The overarching goal of this competing renewal is to investigate systematically the mechanisms of stress- potentiated opioid seeking and biobehavioral responses. The proposed aims build programmatically on the very productive human laboratory paradigm and significant findings from this project's initial funding cycle. We combine a sensitive choice progressive ratio (exponentially escalating response requirement) procedure, well- established subjective drug effect and mood state measures, innovative hippocampal/prefrontal cortical vs. dorsal striatal-dependent learning tasks, and physiological indices of sympathetic- and HPA-mediated responses (i.e. heart period variability, blood pressure, body temperature, and salivary cortisol and 1-amylase). The primary drug-seeking outcomes will be analyzed using sensitive behavioral economic methods. Three proposed studies will systematically extend this useful laboratory model in significant, innovative and impactful directions (including validation of alternative stressors). The proposed study designs are sound and employ within-subject, randomized crossover, placebo-controlled, double-blind methodology. Our goal is to advance theoretical understanding (e.g. biobehavioral responses should be differentially sensitive to the stressors) and generate hypotheses for practical applications (e.g. medication development).
Aim 1. Fully characterize yohimbine-potentiated opioid seeking and biobehavioral responses using an optimized model (methods adjusted based on Prelim. Study 4 findings) and compare to a naturalistic stressor (moderately loud, intermittent, inescapable soundtrack of crying/distressed infants).
Aim 2. Use an alternative neuropharmacological stressor paradigm (reboxetine/hydrocortisone dose combinations) to determine whether activation of noradrenergic (Not applicable) and glucocorticoid transmission increases opioid seeking and biobehavioral responses.
Aim 3. Determine whether neuromodulating agents at 12A-adrenergic (guanfacine 1 mg), 5-HT1A (buspirone 30 mg), CB1 (cannabidiol 1000 mg), and GABAB (baclofen 40 mg) receptors differentially modulate yohimbine- potentiated opioid seeking and biobehavioral responses.

Public Health Relevance

Yohimbine (YOH), an 12-adrenoceptor antagonist, is a neuropharmacological stressor that has been shown in preclinical studies to increase drug seeking. In this competing renewal application, we propose to build on our productive human laboratory model of opioid seeking. Our aims are to: (1) characterize YOH-potentiated opioid seeking and biobehavioral responses using an optimized model (methodological adjustments based on our preliminary data) and compare to a naturalistic stressor;(2) use an alternative neuropharmacological paradigm (reboxetine/hydrocortisone dose combinations) to determine whether direct manipulation of noradrenergic and glucocorticoid transmission increases opioid seeking and biobehavioral responses;and (3) determine whether neuromodulating agents at 12A-adrenergic, 5-HT1A, CB1, and GABAB receptors differentially modulate YOH- potentiated opioid seeking and biobehavioral responses.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA015462-08
Application #
8466298
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Gordon, Harold
Project Start
2002-07-01
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
8
Fiscal Year
2014
Total Cost
$353,395
Indirect Cost
$120,898
Name
Wayne State University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Jacques-Tiura, Angela J; Greenwald, Mark K (2016) Behavioral Economic Factors Related to Pediatric Obesity. Pediatr Clin North Am 63:425-46
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Greenwald, Mark K; Steinmiller, Caren L; Sliwerska, Elzbieta et al. (2013) BDNF Val(66)Met genotype is associated with drug-seeking phenotypes in heroin-dependent individuals: a pilot study. Addict Biol 18:836-45
Greenwald, Mark K; Lundahl, Leslie H; Steinmiller, Caren L (2013) Yohimbine increases opioid-seeking behavior in heroin-dependent, buprenorphine-maintained individuals. Psychopharmacology (Berl) 225:811-24

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