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Dysfunction in fatty acid amide hydrolase is associated with depressive-like behavior in Wistar Kyoto rats.

Vinod KY, Xie S, Psychoyos D, Hungund BL, Cooper TB, Tejani-Butt SM - PLoS ONE (2012)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Division of Analytical Psychopharmacology, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York, United States of America. vyaragudri@nki.rfmh.org

ABSTRACT

Background: 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.

Methodology/principal findings: The 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/significance: These 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.

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Related in: MedlinePlus

Basal differences in CB1 receptor in the brain of WKY rats.The CB1 receptor agonist-stimulated [35S]GTPγS binding was significantly higher in frontal cortex (24%, p<0.05) and hippocampus (44%, p<0.01) of WKY rats compared to WIS rats (A). Data is presented as percentage of stimulation over basal binding. Western blot analysis revealed significantly higher levels of CB1 receptors in hippocampus (45%, p<0.05), while they were found to be slightly higher in frontal cortex of WKY rats (18%, B). Hippo; Hippocampus.
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pone-0036743-g003: Basal differences in CB1 receptor in the brain of WKY rats.The CB1 receptor agonist-stimulated [35S]GTPγS binding was significantly higher in frontal cortex (24%, p<0.05) and hippocampus (44%, p<0.01) of WKY rats compared to WIS rats (A). Data is presented as percentage of stimulation over basal binding. Western blot analysis revealed significantly higher levels of CB1 receptors in hippocampus (45%, p<0.05), while they were found to be slightly higher in frontal cortex of WKY rats (18%, B). Hippo; Hippocampus.

Mentions: Basal levels of eCB, AEA were found to be significantly lower in hippocampus of WKY rats compared to WIS rats (31%, p<0.01, n = 5−6; Fig. 1A). Basal level of FAAH enzyme was significantly higher in frontal cortex (40%, p<0.05) and hippocampus (40%, p<0.05) of WKY rats compared to WIS rats (n = 6 in each group; Fig. 1B). A representative immunoblot is provided in the upper panel (Fig. 1B). The qPCR analysis also confirmed higher levels of mFAAH in hippocampus of WKY rats than WIS rats (24%, p<0.05; Fig. 1C; n = 4). A subtle but statistically significant higher activity of FAAH enzyme was observed in frontal cortex (15%, p<0.05) and hippocampus (17%, p<0.05; n = 6−8; Fig. 1D) of WKY rats than WIS rats. There were no significant differences in the levels of NAPE-PLD enzyme in frontal cortex and hippocampus of WKY compared to WIS rats (Fig. 2). A representative immunoblot is provided in the upper panel (Fig. 2). The CB1 receptor-stimulated [35S]GTPγS 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 = 6−8; Fig. 3A). Western blot analysis revealed significantly higher levels of CB1 receptors in hippocampus (45%, p<0.05), however, they were slightly higher in frontal cortex of WKY rats (18%, n = 6−8; Fig. 3B).


Dysfunction in fatty acid amide hydrolase is associated with depressive-like behavior in Wistar Kyoto rats.

Vinod KY, Xie S, Psychoyos D, Hungund BL, Cooper TB, Tejani-Butt SM - PLoS ONE (2012)

Basal differences in CB1 receptor in the brain of WKY rats.The CB1 receptor agonist-stimulated [35S]GTPγS binding was significantly higher in frontal cortex (24%, p<0.05) and hippocampus (44%, p<0.01) of WKY rats compared to WIS rats (A). Data is presented as percentage of stimulation over basal binding. Western blot analysis revealed significantly higher levels of CB1 receptors in hippocampus (45%, p<0.05), while they were found to be slightly higher in frontal cortex of WKY rats (18%, B). Hippo; Hippocampus.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3351478&req=5

pone-0036743-g003: Basal differences in CB1 receptor in the brain of WKY rats.The CB1 receptor agonist-stimulated [35S]GTPγS binding was significantly higher in frontal cortex (24%, p<0.05) and hippocampus (44%, p<0.01) of WKY rats compared to WIS rats (A). Data is presented as percentage of stimulation over basal binding. Western blot analysis revealed significantly higher levels of CB1 receptors in hippocampus (45%, p<0.05), while they were found to be slightly higher in frontal cortex of WKY rats (18%, B). Hippo; Hippocampus.
Mentions: Basal levels of eCB, AEA were found to be significantly lower in hippocampus of WKY rats compared to WIS rats (31%, p<0.01, n = 5−6; Fig. 1A). Basal level of FAAH enzyme was significantly higher in frontal cortex (40%, p<0.05) and hippocampus (40%, p<0.05) of WKY rats compared to WIS rats (n = 6 in each group; Fig. 1B). A representative immunoblot is provided in the upper panel (Fig. 1B). The qPCR analysis also confirmed higher levels of mFAAH in hippocampus of WKY rats than WIS rats (24%, p<0.05; Fig. 1C; n = 4). A subtle but statistically significant higher activity of FAAH enzyme was observed in frontal cortex (15%, p<0.05) and hippocampus (17%, p<0.05; n = 6−8; Fig. 1D) of WKY rats than WIS rats. There were no significant differences in the levels of NAPE-PLD enzyme in frontal cortex and hippocampus of WKY compared to WIS rats (Fig. 2). A representative immunoblot is provided in the upper panel (Fig. 2). The CB1 receptor-stimulated [35S]GTPγS 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 = 6−8; Fig. 3A). Western blot analysis revealed significantly higher levels of CB1 receptors in hippocampus (45%, p<0.05), however, they were slightly higher in frontal cortex of WKY rats (18%, n = 6−8; Fig. 3B).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Division of Analytical Psychopharmacology, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York, United States of America. vyaragudri@nki.rfmh.org

ABSTRACT

Background: 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.

Methodology/principal findings: The 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/significance: These 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.

Show MeSH
Related in: MedlinePlus