Abstract

There are currently no FDA-approved medications for cocaine addiction. In the previous funding period, several animal models of cocaine abuse were used by this Center to investigate the neuropharmacology of chronic cocaine exposure. The studies described in Project 1 combine three research areas that were separated into distinct Projects in the previous version of the Center (formerly Projects 3, 5 and 6). These studies are designed to systematically investigate in monkeys and rats current medications used clinically to beat cocaine addiction, as well as drugs in the clinical """"""""pipeline"""""""" and drugs that are not approved for human use, but could provide information related to mechanisms of action related to clinical efficacy.
Specific Aim 1 will use rhesus monkeys self-administering cocaine to examine the effects of chronic administration of drugs. Treatment drugs that selective decrease cocaine- relative to food-reinforced responding, with no evidence of tolerance or attenuation by higher cocaine doses, will be evaluated in monkey models of cognition (Specific Aim 2). A positive outcome in models of cognition (i.e., improvement in performance) will yield additional studies in experimentally naive monkeys in combination with imaging studies (Projects 2 and 3). Finally, Specific Aim 3 will examine the effects of acute and chronic administration of drug treatments in several rat models of cocaine self-administration. When complete, the studies in this Project will provide basic science information in monkeys and rats across several behavioral endpoints in which different aspects of addiction are modeled, which should be of relevance to clinicians.

Public Health Relevance

By combining a top-down approach, using drugs currently being evaluated clinically, with a mechanistic approach in several animal models of self-administration and cognition, areas of convergence will be identified that are relevant to identifying neuropharmacological mechanisms for effective treatment agents for cocaine addiction.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Specialized Center (P50)
Project #
5P50DA006634-22
Application #
8471086
Study Section
Special Emphasis Panel (ZDA1-EXL-T)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
22
Fiscal Year
2013
Total Cost
$482,707
Indirect Cost
$184,837

  Institution

Name
Wake Forest University Health Sciences
Department
Type
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157

  Publications

Siciliano, Cody A; Saha, Kaustuv; Calipari, Erin S et al. (2018) Amphetamine Reverses Escalated Cocaine Intake via Restoration of Dopamine Transporter Conformation. J Neurosci 38:484-497
Ilyasov, Alexander A; Milligan, Carolanne E; Pharr, Emily P et al. (2018) The Endocannabinoid System and Oligodendrocytes in Health and Disease. Front Neurosci 12:733
Ding, Huiping; Kiguchi, Norikazu; Yasuda, Dennis et al. (2018) A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates. Sci Transl Med 10:
Chen, R; McIntosh, S; Hemby, S E et al. (2018) High and low doses of cocaine intake are differentially regulated by dopamine D2 receptors in the ventral tegmental area and the nucleus accumbens. Neurosci Lett 671:133-139
John, William S; Martin, Thomas J; Solingapuram Sai, Kiran Kumar et al. (2018) Chronic ?9-THC in Rhesus Monkeys: Effects on Cognitive Performance and Dopamine D2/D3 Receptor Availability. J Pharmacol Exp Ther 364:300-310
Siciliano, Cody A; Jones, Sara R (2017) Cocaine Potency at the Dopamine Transporter Tracks Discrete Motivational States During Cocaine Self-Administration. Neuropsychopharmacology 42:1893-1904
Brodnik, Zachary D; Ferris, Mark J; Jones, Sara R et al. (2017) Reinforcing Doses of Intravenous Cocaine Produce Only Modest Dopamine Uptake Inhibition. ACS Chem Neurosci 8:281-289
Fordahl, Steve C; Jones, Sara R (2017) High-Fat-Diet-Induced Deficits in Dopamine Terminal Function Are Reversed by Restoring Insulin Signaling. ACS Chem Neurosci 8:290-299
Eldeeb, Khalil; Leone-Kabler, Sandra; Howlett, Allyn C (2017) Mouse Neuroblastoma CB1 Cannabinoid Receptor-Stimulated [35S]GTP?S Binding: Total and Antibody-Targeted G? Protein-Specific Scintillation Proximity Assays. Methods Enzymol 593:1-21
Raab-Graham, Kimberly F; Niere, Farr (2017) mTOR referees memory and disease through mRNA repression and competition. FEBS Lett 591:1540-1554

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