A growing body of evidence indicates that increases in dopamine and glutamate transmission in the nucleus accumbens independently promote the reinstatement of cocaine seeking, an animal model of relapse. The preliminary data presented in the current application demonstrate for the first time that cocaine reinstatement depends on interactions between accumbal shell dopamine and glutamate that are mediated by calcium/calmodulin-dependent protein kinase II (CaM-KII). Stimulation of D1-like (i.e. D1/D5) dopamine receptors in the nucleus accumbens shell reinstated cocaine seeking via the activation of L-type calcium channels. Reinstatement of cocaine seeking also was attenuated by injection of a CaM-KII inhibitor into the accumbens shell. Cocaine reinstatement was associated with increases in pCaM-KII and enhanced phosphorylation of GluR1 AMPA glutamate receptor subunits at S831, a site linked to CaM-KII-dependent trafficking of AMPA receptors to surface membranes. Finally, cocaine reinstatement was attenuated by intra- accumbal shell administration of a membrane-permeable form of Pep2-EVKI, a peptide that impairs AMPA receptor trafficking. Collectively, these results indicate that CaM-KII is a critical link between nucleus accumbens shell dopamine and glutamate systems involved in the neuronal plasticity underlying cocaine priming-induced reinstatement of drug seeking in rats. The current application will further examine the hypothesis that cocaine priming-induced reinstatement of cocaine seeking depends on the serial activation of D1-like dopamine receptors, PKA, L-type calcium channels and CaM-KII as well as the CaM-KII-dependent trafficking of AMPA receptor subunits to the synapse in the nucleus accumbens shell. Moreover, we propose to determine if similar or identical processes underlying cue-induced reinstatement of cocaine seeking. The experiments outlined in this proposal will define fundamental changes in D1-like dopamine receptor signaling that are associated with the reinstatement of cocaine seeking. The ultimate goal of these experiments is to identify novel targets for the development of pharmacotherapies for cocaine addiction. Our preliminary data indicate that L-type calcium channel and CaM-KII inhibitors as well as drugs that specifically influence AMPA receptor trafficking may be appropriate candidates for the treatment of cocaine addiction.The ultimate goal of these experiments is to identify novel targets for the development of drug therapies for cocaine craving and addiction. Using an animal model of cocaine craving, our preliminary data reveal that several classes of therapeutic drugs, including those that modulate dopamine and glutamate transmission in the brain, may be appropriate candidates for the treatment of cocaine addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA022339-06
Application #
8261961
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Frankenheim, Jerry
Project Start
2008-05-15
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
6
Fiscal Year
2012
Total Cost
$341,807
Indirect Cost
$72,339
Name
University of Pennsylvania
Department
Psychiatry
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Rasakham, Khampaseuth; Schmidt, Heath D; Kay, Kevin et al. (2014) Synapse density and dendritic complexity are reduced in the prefrontal cortex following seven days of forced abstinence from cocaine self-administration. PLoS One 9:e102524
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Akay, Cagla; Cooper, Michael; Odeleye, Akinleye et al. (2014) Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system. J Neurovirol 20:39-53
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Challis, Collin; Boulden, Janette; Veerakumar, Avin et al. (2013) Raphe GABAergic neurons mediate the acquisition of avoidance after social defeat. J Neurosci 33:13978-88, 13988a
Vassoler, Fair M; White, Samantha L; Schmidt, Heath D et al. (2013) Epigenetic inheritance of a cocaine-resistance phenotype. Nat Neurosci 16:42-7
Pierce, R Christopher; Wolf, Marina E (2013) Psychostimulant-induced neuroadaptations in nucleus accumbens AMPA receptor transmission. Cold Spring Harb Perspect Med 3:a012021

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