacol Sci 39:276-294
Hearing, Matthew C; Jedynak, Jakub; Ebner, Stephanie R et al. (2016) Reversal of morphine-induced cell-type-specific synaptic plasticity in the nucleus accumbens shell blocks reinstatement. Proc Natl Acad Sci U S A 113:757-62
Jedynak, Jakub; Hearing, Matthew; Ingebretson, Anna et al. (2016) Cocaine and Amphetamine Induce Overlapping but Distinct Patterns of AMPAR Plasticity in Nucleus Accumbens Medium Spiny Neurons. Neuropsychopharmacology 41:464-76
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Robison, Alfred J; Vialou, Vincent; Mazei-Robison, Michelle et al. (2013) Behavioral and structural responses to chronic cocaine require a feedforward loop involving ?FosB and calcium/calmodulin-dependent protein kinase II in the nucleus accumbens shell. J Neurosci 33:4295-307
Kourrich, Said; Klug, Jason R; Mayford, Mark et al. (2012) AMPAR-independent effect of striatal ýýCaMKII promotes the sensitization of cocaine reward. J Neurosci 32:6578-86

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