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
Smith, Laura N; Jedynak, Jakub P; Fontenot, Miles R et al. (2014) Fragile X mental retardation protein regulates synaptic and behavioral plasticity to repeated cocaine administration. Neuron 82:645-58
Rothwell, Patrick E; Kourrich, Said; Thomas, Mark J (2011) Synaptic adaptations in the nucleus accumbens caused by experiences linked to relapse. Biol Psychiatry 69:1124-6
Penrod, Rachel D; Kourrich, Said; Kearney, Esther et al. (2011) An embryonic culture system for the investigation of striatal medium spiny neuron dendritic spine development and plasticity. J Neurosci Methods 200:1-13
Rothwell, Patrick E; Kourrich, Said; Thomas, Mark J (2011) Environmental novelty causes stress-like adaptations at nucleus accumbens synapses: implications for studying addiction-related plasticity. Neuropharmacology 61:1152-9
Xie, Keqiang; Allen, Kevin L; Kourrich, Said et al. (2010) Gbeta5 recruits R7 RGS proteins to GIRK channels to regulate the timing of neuronal inhibitory signaling. Nat Neurosci 13:661-3
Rothwell, Patrick E; Gewirtz, Jonathan C; Thomas, Mark J (2010) Episodic withdrawal promotes psychomotor sensitization to morphine. Neuropsychopharmacology 35:2579-89
Anderson, Garret R; Cao, Yan; Davidson, Steve et al. (2010) R7BP complexes with RGS9-2 and RGS7 in the striatum differentially control motor learning and locomotor responses to cocaine. Neuropsychopharmacology 35:1040-50
Rothwell, Patrick E; Thomas, Mark J; Gewirtz, Jonathan C (2009) Distinct profiles of anxiety and dysphoria during spontaneous withdrawal from acute morphine exposure. Neuropsychopharmacology 34:2285-95
Kourrich, Said; Thomas, Mark J (2009) Similar neurons, opposite adaptations: psychostimulant experience differentially alters firing properties in accumbens core versus shell. J Neurosci 29:12275-83
Carlezon Jr, William A; Thomas, Mark J (2009) Biological substrates of reward and aversion: a nucleus accumbens activity hypothesis. Neuropharmacology 56 Suppl 1:122-32

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