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.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Study Section
Special Emphasis Panel (ZRG1-MDCN-F (02))
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Sorensen, Roger
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Vanderbilt University Medical Center
Schools of Medicine
United States
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Harris, Nicholas A; Winder, Danny G (2018) Synaptic Plasticity in the Bed Nucleus of the Stria Terminalis: Underlying Mechanisms and Potential Ramifications for Reinstatement of Drug- and Alcohol-Seeking Behaviors. ACS Chem Neurosci 9:2173-2187
Vranjkovic, Oliver; Pina, Melanie; Kash, Thomas L et al. (2017) The bed nucleus of the stria terminalis in drug-associated behavior and affect: A circuit-based perspective. Neuropharmacology 122:100-106
Silberman, Yuval; Winder, Danny G (2015) Ethanol and corticotropin releasing factor receptor modulation of central amygdala neurocircuitry: An update and future directions. Alcohol 49:179-84
Silberman, Yuval; Fetterly, Tracy L; Awad, Elias K et al. (2015) Ethanol produces corticotropin-releasing factor receptor-dependent enhancement of spontaneous glutamatergic transmission in the mouse central amygdala. Alcohol Clin Exp Res 39:2154-62
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
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
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
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
Conrad, Kelly L; Davis, Adeola R; Silberman, Yuval et al. (2012) Yohimbine depresses excitatory transmission in BNST and impairs extinction of cocaine place preference through orexin-dependent, norepinephrine-independent processes. Neuropsychopharmacology 37:2253-66

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