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Cyclooxygenase-2 inhibition reduces stress-induced affective pathology.

Gamble-George JC, Baldi R, Halladay L, Kocharian A, Hartley N, Silva CG, Roberts H, Haymer A, Marnett LJ, Holmes A, Patel S - Elife (2016)

Bottom Line: We show that traditional COX-2 inhibitors and a newly developed substrate-selective COX-2 inhibitor (SSCI) reduce a variety of stress-induced behavioral pathologies in mice.We found that these behavioral effects were associated with a dampening of neuronal excitability in the basolateral amygdala (BLA) ex vivo and in vivo, and were mediated by small-conductance calcium-activated potassium (SK) channel and CB1 cannabinoid receptor activation.Taken together, these data provide further support for the potential utility of SSCIs, as well as traditional COX-2 inhibitors, as novel treatment approaches for stress-related psychiatric disorders.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, United States.

ABSTRACT
Mood and anxiety disorders are the most prevalent psychiatric conditions and are exacerbated by stress. Recent studies have suggested cyclooxygenase-2 (COX-2) inhibition could represent a novel treatment approach or augmentation strategy for affective disorders including anxiety disorders and major depression. We show that traditional COX-2 inhibitors and a newly developed substrate-selective COX-2 inhibitor (SSCI) reduce a variety of stress-induced behavioral pathologies in mice. We found that these behavioral effects were associated with a dampening of neuronal excitability in the basolateral amygdala (BLA) ex vivo and in vivo, and were mediated by small-conductance calcium-activated potassium (SK) channel and CB1 cannabinoid receptor activation. Taken together, these data provide further support for the potential utility of SSCIs, as well as traditional COX-2 inhibitors, as novel treatment approaches for stress-related psychiatric disorders.

No MeSH data available.


Related in: MedlinePlus

Effects of FAAH inhibition on ex vivo BLA neuronal excitability.(A) Effects of PF-3845 on BLA neuron excitability and in non-stressed mice, and (B) 24 hr after foot-chock stress. F and P values for drug effects by two-way ANOVA shown in A and B.DOI:http://dx.doi.org/10.7554/eLife.14137.020
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fig8s2: Effects of FAAH inhibition on ex vivo BLA neuronal excitability.(A) Effects of PF-3845 on BLA neuron excitability and in non-stressed mice, and (B) 24 hr after foot-chock stress. F and P values for drug effects by two-way ANOVA shown in A and B.DOI:http://dx.doi.org/10.7554/eLife.14137.020

Mentions: Given our behavioral data had indicated a role for COX-2-mediated enhancement of anandamide signaling in the anxiolytic effects of LM-4131, we tested whether directly increasing anandamide levels, via FAAH inhibition, mimicked the effects of LM-4131 on cellular excitability and glutamatergic transmission. Indeed, incubation of brain slices from both control and stressed mice with the FAAH inhibitor, PF-3845 (10 μM), resulted in a decrease in cellular excitability (Figure 8—figure supplement 2). These data suggest LM-4131 may reduce stress-induced anxiety-like behavior by dampening neuronal activity in the BLA and, moreover, that these cellular effects can be mimicked by anandamide augmentation via FAAH inhibition.


Cyclooxygenase-2 inhibition reduces stress-induced affective pathology.

Gamble-George JC, Baldi R, Halladay L, Kocharian A, Hartley N, Silva CG, Roberts H, Haymer A, Marnett LJ, Holmes A, Patel S - Elife (2016)

Effects of FAAH inhibition on ex vivo BLA neuronal excitability.(A) Effects of PF-3845 on BLA neuron excitability and in non-stressed mice, and (B) 24 hr after foot-chock stress. F and P values for drug effects by two-way ANOVA shown in A and B.DOI:http://dx.doi.org/10.7554/eLife.14137.020
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4862754&req=5

fig8s2: Effects of FAAH inhibition on ex vivo BLA neuronal excitability.(A) Effects of PF-3845 on BLA neuron excitability and in non-stressed mice, and (B) 24 hr after foot-chock stress. F and P values for drug effects by two-way ANOVA shown in A and B.DOI:http://dx.doi.org/10.7554/eLife.14137.020
Mentions: Given our behavioral data had indicated a role for COX-2-mediated enhancement of anandamide signaling in the anxiolytic effects of LM-4131, we tested whether directly increasing anandamide levels, via FAAH inhibition, mimicked the effects of LM-4131 on cellular excitability and glutamatergic transmission. Indeed, incubation of brain slices from both control and stressed mice with the FAAH inhibitor, PF-3845 (10 μM), resulted in a decrease in cellular excitability (Figure 8—figure supplement 2). These data suggest LM-4131 may reduce stress-induced anxiety-like behavior by dampening neuronal activity in the BLA and, moreover, that these cellular effects can be mimicked by anandamide augmentation via FAAH inhibition.

Bottom Line: We show that traditional COX-2 inhibitors and a newly developed substrate-selective COX-2 inhibitor (SSCI) reduce a variety of stress-induced behavioral pathologies in mice.We found that these behavioral effects were associated with a dampening of neuronal excitability in the basolateral amygdala (BLA) ex vivo and in vivo, and were mediated by small-conductance calcium-activated potassium (SK) channel and CB1 cannabinoid receptor activation.Taken together, these data provide further support for the potential utility of SSCIs, as well as traditional COX-2 inhibitors, as novel treatment approaches for stress-related psychiatric disorders.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, United States.

ABSTRACT
Mood and anxiety disorders are the most prevalent psychiatric conditions and are exacerbated by stress. Recent studies have suggested cyclooxygenase-2 (COX-2) inhibition could represent a novel treatment approach or augmentation strategy for affective disorders including anxiety disorders and major depression. We show that traditional COX-2 inhibitors and a newly developed substrate-selective COX-2 inhibitor (SSCI) reduce a variety of stress-induced behavioral pathologies in mice. We found that these behavioral effects were associated with a dampening of neuronal excitability in the basolateral amygdala (BLA) ex vivo and in vivo, and were mediated by small-conductance calcium-activated potassium (SK) channel and CB1 cannabinoid receptor activation. Taken together, these data provide further support for the potential utility of SSCIs, as well as traditional COX-2 inhibitors, as novel treatment approaches for stress-related psychiatric disorders.

No MeSH data available.


Related in: MedlinePlus