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.
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.
|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|
|Daigle, Tanya L; Ferris, Mark J; Gainetdinov, Raul R et al. (2014) Selective deletion of GRK2 alters psychostimulant-induced behaviors and dopamine neurotransmission. Neuropsychopharmacology 39:2450-62|
|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|
|Siciliano, Cody A; Calipari, Erin S; Ferris, Mark J et al. (2014) Biphasic mechanisms of amphetamine action at the dopamine terminal. J Neurosci 34:5575-82|
|Ferris, Mark J; España, Rodrigo A; Locke, Jason L et al. (2014) Dopamine transporters govern diurnal variation in extracellular dopamine tone. Proc Natl Acad Sci U S A 111:E2751-9|
|Yorgason, Jordan T; Ferris, Mark J; Steffensen, Scott C et al. (2014) Frequency-dependent effects of ethanol on dopamine release in the nucleus accumbens. Alcohol Clin Exp Res 38:438-47|
|Calipari, Erin S; Ferris, Mark J; Jones, Sara R (2014) Extended access of cocaine self-administration results in tolerance to the dopamine-elevating and locomotor-stimulating effects of cocaine. J Neurochem 128:224-32|
|Calipari, Erin S; Ferris, Mark J; Salahpour, Ali et al. (2013) Methylphenidate amplifies the potency and reinforcing effects of amphetamines by increasing dopamine transporter expression. Nat Commun 4:2720|
|Calipari, Erin S; Ferris, Mark J; Zimmer, Benjamin A et al. (2013) Temporal pattern of cocaine intake determines tolerance vs sensitization of cocaine effects at the dopamine transporter. Neuropsychopharmacology 38:2385-92|
|Ferris, Mark J; Calipari, Erin S; Yorgason, Jordan T et al. (2013) Examining the complex regulation and drug-induced plasticity of dopamine release and uptake using voltammetry in brain slices. ACS Chem Neurosci 4:693-703|
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