Epidemiological evidence suggests that there is an inverse correlation between the age of first exposure to a drug of abuse and the likelihood of developing dependence, suggesting that periadolescence is a time of high vulnerability to drugs of abuse compared with adulthood. One key difference between periadolescents and adults is in their respective responses to stressors. Periadolescence is associated with a period of increased risk-taking, which is accompanied by hyporesponsiveness to many stressors compared to adults. In contrast, periadolescent animals have higher basal levels of circulating corticosterones, and under certain contexts appear more anxious than adults. Stress and anxiety play critical roles in drug abuse, thus an understanding of the basic mechanisms underlying these age-specific differences in anxiety-related behaviors will lead to more specific and age-appropriate therapeutic interventions both for drug abuse and anxiety disorders in general. The ventral noradrenergic bundle (VNAB) emanating from the nucleus of the solitary tract plays a key role in stress/anxiety responses. Lesions of the VNAB or manipulations of noradrenergic transmission within the major target of this projection, the bed nucleus of the stria terminalis (BNST), abolish stress-induced reinstatement of cocaine intake and conditioned place aversion to morphine withdrawal. The BNST is an assembly of sub-nuclei within the extended amygdala with rich interconnections between stress and reward centers. Stimulation of the anterolateral regions of the BNST evokes firing of dopaminergic neurons of the VTA, as well as increases PVN output, increasing peripheral corticosterone levels. Thus altering the level of output of the BNST would be predicted to have a dramatic impact on behavioral responses to drugs of abuse. We have identified two adrenergic receptors that play opposing roles in regulating inputs to the BNST. Here we will test the hypothesis that this regulation is altered in the periadolescent compared to the adult BNST. We will also determine whether psychostimulants, which indirectly target these receptors through altering endogenous catecholamine levels, produce similar effects on transmission. Finally, we will assess the impact of alterations in the relative levels of the receptors on both regulation of transmission and basal anxiety levels by screening recombinant inbred strains of mice (BxDs) with varying levels of receptor expression. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA019112-01
Application #
6876274
Study Section
Special Emphasis Panel (ZDA1-MXS-M (11))
Program Officer
Pilotte, Nancy S
Project Start
2004-09-30
Project End
2009-07-31
Budget Start
2004-09-30
Budget End
2005-07-31
Support Year
1
Fiscal Year
2004
Total Cost
$302,000
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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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