The existence of an endogenous cannabinoid system, comprising cannabinoid receptors and endogenous ligands is now well recognized. However, the distribution of cannabinoid receptors and the impact of cannabinoid agonists on monoaminergic neurotransmitter systems is only slowly beginning to emerge. This information is essential for understanding cellular adaptations following chronic recreational drug exposure as well as elucidating potential therapeutic uses for cannabinoid-based compounds. Acute effects of cannabinoid receptor agonist administration include deficits in learning and memory, distorted perception, difficulty in problem solving and loss of coordination. Repeated administration leads to increases in the activation of the stress-response system, anxiety, depression, cognitive impairment, and psychosis. The question remains as to where cannabinoids act to induce cellular adaptations that may result in long term behavioral dysfunction. Preliminary data from our laboratories suggest that one potential target is the noradrenergic coeruleo-cortical pathway, a biogenic amine system involved in modulating higher cognitive function and mood. This system is implicated in setting the attentional mode, and is engaged as part of the stress response to facilitate arousal. Our guiding hypothesis is that chronic cannabinoid administration results in a potentiated noradrenergic system that may contribute to the pathophysiology of affective disorders. The proposed aims, which integrate neuroanatomical, neurochemical and behavioral approaches, promise to further our understanding of the cellular substrates for cannabinoid receptor modulation of the locus coeruleus (LC)-frontal cortex pathway and reveal the participation of this circuit in cannabinoid-induced anxiety.
Four specific aims are proposed to answer the following questions: 1) What are the cellular sites mediating cortical norepinephrine efflux induced by cannabinoids ? 2) What is the neuroanatomical distribution of CB1 receptors in the frontal cortex and LC ? 3) Does repeated administration of cannabinoid agonists result in long term effects on noradrenergic function (as detected by increases in tyrosine hydroxylase gene express and release) 4) What are the effects of noradrenergic lesions on cannabinoid-induced anxiety ? By accomplishing the proposed specific aims, we will have a firm understanding of the cellular sites of action of cannabinoids on brain noradrenergic function and the behavioral consequences of chronic exposure to cannabinoids on the noradrenergic system. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA020129-03
Application #
7209766
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Pilotte, Nancy S
Project Start
2005-04-01
Project End
2010-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
3
Fiscal Year
2007
Total Cost
$330,677
Indirect Cost
Name
Thomas Jefferson University
Department
Pathology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Ross, Jennifer A; Gliebus, Gediminas; Van Bockstaele, Elisabeth J (2017) Stress induced neural reorganization: A conceptual framework linking depression and Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatry :
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
Scavone, Jillian L; Sterling, Robert C; Weinstein, Stephen P et al. (2013) Impact of cannabis use during stabilization on methadone maintenance treatment. Am J Addict 22:344-51

Showing the most recent 10 out of 24 publications