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.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Pilotte, Nancy S
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Drexel University
Schools of Medicine
United States
Zip Code
Ross, J A; Mathews, P M; Van Bockstaele, E J (2018) High resolution approaches for the identification of amyloid fragments in brain. J Neurosci Methods :
Ross, Jennifer A; Gliebus, Gediminas; Van Bockstaele, Elisabeth J (2018) Stress induced neural reorganization: A conceptual framework linking depression and Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatry 85:136-151
Reyes, B A S; Carvalho, A F; Szot, P et al. (2017) Cortical adrenoceptor expression, function and adaptation under conditions of cannabinoid receptor deletion. Exp Neurol 292:179-192
Carvalho, A F; Reyes, B A S; Ramalhosa, F et al. (2016) Repeated administration of a synthetic cannabinoid receptor agonist differentially affects cortical and accumbal neuronal morphology in adolescent and adult rats. Brain Struct Funct 221:407-19
Retson, T A; Sterling, R C; Van Bockstaele, E J (2016) Alcohol-induced dysregulation of stress-related circuitry: The search for novel targets and implications for interventions across the sexes. Prog Neuropsychopharmacol Biol Psychiatry 65:252-9
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
Wyrofsky, Ryan; McGonigle, Paul; Van Bockstaele, Elisabeth J (2015) Drug discovery strategies that focus on the endocannabinoid signaling system in psychiatric disease. Expert Opin Drug Discov 10:17-36
Reyes, B A S; Heldt, N A; Mackie, K et al. (2015) Ultrastructural evidence for synaptic contacts between cortical noradrenergic afferents and endocannabinoid-synthesizing post-synaptic neurons. Neuroscience 303:323-37
Retson, T A; Hoek, J B; Sterling, R C et al. (2015) Amygdalar neuronal plasticity and the interactions of alcohol, sex, and stress. Brain Struct Funct 220:3211-32
Cathel, Alessandra M; Reyes, Beverly A S; Wang, Qin et al. (2014) Cannabinoid modulation of alpha2 adrenergic receptor function in rodent medial prefrontal cortex. Eur J Neurosci 40:3202-14

Showing the most recent 10 out of 25 publications