Addiction is a tremendous health and financial burden on our society. A growing literature indicates that norepinephrine in the brain plays a key role in stress-reward interactions that may mediate key behavioral responses to drugs of abuse. A previously unappreciated group of noradrenergic neurons in the field of addiction, cells that project through the ventral noradrenergic bundle (VNAB), are thought to supply the key norepinephrine. The primary target of the VNAB in the brain is a group of nuclei referred to as the extended amygdala. In the previous funding period, we identified actions of each of the major classes of noradrenergic receptors on excitatory synaptic transmission in the bed nucleus of the stria terminalis, a major component of the extended amygdala. Here, we propose experiments to assess molecular mechanisms involved in these actions, and to begin to place these actions in the context of microcircuitry within the extended amygdala. Further, we propose to examine whether overlapping populations of neurons in the extended amygdala are activated by drugs of abuse and stressors, and whether this activation is regulated by noradrenergic ligands. In total, the proposed work will begin to define specific mechanisms likely to play key roles in stress-induced reinstatement of drug seeking behavior, thus providing new potential opportunities for therapeutic development.

Public Health Relevance

Addiction poses an enormous health and financial burden on our society. Currently, our understanding of the brain circuitries involved in addiction is far from complete. The successful completion of these proposed studies will result in important new information about neurons that may be involved in addiction, potentially creating new targets for therapeutics development.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA019112-08
Application #
8247693
Study Section
Special Emphasis Panel (ZRG1-MDCN-F (02))
Program Officer
Sorensen, Roger
Project Start
2004-09-30
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
8
Fiscal Year
2012
Total Cost
$344,840
Indirect Cost
$109,985
Name
Vanderbilt University Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Williams, Megan A; Li, Chia; Kash, Thomas L et al. (2014) Excitatory drive onto dopaminergic neurons in the rostral linear nucleus is enhanced by norepinephrine in an ?1 adrenergic receptor-dependent manner. Neuropharmacology 86:116-24
Conrad, Kelly L; Louderback, Katherine M; Milano, Elana J et al. (2013) Assessment of the impact of pattern of cocaine dosing schedule during conditioning and reconditioning on magnitude of cocaine CPP, extinction, and reinstatement. Psychopharmacology (Berl) 227:109-16
Flavin, Stephanie A; Winder, Danny G (2013) Noradrenergic control of the bed nucleus of the stria terminalis in stress and reward. Neuropharmacology 70:324-30
Silberman, Yuval; Winder, Danny G (2013) Corticotropin releasing factor and catecholamines enhance glutamatergic neurotransmission in the lateral subdivision of the central amygdala. Neuropharmacology 70:316-23
Silberman, Yuval; Matthews, Robert T; Winder, Danny G (2013) A corticotropin releasing factor pathway for ethanol regulation of the ventral tegmental area in the bed nucleus of the stria terminalis. J Neurosci 33:950-60
Gosnell, Heather B; Silberman, Yuval; Grueter, Brad A et al. (2011) mGluR8 modulates excitatory transmission in the bed nucleus of the stria terminalis in a stress-dependent manner. Neuropsychopharmacology 36:1599-607
Nobis, William P; Kash, Thomas L; Silberman, Yuval et al. (2011) ?-Adrenergic receptors enhance excitatory transmission in the bed nucleus of the stria terminalis through a corticotrophin-releasing factor receptor-dependent and cocaine-regulated mechanism. Biol Psychiatry 69:1083-90
Conrad, Kelly L; Louderback, Katherine M; Gessner, Caitlin P et al. (2011) Stress-induced alterations in anxiety-like behavior and adaptations in plasticity in the bed nucleus of the stria terminalis. Physiol Behav 104:248-56
Olsen, Christopher M; Childs, Daniel S; Stanwood, Gregg D et al. (2010) Operant sensation seeking requires metabotropic glutamate receptor 5 (mGluR5). PLoS One 5:e15085
Olsen, Christopher M; Winder, Danny G (2010) Operant sensation seeking in the mouse. J Vis Exp :

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