Abstract
BackgroundWhile the etiology of depression is not clearly understood at the present time, this mental disorder is thought be a complex and multifactorial trait with important genetic and environmental contributing factors.Methodology/Principal FindingsThe role of the endocannabinoid (eCB) system in depressive behavior was examined in Wistar Kyoto (WKY) rat strain, a genetic model of depression. Our findings revealed selective abnormalities in the eCB system in the brains of WKY rats compared to Wistar (WIS) rats. Immunoblot analysis indicated significantly higher levels of fatty acid amide hydrolase (FAAH) in frontal cortex and hippocampus of WKY rats with no alteration in the level of N-arachidonyl phosphatidyl ethanolamine specific phospholipase-D (NAPE-PLD). Significantly higher levels of CB1 receptor-mediated G-protein coupling and lower levels of anandamide (AEA) were found in frontal cortex and hippocampus of WKY rats. While the levels of brain derived neurotropic factor (BDNF) were significantly lower in frontal cortex and hippocampus of WKY rats compared to WIS rats, pharmacological inhibition of FAAH elevated BDNF levels in WKY rats. Inhibition of FAAH enzyme also significantly increased sucrose consumption and decreased immobility in the forced swim test in WKY rats.Conclusions/SignificanceThese findings suggest a critical role for the eCB system and BDNF in the genetic predisposition to depressive-like behavior in WKY rats and point to the potential therapeutic utility of eCB enhancing agents in depressive disorder.
Highlights
Major depressive disorder (MDD) is characterized by a significant impairment in mood and motivation [1], and exhibits a chronic, relapsing course and is associated with high morbidity and mortality worldwide
Basal level of fatty acid amide hydrolase (FAAH) enzyme was significantly higher in frontal cortex (40%, p,0.05) and hippocampus (40%, p,0.05) of Wistar Kyoto (WKY) rats compared to WIS rats (n = 6 in each group; Fig. 1B)
The CB1 receptor-stimulated [35S]GTPcS binding was significantly higher in frontal cortex (24%, p,0.05) and hippocampus (44%, p,0.01) of WKY rats compared to WIS rats (n = 628; Fig. 3A)
Summary
Major depressive disorder (MDD) is characterized by a significant impairment in mood and motivation [1], and exhibits a chronic, relapsing course and is associated with high morbidity and mortality worldwide. In the United States alone, more than 30,000 people commit suicide each year; majority of which are associated with depression [2,3]. The etiology of this disorder is not clearly understood, clinical observations suggest a significant role for the monoamine neurotransmitter systems [4]. Currently used antidepressants, which alter the monoamine systems, appear to be therapeutically inadequate in many patients. While the etiology of depression is not clearly understood at the present time, this mental disorder is thought be a complex and multifactorial trait with important genetic and environmental contributing factors
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