Cocaine abuse in the United States is a dangerous and pervasive health, social and economic issue that consumes an enormous amount of federal and state resources. A key site of cocaine's actions in the brain, both in humans and in experimental animals, is the nucleus accumbens (NAc)-a regulator of motivated behaviors. Repeated exposure to cocaine results in persistent adaptations in the NAc that are thought to underlie behavioral abnormaltites in well-established animal models of addiction, such as behavioral sensitization. Adaptations in glutamatergic synaptic transmission in the NAc appear to be particularly important. Recent studies have established that repeated cocaine exposure that induces robust behavioral sensitization also induces a depression in synaptic efficacy at glutamatergic synapses formed by prefrontal cortical afferents to the NAc. Our proposed studies will combine behavioral analysis with whole-cell electrophysiology in NAc brain slices to delineate the relationship between cocaine-induced synaptic plasticity and behavioral sensitization. We hypothesize that depression at NAc glutamatergic synapses is a critical neural substrate for sensitization. As such, fundamental factors controlling the behavioral adaptations, such as dose, temporal pattern and context of drug administration will similarly regulate NAc synaptic plasticity and the time course of the cellular modification will mirror the behavioral changes. In fulfilling the aims of the current proposal, the study of synaptic function in brain slices from animals exposed to drugs of abuse should provide crucial information necessary to make the link between drug-induced adaptations at the level of molecules and gene expression to those systems level adaptations that ultimately must underlie addiction ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA019666-01A1
Application #
7037335
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Volman, Susan
Project Start
2006-03-01
Project End
2011-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
1
Fiscal Year
2006
Total Cost
$255,064
Indirect Cost
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
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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
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
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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