instrucfions): Estimates indicate that addiction cost the U.S. economy neariy one half-trillion dollars per year. The mechanisms driving this behavior are unclear, but involve drug-conditioned cues. In animal models this is attributed to an interaction between dopamine and glutamate neurons In the prefrontal cortex (PFC). However, there remains a lack of understanding ofthe cellular mechanism underiying this interaction. This hampers the development of effective pharmacological treatment strategies for addiction. The long-term objective of this proposal is to identify cellular abnormalities in the PFC that may provide effective therapeutic targets to restore function and thereby prevent relapse to drug seeking. In pyramidal neurons, firing patterns during drug self-administration are regulated in part by dopamine activation of beta-adrenergic receptors ((3- AR), which increase intracellular calcium. This activates KCNQ channels to control spike frequency adaptation, which limits the frequency of action potential firing. The central hypothesis of this proposal Is that the p-AR -signaling cascade is upregulated by chronic cocaine self-administration and depresses KCNQ- mediated inhibition during cue-induced reinstatement of cocaine seeking. To explore the interaction between dopamine and KCNQ-inhibition in PFC neurons, we will record currents mediated by KCNQ that are coupled to of P-ARs. Patch-clamp recordings will be performed in acute brain slices from rats trained to self- administer cocaine and control (yoked saline) rats, before or after cue-induced reinstatement. The mechanism and functional impact ofthe dopamine-suppressed KCNQ signal on reinstatement is unknown and will be examined in the first two specific aims of this proposal. While activation ofthe prelimbic PFC (PL) initiates cocaine seeking, the projection from the infralimbic PFC (IL) inhibits cocaine seeking. Thus, Aim-2 will examine whether dopamine-suppressed KCNQ signaling is specific to the PL, or also occurs in the IL.
Aim -3 will evaluate if manipulation of P-AR signaling normalizes the KCNQ adaptation during relapse. The results of the proposed experiments are expected to positively influence human health because they should identify novel cellular targets for development of improved therapies to treat drug-seeking behaviors.

Public Health Relevance

Substance abuse costs the U.S. neariy one half-trillion dollars annually (NIDA), and pharmacological treatment can help reduce these costs. At present, there are no effective pharmacotherapeutic interventions for cocaine addiction. Identification ofthe KCNQ-mediated neuroadaptations in glutamate transmission in cortical neurons after cocaine self-administration is expected to reveal novel cellular targets for therapeutic development and therebv lead to a better understanding of. and treatment for, relaose to drug seeking.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Specialized Center (P50)
Project #
2P50DA015369-11
Application #
8585277
Study Section
Special Emphasis Panel (ZDA1-EXL-T (01))
Project Start
Project End
Budget Start
2013-05-15
Budget End
2014-04-30
Support Year
11
Fiscal Year
2013
Total Cost
$147,881
Indirect Cost
$63,173
Name
Medical University of South Carolina
Department
Type
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
McClure, Erin A; Baker, Nathaniel L; Gipson, Cassandra D et al. (2015) An open-label pilot trial of N-acetylcysteine and varenicline in adult cigarette smokers. Am J Drug Alcohol Abuse 41:52-6
McGinty, Jacqueline F; Zelek-Molik, Agnieska; Sun, Wei-Lun (2014) Cocaine self-administration causes signaling deficits in corticostriatal circuitry that are reversed by BDNF in early withdrawal. Brain Res :
Scofield, Michael D; Kalivas, Peter W (2014) Astrocytic dysfunction and addiction: consequences of impaired glutamate homeostasis. Neuroscientist 20:610-22
Stankeviciute, Neringa M; Scofield, Michael D; Kalivas, Peter W et al. (2014) Rapid, transient potentiation of dendritic spines in context-induced relapse to cocaine seeking. Addict Biol 19:972-4
McClure, Erin A; Gipson, Cassandra D; Malcolm, Robert J et al. (2014) Potential role of N-acetylcysteine in the management of substance use disorders. CNS Drugs 28:95-106
Mahler, Stephen V; Vazey, Elena M; Beckley, Jacob T et al. (2014) Designer receptors show role for ventral pallidum input to ventral tegmental area in cocaine seeking. Nat Neurosci 17:577-85
Moorman, David E; Aston-Jones, Gary (2014) Orbitofrontal cortical neurons encode expectation-driven initiation of reward-seeking. J Neurosci 34:10234-46
Gipson, Cassandra D; Kupchik, Yonatan M; Kalivas, Peter W (2014) Rapid, transient synaptic plasticity in addiction. Neuropharmacology 76 Pt B:276-86
Sun, Wei-Lun; Coleman, Nortorious T; Zelek-Molik, Agnieszka et al. (2014) Relapse to cocaine-seeking after abstinence is regulated by cAMP-dependent protein kinase A in the prefrontal cortex. Addict Biol 19:77-86
Kalivas, Peter W; Gipson, Cassandra D (2014) "Mourning" a lost opportunity. Psychopharmacology (Berl) 231:3921-2

Showing the most recent 10 out of 118 publications