Mood and anxiety disorders exert substantial societal cost and personal burden for patients and families. Current treatment approaches for these disorders are primarily focused on increasing brain neurotransmitters like serotonin, i.e. via selective serotonin-reuptake inhibitors (SSRIs). However, large-scale effectiveness studies have demonstrated this class of drugs is only partially effective. Recent studies have suggested that elevating levels of endogenous brain cannabinoids could exert therapeutic benefit in mood and anxiety disorders including PTSD. We have recently developed novel inhibitors of cyclooxygenase-2 (COX-2) that selectively prevent inactivation of brain endocannabinoids without preventing synthesis of prostaglandins;which are inflammatory mediators required for normal immune and vascular function. Given that long-term inhibition of prostaglandin synthesis is associated with gastrointestinal and cardiovascular toxicity, development, validation, and preclinical evaluation of novel pharmacological strategies to modulate COX-2 activity to enhance endocannabinoid signaling without affecting prostaglandin synthesis is a high research priority. We will test the hypothesis that "substrate-selective" inhibitors of COX-2 selectively increase brain endocannabinoid levels without affecting prostaglandin levels and that they exert preclinical efficacy in models of mood and anxiety disorders. Completion of these studies will provide preclinical evidence for the efficacy of a novel class of antidepressant and anxiolytic drugs, and could validate COX-2 as a viable molecular target for future drug discovery directed at the treatment of affective disorders.

Public Health Relevance

Mood and anxiety disorders including major depression and post-traumatic stress disorder exert a high societal cost and personal burden to patients and families. Treatment approaches for mood and anxiety disorders are currently focused on increasing brain monoamines such as serotonin;however, these drugs are only partially effective. We will test the global hypothesis that increasing brain endogenous cannabinoid levels via a novel pharmacological strategy involving substrate-selective inhibition of cyclooxygenase-2 could represent a novel treatment approach for mood and anxiety disorders. These studies could lead to the development of novel therapeutics for affective disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH100096-01
Application #
8477649
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Winsky, Lois M
Project Start
2013-07-01
Project End
2018-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$390,000
Indirect Cost
$140,000
Name
Vanderbilt University Medical Center
Department
Psychiatry
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Reddy, I A; Pino, J A; Weikop, P et al. (2016) Glucagon-like peptide 1 receptor activation regulates cocaine actions and dopamine homeostasis in the lateral septum by decreasing arachidonic acid levels. Transl Psychiatry 6:e809
Robinson, Stacey L; Alexander, Nancy J; Bluett, Rebecca J et al. (2016) Acute and chronic ethanol exposure differentially regulate CB1 receptor function at glutamatergic synapses in the rat basolateral amygdala. Neuropharmacology 108:474-84
Gunduz-Cinar, Ozge; Flynn, Shaun; Brockway, Emma et al. (2016) Fluoxetine Facilitates Fear Extinction Through Amygdala Endocannabinoids. Neuropsychopharmacology 41:1598-609
Hartley, N D; Gunduz-Cinar, O; Halladay, L et al. (2016) 2-arachidonoylglycerol signaling impairs short-term fear extinction. Transl Psychiatry 6:e749
Gamble-George, Joyonna Carrie; Baldi, Rita; Halladay, Lindsay et al. (2016) Cyclooxygenase-2 inhibition reduces stress-induced affective pathology. Elife 5:
Báldi, Rita; Ghosh, Dipanwita; Grueter, Brad A et al. (2016) Electrophysiological Measurement of Cannabinoid-Mediated Synaptic Modulation in Acute Mouse Brain Slices. Curr Protoc Neurosci 75:6.29.1-6.29.19
Morena, Maria; Patel, Sachin; Bains, Jaideep S et al. (2016) Neurobiological Interactions Between Stress and the Endocannabinoid System. Neuropsychopharmacology 41:80-102
Gray, J Megan; Vecchiarelli, Haley A; Morena, Maria et al. (2015) Corticotropin-releasing hormone drives anandamide hydrolysis in the amygdala to promote anxiety. J Neurosci 35:3879-92
Shonesy, Brian C; Bluett, Rebecca J; Ramikie, Teniel S et al. (2014) Genetic disruption of 2-arachidonoylglycerol synthesis reveals a key role for endocannabinoid signaling in anxiety modulation. Cell Rep 9:1644-53
Hermanson, Daniel J; Gamble-George, Joyonna C; Marnett, Lawrence J et al. (2014) Substrate-selective COX-2 inhibition as a novel strategy for therapeutic endocannabinoid augmentation. Trends Pharmacol Sci 35:358-67

Showing the most recent 10 out of 15 publications