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.
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.
|Bluett, R J; Gamble-George, J C; Hermanson, D J et al. (2014) Central anandamide deficiency predicts stress-induced anxiety: behavioral reversal through endocannabinoid augmentation. Transl Psychiatry 4:e408|
|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|
|Tchantchou, Flaubert; Tucker, Laura B; Fu, Amanda H et al. (2014) The fatty acid amide hydrolase inhibitor PF-3845 promotes neuronal survival, attenuates inflammation and improves functional recovery in mice with traumatic brain injury. Neuropharmacology 85:427-39|
|Hermanson, Daniel J; Hartley, Nolan D; Gamble-George, Joyonna et al. (2013) Substrate-selective COX-2 inhibition decreases anxiety via endocannabinoid activation. Nat Neurosci 16:1291-8|