The noradrenergic system continues to be an important target in the development of new therapies for anxiety disorders because of its critical role in the modulation of emotional state and regulation of arousal and stress responses. Synthetic cannabinoid receptor agonists/antagonists and compounds targeting endocannabinoid synthesis/metabolism in brain have received widespread attention as these approaches may hold some therapeutic potential for psychiatric disorders. Over the prior funding period, we demonstrated that the coeruleo-cortical pathway is an important target of cannabinoid actions. We provided evidence that, under basal conditions, exposure to a synthetic cannabinoid receptor agonist increases anxiety- like behaviors that correlate with increases in multiple indices of brain noradrenergic activity. We also provided the first evidence of alterations in expression levels for several adrenergic receptor subtypes in cortical and limbic areas following acute and repeated exposure to cannabinoid receptor agonists. Finally, we established that noradrenergic transmission in limbic circuitry is critical for selected cannabinoi-induced behaviors. In the competing renewal application, circuit and cellular level studies are proposed to refine our model of how the noradrenergic system is regulated by the endocannabinoid system under conditions of stress.
AIM 1 will define how molecular elements of the endocannabinoid system are positioned to impact the coeruleo-cortical pathway.
AIM 2 builds on studies in AIM 1 by investigating the regulation of cortical endocannabinoid levels by noradrenergic circuitry.
AIM 3 will determine if deletion of the cannabinoid type 1 receptor alters molecular and electrophysiological indices of noradrenergic activity. Finally, AIM 4 will identify stress-induced molecular and cellular adaptations in cannabinoid modulation of the coeruleo-cortical pathway. Understanding the nature of state dependent alterations of this integrative system may provide a novel substrate for the treatment of stress-induced anxiety disorders.

Public Health Relevance

The noradrenergic system continues to be an important target in the development of new therapies for psychiatric disorders because of its critical role in the modulation of emotional state and regulation of arousal and stress responses. The proposed preclinical studies will advance our knowledge regarding the interaction of the endocannabinoid system with noradrenergic brain circuitry. Understanding the interaction of this integrative system will contribute to the development of improved therapies for stress-induced anxiety disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
7R01DA020129-07
Application #
8670706
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Pilotte, Nancy S
Project Start
2005-04-01
Project End
2018-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
7
Fiscal Year
2014
Total Cost
$320,297
Indirect Cost
$101,254
Name
Drexel University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Retson, T A; Reyes, B A; Van Bockstaele, E J (2015) Chronic alcohol exposure differentially affects activation of female locus coeruleus neurons and the subcellular distribution of corticotropin releasing factor receptors. Prog Neuropsychopharmacol Biol Psychiatry 56:66-74
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Scavone, J L; Sterling, R C; Van Bockstaele, E J (2013) Cannabinoid and opioid interactions: implications for opiate dependence and withdrawal. Neuroscience 248:637-54
Reyes, B A S; Szot, P; Sikkema, C et al. (2012) Stress-induced sensitization of cortical adrenergic receptors following a history of cannabinoid exposure. Exp Neurol 236:327-35

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