EFFECTS OF CHRONIC DRUG COMBINATION TREATMENTS ON THE REINFORCING AND COGNITIVE EFFECTS OF COCAINE IN RODENTS AND MONKEYS Michael A. Nader, PI Paul W. Czoty, Thomas J. Martin, Mark J. Ferris, Mei-Chuan Ko, Daniel Yohannes, Co-Is The goal of this Project is to achieve a better understanding of the pharmacological determinants of the reinforcing effects of cocaine in rodent and nonhuman primate models of drug abuse. In the previous funding period, we found that monoamine releasers d-amphetamine, phenmetrazine (PM) and phendimetrazine (PDM) effectively decreased cocaine self-administration in rats and monkeys. For the studies proposed in Project 1, we will incorporate a strategy that involves drug combinations in order to meet two goals: (1) reduce the amount of drug (i.e., PM or PDM) necessary to decrease cocaine self-administration and (2) improve treatment efficacy. For all studies, one of the drugs (Drug A) will be PM (in rats) and PDM (in monkeys). The combination drug (Drug B) will be based on input from our clinicial colloborators and be a compound that improves cognitive performance in animals with a cocaine history.
In Specific Aim 1, rats will self-administer cocaine under a long-access 6-hr session; some rats will then be tested in two paradigms designed to assess cognition/attention/impulsivity, the delayed discounting procedure and the 5-choice serial reaction time task. Drug B candidates that show remediation of cocaine-induced disruptions in cognitive performance will be tested in another group of rats self-administering cocaine and co-treated with PM. Drug B candidates that effectively reduce rodent self-administration will be tested in nonhuman primates (Specific Aim 2) under two different cocaine access conditions - progressive-ratio and concurrent food-cocaine choice. If the combination of PDM and Drug B effectively decreases cocaine self-administration under either condition, the effects of the combination on cognitive performance and physiology, as assessed with telemetry, will be examined in these same monkeys (Specific Aim 3). These studies combine chronic drug treatment and drug combinations under multiple behavioral conditions in rats and monkeys and should provide valuable translational information for the development of novel cocaine pharmacotherapies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Specialized Center (P50)
Project #
5P50DA006634-25
Application #
9232104
Study Section
Special Emphasis Panel (ZDA1-NXR-B)
Project Start
Project End
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
25
Fiscal Year
2017
Total Cost
$420,203
Indirect Cost
$149,104
Name
Wake Forest University Health Sciences
Department
Type
Domestic Higher Education
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Brodnik, Zachary D; Ferris, Mark John; Jones, Sara R et al. (2016) Reinforcing Doses of Intravenous Cocaine Produce Only Modest Dopamine Uptake Inhibition. ACS Chem Neurosci :
Eldeeb, Khalil; Leone-Kabler, Sandra; Howlett, Allyn C (2016) CB1 cannabinoid receptor-mediated increases in cyclic AMP accumulation are correlated with reduced Gi/o function. J Basic Clin Physiol Pharmacol 27:311-22
Porrino, Linda J; Beveridge, Thomas J R; Smith, Hilary R et al. (2016) Functional consequences of cocaine expectation: findings in a non-human primate model of cocaine self-administration. Addict Biol 21:519-29
Karkhanis, Anushree N; Beveridge, Thomas J R; Blough, Bruce E et al. (2016) The individual and combined effects of phenmetrazine and mgluR2/3 agonist LY379268 on the motivation to self-administer cocaine. Drug Alcohol Depend 166:51-60
McGinnis, Molly M; Siciliano, Cody A; Jones, Sara R (2016) Dopamine D3 autoreceptor inhibition enhances cocaine potency at the dopamine transporter. J Neurochem 138:821-9
Czoty, P W; Blough, B E; Fennell, T R et al. (2016) Attenuation of cocaine self-administration by chronic oral phendimetrazine in rhesus monkeys. Neuroscience 324:367-76
Porrino, Linda J; Miller, Mack D; Smith, Hilary R et al. (2016) Neural Correlates of Exposure to Cocaine Cues in Rhesus Monkeys: Modulation by the Dopamine Transporter. Biol Psychiatry :
Siciliano, Cody A; Fordahl, Steve C; Jones, Sara R (2016) Cocaine Self-Administration Produces Long-Lasting Alterations in Dopamine Transporter Responses to Cocaine. J Neurosci 36:7807-16
Gould, R W; Czoty, P W; Porrino, L J et al. (2016) Social Status in Monkeys: Effects of Social Confrontation on Brain Function and Cocaine Self-Administration. Neuropsychopharmacology :
Brust, Tarsis F; Morgenweck, Jenny; Kim, Susy A et al. (2016) Biased agonists of the kappa opioid receptor suppress pain and itch without causing sedation or dysphoria. Sci Signal 9:ra117

Showing the most recent 10 out of 291 publications