Abstract

Stress increases addictive behaviors. Corticotropin-releasing factor (CRF) is released in the ventral tegmental area (VTA) during stressful events, and produces relapse to cocaine seeking. However, the mechanism by which CRF produces stress-dependent relapse to cocaine seeking is poorly understood. The main goal of this proposal is to understand the role of CRF-R1 and CRF-R2, and the CRF-BP in the VTA in modulating dopamine release and stress-induced relapse to cocaine seeking. Over the past four years, my laboratory has collected evidence showing that CRF activates CRF-R2 to increase NMDAR-mediated currents in VTA DA neurons. Furthermore, we have evidence that CRF-R1 activation in VTA DA neurons increases firing activity via activation of Ih. By performing patch-clamp recordings in the VTA, specific aim 1 will elucidate in detail: a) the intracellular pathway responsible for the CRFR1-dependent increase in firing rate, and b) the intracellular pathways responsible for the CRF-R2-dependent increase in NMDAR currents in the VTA.
Specific aim 2 will determine the role of CRF-R1 and CRF-R2 in modulating DA release in the ventral striatum.
Specific aim 3 will determine the role of CRF-R1- and CRF-R2-dependent pathways in inhibiting footshock- induced relapse to cocaine seeking. Finally, specific aim 4 will take a deep mechanistic look at the CRF-BP. The results from this grant will produced a deep mechanistic and behavioral understanding of the various effects of CRF on VTA neurons. Our results will likely create new therapeutic leads toward agents that disrupt the CRF-R1- and CRF- R2-dependent effects on VTA neurons and thus stress-induced cocaine seeking.

Public Health Relevance

Stress increases addictive behavior. However, the mechanism by which stress-released molecules exert their negative effects on drug-seeking are poorly understood. The main goal of this project is to elucidate the role of CRFR1 and CRFR2 in promoting stress-enhanced relapse to cocaine seeking. Relapse to drug seeking is a major health problem that still has no cure. The results from this proposal could enable us to create new therapeutic targets aimed at inhibiting the ability of stressful event to increase relapse to substance abuse.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
7R01DA016782-09
Application #
8683611
Study Section
Special Emphasis Panel (ZRG1-IFCN-H (02))
Program Officer
Sorensen, Roger
Project Start
2013-07-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
9
Fiscal Year
2013
Total Cost
$332,361
Indirect Cost
$105,660

  Institution

Name
University of California San Francisco
Department
Neurology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143

  Publications

Goertz, Richard Brandon; Wanat, Matthew J; Gomez, Jorge A et al. (2015) Cocaine increases dopaminergic neuron and motor activity via midbrain ?1 adrenergic signaling. Neuropsychopharmacology 40:1151-62
Wanat, Matthew J; Bonci, Antonello; Phillips, Paul E M (2013) CRF acts in the midbrain to attenuate accumbens dopamine release to rewards but not their predictors. Nat Neurosci 16:383-5
Wang, Wengang; Nitulescu, Ioana; Lewis, Justin S et al. (2013) Overinhibition of corticostriatal activity following prenatal cocaine exposure. Ann Neurol 73:355-69
Hollon, Nick G; Soden, Marta E; Wanat, Matthew J (2013) Dopaminergic prediction errors persevere in the nucleus accumbens core during negative reinforcement. J Neurosci 33:3253-5
Sparta, Dennis R; Hopf, Frederic Woodward; Gibb, Stuart L et al. (2013) Binge ethanol-drinking potentiates corticotropin releasing factor R1 receptor activity in the ventral tegmental area. Alcohol Clin Exp Res 37:1680-7
Lemos, Julia C; Wanat, Matthew J; Smith, Jeffrey S et al. (2012) Severe stress switches CRF action in the nucleus accumbens from appetitive to aversive. Nature 490:402-6
Mitchell, Jennifer M; Margolis, Elyssa B; Coker, Allison R et al. (2012) Alcohol self-administration, anxiety, and cortisol levels predict changes in delta opioid receptor function in the ventral tegmental area. Behav Neurosci 126:515-22
van de Bospoort, Rhea; Farina, Margherita; Schmitz, Sabine K et al. (2012) Munc13 controls the location and efficiency of dense-core vesicle release in neurons. J Cell Biol 199:883-91
Fields, Howard L (2011) The doctor's dilemma: opiate analgesics and chronic pain. Neuron 69:591-4
Margolis, Elyssa B; Mitchell, Jennifer M; Hjelmstad, Gregory O et al. (2011) A novel opioid receptor-mediated enhancement of GABAA receptor function induced by stress in ventral tegmental area neurons. J Physiol 589:4229-42

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