The neurobiological consequences of cocaine self-administration vary according to the experimental protocol used and are highly dependent upon the dose and frequency of administration. We have recently found that high-dose """"""""binge"""""""" cocaine self-administration and deprivation in rats produces dramatic decreases in the potency of cocaine to alter dopamine (DA) neurotransmission. Using microdialysis to get an overall view of DA levels, we found that an i.v. administered dose of cocaine (1.5 mg/kg) no longer significantly elevated extracellular DA levels in the nucleus accumbens (NAc). To examine cocaine effects on the DA transporter, we used voltammetry in brain slices to measure DA uptake directly. The ability of cocaine to inhibit DA uptake was severely limited in rats that had self-administered cocaine compared to drug naive animals. In addition, the maximal rate of DA uptake was either increased or decreased, depending on the protocol, but the potency of cocaine was consistently decreased. This suggested a dissociation between DA uptake and inhibition of uptake by cocaine, although binding studies show that cocaine still binds to the transporter with unaltered affinity. This is a unique situation, caused by self-administration of high doses of cocaine. The implication of these findings is that cocaine effects can be manipulated independently of DA uptake, which may ultimately have relevance for the design of pharmacotherapies for cocaine addiction which would block cocaine inhibition but leave DA uptake intact. These are early days, however, in the documentaion of the dissociation between DA uptake and cocaine effects. The goal of this proposal is to provide a thorough investigation of the reduction in the potency of cocaine following self-administration. Relevance: The overall aim of this proposal is to understand how the dopamine transporter, the main target of cocaine in the brain, becomes insensitive to cocaine after several days of high-dose treatment with cocaine. The results will provide a new direction in the design of drugs to treat cocaine addiction. Potentially, the new drugs could change the dopamine transporter so that cocaine has no addictive effects and would not be abused.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA021325-05
Application #
8101228
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Pilotte, Nancy S
Project Start
2007-07-20
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2011
Total Cost
$278,564
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Physiology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
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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
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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
Calipari, Erin S; Ferris, Mark J; Siciliano, Cody A et al. (2015) Differential influence of dopamine transport rate on the potencies of cocaine, amphetamine, and methylphenidate. ACS Chem Neurosci 6:155-62
Ferris, Mark J; Calipari, Erin S; Rose, Jamie H et al. (2015) A Single Amphetamine Infusion Reverses Deficits in Dopamine Nerve-Terminal Function Caused by a History of Cocaine Self-Administration. Neuropsychopharmacology 40:1826-36
Richardson, Jason R; Taylor, Michele M; Shalat, Stuart L et al. (2015) Developmental pesticide exposure reproduces features of attention deficit hyperactivity disorder. FASEB J 29:1960-72

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