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 #
5P50DA006634-27
Application #
9653119
Study Section
Special Emphasis Panel (ZDA1)
Project Start
Project End
2020-11-30
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
27
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Type
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
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; McIntosh, J Michael; Jones, Sara R et al. (2017) ?6?2 subunit containing nicotinic acetylcholine receptors exert opposing actions on rapid dopamine signaling in the nucleus accumbens of rats with high-versus low-response to novelty. Neuropharmacology 126:281-291
Shaw, Jessica K; Ferris, Mark J; Locke, Jason L et al. (2017) Hypocretin/orexin knock-out mice display disrupted behavioral and dopamine responses to cocaine. Addict Biol 22:1695-1705
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

Showing the most recent 10 out of 310 publications