Stress increases addictive behaviors such as behavioral sensitization. Although it has been well documented that the ventral tegmental area (VTA) is the brain region whose activation is essential to induce behavioral sensitization, the mechanism through which stress increases behavioral sensitization is unknown. The main goal of this proposal is to elucidate the mechanism through which the corticotropin releasing factor (CRF) mediates NMDA receptor function and behavioral sensitization. Our preliminary data provide the first evidence for a direct synaptic modulation by CRF of synaptic transmission on a subclass of VTA dopamine (DA) neurons. Specifically, our data show that CRF activates CRF 2 receptors (CRF2R), which in combination with the CRF binding-protein (CRF-BP) increases NMDA currents in the VTA. Further, our data show that the CRF-dependent increase of NMDA currents in the VTA depends on the activation of phospholipase C (PLC) and PKC. We hypothesize that the potentiation of NMDA currents by CRF and the CRF-BP represents a key cellular phenomenon underlying stress-induced sensitization to cocaine.
In specific aim 1, we want to characterize in detail the anatomical projections of the subset of DA neurons that are sensitive to CRF.
Specific aim 2 will define the intracellular pathway activated by PLC that is responsible for the CRF-dependent increase of NMDA currents. Finally, specific aim 3 will study the role of CRF and of CRF2R agonists and antagonists in modulating context-dependent behavioral sensitization and stress-dependent behavioral sensitization to cocaine.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA016782-04
Application #
7192576
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Sorensen, Roger
Project Start
2004-07-01
Project End
2008-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
4
Fiscal Year
2007
Total Cost
$268,312
Indirect Cost
Name
Ernest Gallo Clinic and Research Center
Department
Type
DUNS #
173995366
City
Emeryville
State
CA
Country
United States
Zip Code
94608
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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