Functional Consequences of Putative Pharmacotherapies for Cocaine Dependence in Animal Models of Cocaine Exposure Drs. Sara Jones/Linda Porrino, co-PI's; Drs. Sam Deadwyler and Mark Ferris, co-I's Cocaine abuse is a significant public health problem, but attempts to develop effective treatments for cocaine abuse and dependence have met with only limited success. One promising development in the clinic has been the use of combination medications to treat the broad range of symptoms and neuroadaptations that result from cocaine exposure. In the prior funding period, the Center found that stimulant drugs, specifically amphetamines, were among the more efficacious strategies for reducing cocaine reinforcement. Building on this foundation, new preliminary data, and advice from the Center's clinical partners we have chosen to examine the stimulant releaser phenmetrazine and its oral pro-drug, phendimetrazine, which have much lower abuse liability to address the dysregulation of dopamine function that is characteristic of cocaine abuse. Another hallmark characteristic of cocaine dependence is reduced prefrontal cortical function and accompanying deficits in behavioral control and cognition. Because multiple transmitter systems are involved in regulating prefrontal cortical function and glutamatergic output from this region, drugs that act on specific prefrontal circuits have been selected for testing as combination drug candidates with phenmetrazine. These drug combinations will be chosen in consultation with other Center Projects and our clinical partners. In the previous funding cycle, we established neurobiological ?signatures? of functional activity, dopamine dynamics, cognitive function and cortical processing that relate to cocaine self-administration and its pharmacological manipulation. This Project will use these data to form the foundation of studies proposed here to examine the neurobiological consequences of chronic phenmetrazine and combination drug therapies in rodent and nonhuman primate models of cocaine use and abuse.
Specific Aim 1 will use rats to measure changes in the function of the dopamine system and identify brain regions with altered metabolic activity after cocaine self- administration and chronic treatment with combinations of candidate medications.
Specific Aim 2 A will use nonhuman primates to characterize the effects of cocaine cues on PET measures of cerebral metabolism after chronic cocaine exposure and treatment with combination medications.
Specific Aim 2 B will evaluate the effects of chronic cocaine exposure with combination medications on cerebral metabolism during the performance of a cognitive task. In addition, electrophysiological recordings of prefrontal cortex will be used to evaluate changes in neural circuitry induced by combination medications that alleviate cocaine addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Specialized Center (P50)
Project #
5P50DA006634-25
Application #
9232105
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
$390,121
Indirect Cost
$138,429
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

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