A central feature of addiction is compulsive drug taking, characterized by loss of control over drug use despite adverse physiological and social consequences. A prevailing theory in the neurobiology of cocaine addiction is that repeated drug exposure imposes persistent neurochemical and molecular changes, e.g. altered gene expression, in the mesocorticolimbic brain circuitry underlying reward. These cocaine-induced neuroadaptations may contribute to the complex manifestations of addiction but are poorly defined, especially in primates. The purpose of this application is to comprehensively investigate gene expression dysregulation within the reward circuit that may mediate compulsive cocaine taking, using nonhuman primate models of moderate or excessive cocaine self-administration. Monkeys self-administering cocaine will be yoked to monkeys passively receiving cocaine or saline injections for different exposure periods that reflect initial stages of addiction, or """"""""recreational"""""""", drug use and more chronic cocaine use associated with addiction. A similar study will be conducted in which monkeys self-administer a non-drug reinforcer (sucrose pellets). We postulate that a dysregulation of the dopamine (DA) and glutamate (Glu) systems is associated with chronic cocaine taking. We further postulate that ensemble adaptations in multiple brain structures within the reward circuit as a consequence of DA/Glu dysregulation may accompany chronic cocaine taking. We specifically will investigate adaptations in mesocorticolimbic DA and Glu systems induced by initial and chronic cocaine self-administration by characterizing changes in key components of DA and Glu systems using in situ hybridization, quantitative PCR, and immunoblotting (Aim I).
Aim II will define gene expression patterns at the genome level associated with initial and chronic cocaine self-administration, using a newly developed Rhesus Macaque Gene Chip. Successful completion of the proposed research will provide an integrated assessment of the DA and Glu systems, identify individual novel dysregulated gene candidates, and provide a near genome view of transcriptome changes associated with the reinforcing effects of cocaine in multiple brain structures within the reward circuit. The outcome of the research should deepen our understanding of the molecular and cellular basis of compulsive drug taking.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA021420-04
Application #
7749050
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Caulder, Mark
Project Start
2007-04-10
Project End
2012-12-31
Budget Start
2010-01-01
Budget End
2012-12-31
Support Year
4
Fiscal Year
2010
Total Cost
$344,311
Indirect Cost
Name
Harvard University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Vallender, Eric J; Goswami, Dharmendra B; Shinday, Nina M et al. (2017) Transcriptomic profiling of the ventral tegmental area and nucleus accumbens in rhesus macaques following long-term cocaine self-administration. Drug Alcohol Depend 175:9-23
Zhang, Jingping; Saur, Taixiang; Duke, Angela N et al. (2014) Motor impairments, striatal degeneration, and altered dopamine-glutamate interplay in mice lacking PSD-95. J Neurogenet 28:98-111
Liu, Qian; Yao, Wei-Dong; Suzuki, Tatsuo (2013) Specific interaction of postsynaptic densities with membrane rafts isolated from synaptic plasma membranes. J Neurogenet 27:43-58
Shulha, Hennady P; Crisci, Jessica L; Reshetov, Denis et al. (2012) Human-specific histone methylation signatures at transcription start sites in prefrontal neurons. PLoS Biol 10:e1001427
Suzuki, Tatsuo; Zhang, Jingping; Miyazawa, Shoko et al. (2011) Association of membrane rafts and postsynaptic density: proteomics, biochemical, and ultrastructural analyses. J Neurochem 119:64-77
Xu, Tai-Xiang; Yao, Wei-Dong (2010) D1 and D2 dopamine receptors in separate circuits cooperate to drive associative long-term potentiation in the prefrontal cortex. Proc Natl Acad Sci U S A 107:16366-71
Xu, Tai-Xiang; Ma, Qi; Spealman, Roger D et al. (2010) Amphetamine modulation of long-term potentiation in the prefrontal cortex: dose dependency, monoaminergic contributions, and paradoxical rescue in hyperdopaminergic mutant. J Neurochem 115:1643-54
Abbas, Atheir I; Yadav, Prem N; Yao, Wei-Dong et al. (2009) PSD-95 is essential for hallucinogen and atypical antipsychotic drug actions at serotonin receptors. J Neurosci 29:7124-36
Zhang, Jingping; Xu, Tai-Xiang; Hallett, Penelope J et al. (2009) PSD-95 uncouples dopamine-glutamate interaction in the D1/PSD-95/NMDA receptor complex. J Neurosci 29:2948-60
Xu, Tai-Xiang; Sotnikova, Tatyana D; Liang, Chengyu et al. (2009) Hyperdopaminergic tone erodes prefrontal long-term potential via a D2 receptor-operated protein phosphatase gate. J Neurosci 29:14086-99

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