The K99/R00 research and training plan will serve two purposes. The first is to provide substantial career development by: 1) expanding the investigator's area of expertise to include acetylcholine systems and their interaction with mesolimbic dopamine, 2) expanding the investigator's technical skill set to include rodent self-administration and fast scan cyclic voltammetry in freely moving animals, particularly in the detection of cue-evoked dopamine release, and 3) initiating a research program that will lead to research independence through professional development and collection of preliminary data for major research (R01) funding. The second corresponding purpose is to characterize a neurobiological mechanism for individual differences in the acquisition of drug self-administration behavior. Using a series of neurochemical and behavioral measures including microdialysis, HPLC, voltammetry in anesthetized and freely-moving animals, and self-administration, we will characterize individual differences in the magnitude of primary reward and conditioned cue-evoked dopamine release as well as corresponding propensity to self-administer cocaine and natural rewards. In addition, we will pharmacologically manipulate ventral tegmental area (VTA) and nucleus accumbens (NAc) nicotinic acetylcholine receptors (nAChRs) via acute and chronic administration of nicotine and subtype specific nAChR antagonists in order to demonstrate individual differences in their ability to modulate reward and cue-evoked dopamine transients. We propose that an underlying mechanism to explain individual differences in acquisition of drug self-administration behavior resides in the differental ability of VTA and NAc nAChRs to modulate dopamine release in the shell of the NAc in fast and slow acquiring animals.

Public Health Relevance

Drug abuse, including cocaine addiction, is a major concern for public health and safety as it affects millions of individuals worldwide, leading to hospitalizations, incarceration, and even death. The cost to society reaches the hundreds of billions in the United States alone. The goal of this research is to understand the neurochemical mechanisms and potential risk factors that contribute to individual differences in propensity to abuse substances, particularly cocaine, so that ultimately, this information can be used to develop preventative measures to reduce drug abuse in vulnerable populations.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Career Transition Award (K99)
Project #
5K99DA031791-02
Application #
8485566
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Sorensen, Roger
Project Start
2012-07-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$94,122
Indirect Cost
$6,972
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
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
Yorgason, J T; Rose, J H; McIntosh, J M et al. (2015) Greater ethanol inhibition of presynaptic dopamine release in C57BL/6J than DBA/2J mice: Role of nicotinic acetylcholine receptors. Neuroscience 284:854-64
Melchior, James R; Ferris, Mark J; Stuber, Garret D et al. (2015) Optogenetic versus electrical stimulation of dopamine terminals in the nucleus accumbens reveals local modulation of presynaptic release. J Neurochem 134:833-44
Siciliano, Cody A; Ferris, Mark J; Jones, Sara R (2015) Cocaine self-administration disrupts mesolimbic dopamine circuit function and attenuates dopaminergic responsiveness to cocaine. Eur J Neurosci 42:2091-6
Luderman, Kathryn D; Chen, Rong; Ferris, Mark J et al. (2015) Protein kinase C beta regulates the Dâ‚‚-like dopamine autoreceptor. Neuropharmacology 89:335-41
Siciliano, Cody A; Calipari, Erin S; Ferris, Mark J et al. (2015) Adaptations of presynaptic dopamine terminals induced by psychostimulant self-administration. ACS Chem Neurosci 6:27-36
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
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
Calipari, Erin S; Ferris, Mark J; Siciliano, Cody A et al. (2014) Intermittent cocaine self-administration produces sensitization of stimulant effects at the dopamine transporter. J Pharmacol Exp Ther 349:192-8
Ferris, Mark J; Milenkovic, Marija; Liu, Shuai et al. (2014) Sustained N-methyl-d-aspartate receptor hypofunction remodels the dopamine system and impairs phasic signaling. Eur J Neurosci 40:2255-63

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