Despite significant efforts cocaine abuse remains a continuing public health problem. Chronic cocaine use is accompanied by neuroadaptations in multiple neurotransmitter systems, as well as enduring changes in brain functional activity. To date there are no FDA approved medications for treatment of cocaine dependence. Drug development efforts are hampered by the lack of understanding of the neurobiological basis of potential pharmacotherapeutic strategies. The goal of these studies proposed is to characterize at a systems level the neurobiological effects of potential treatment drugs that have shown positive signals in current clinical trials, drugs approved for use In humans being considered for use in treatment;and mechanistic drug treatments for which preliminary animal studies suggest may be useful in reducing cocaine reinforcement based on their mechanisms of action. The convergence of Information from these different strategies will provide critical Information about the neuropharmacological mechanism of effective treatment and guide future drug development.
Aim 1 will evaluate the consequences of chronic administration of candidate medications and then assess the neurobiological effects of these medications in rodent models of chronic cocaine self-administration in neurochemical systems as established in Project 1 We will measure changes in the function of dopamine systems using microdialysis in freely moving rats and voltammetry in brain slices and assess changes in functional brain activity with the 2-deoxyglucose method and the expression of immediate early genes consequent to chronic treatment with candidate medications.
Aim 2 will make use of established nonhuman primate models of cocaine self-administration to evaluate the consequences of these potential pharmacotherapies on brain transmitter systems and to characterize the sites of changes in functional activity accompanying responses to cocaine-associated cues and cognitive processes as established in Project 1 It is only through a systems level analysis with clinically relevant models of substance abuse as proposed in this application that a greater understanding of the neurobiological basis of treatment can emerge. Thus, the systems approach of Project 2 provides a bridge between behavioral evaluations in Project 1 and the cellular approaches in Project 3.

Public Health Relevance

By combining multiple drug strategies in this Project, areas of convergence will be identified that characterize relevant mechanisms of drug action showing positive clinical signals and help delineate specific neuropharmacological mechanisms that can serve as targets for medications development.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Specialized Center (P50)
Project #
5P50DA006634-21
Application #
8378862
Study Section
Special Emphasis Panel (ZDA1-EXL-T)
Project Start
Project End
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
21
Fiscal Year
2012
Total Cost
$493,904
Indirect Cost
$160,185
Name
Wake Forest University Health Sciences
Department
Type
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Melchior, James R; Jones, Sara R (2017) Chronic ethanol exposure increases inhibition of optically targeted phasic dopamine release in the nucleus accumbens core and medial shell ex vivo. Mol Cell Neurosci 85:93-104
Blume, Lawrence C; Patten, Theresa; Eldeeb, Khalil et al. (2017) Cannabinoid Receptor Interacting Protein 1a Competition with ?-Arrestin for CB1 Receptor Binding Sites. Mol Pharmacol 91:75-86
John, William S; Martin, Thomas J; Nader, Michael A (2017) Behavioral Determinants of Cannabinoid Self-Administration in Old World Monkeys. Neuropsychopharmacology 42:1522-1530
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
Howlett, Allyn C; Abood, Mary E (2017) CB1 and CB2 Receptor Pharmacology. Adv Pharmacol 80:169-206
Gould, Robert W; Czoty, Paul W; Porrino, Linda J et al. (2017) Social Status in Monkeys: Effects of Social Confrontation on Brain Function and Cocaine Self-Administration. Neuropsychopharmacology 42:1093-1102
Namjoshi, Sanjeev V; Raab-Graham, Kimberly F (2017) Screening the Molecular Framework Underlying Local Dendritic mRNA Translation. Front Mol Neurosci 10:45
Wesley, Michael J; Lile, Joshua A; Fillmore, Mark T et al. (2017) Neurophysiological capacity in a working memory task differentiates dependent from nondependent heavy drinkers and controls. Drug Alcohol Depend 175:24-35
Siciliano, Cody A; Saha, Kaustuv; Calipari, Erin S et al. (2017) Amphetamine reverses escalated cocaine intake via restoration of dopamine transporter conformation. J Neurosci :
Luessen, D J; Sun, H; McGinnis, M M et al. (2017) Chronic intermittent ethanol exposure selectively alters the expression of G? subunit isoforms and RGS subtypes in rat prefrontal cortex. Brain Res 1672:106-112

Showing the most recent 10 out of 301 publications