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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 COX-2 inhibition in the EPM in ~4-month-old mice.(A) Effects of LM-4131 and Lumiracoxib (LMX) in the EPM in ~4-month-old mice under non-stressed conditions. (B) Effects of LM-4131 and LMX in the EPM in 4-month old mice tested 8 hr after foot-shock stress exposure. Significant F and P values for one-way ANOVA shown above figures. *p<0.05, ** p<0.01, ***p<0.001, ****p<0.0001 by Holm-Sidak multiple comparisons post-hoc test.DOI:http://dx.doi.org/10.7554/eLife.14137.010
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fig2s1: Effects of COX-2 inhibition in the EPM in ~4-month-old mice.(A) Effects of LM-4131 and Lumiracoxib (LMX) in the EPM in ~4-month-old mice under non-stressed conditions. (B) Effects of LM-4131 and LMX in the EPM in 4-month old mice tested 8 hr after foot-shock stress exposure. Significant F and P values for one-way ANOVA shown above figures. *p<0.05, ** p<0.01, ***p<0.001, ****p<0.0001 by Holm-Sidak multiple comparisons post-hoc test.DOI:http://dx.doi.org/10.7554/eLife.14137.010

Mentions: We also examined the effects of COX-2 inhibition in a well-established test for anxiety-like behavior, the elevated-plus maze (EPM). In non-stressed mice, drug treatment increased open arm entries and closed arm latency, without affecting other measures (Figure 2A). In mice stressed 8 hr earlier, treatment with either LM-4131 or LMX reduced the latency to enter an open arm and increased the latency to enter closed arm and to freeze, but did not alter open arm time or entries or total distance traveled (Figure 2B). In a separate cohort of 4-month-old mice, LM-4131 and LMX reduced open-arm latency and latency to freeze regardless of prior stress exposure (Figure 2—figure supplement 1). These data demonstrate the effects of COX-2 inhibition are evident across behavioral assays, and are not restricted to appetitive motivated behavioral tests such as the NIH assay.10.7554/eLife.14137.009Figure 2.Effects of COX-2 inhibition in the elevated-plus maze.


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 COX-2 inhibition in the EPM in ~4-month-old mice.(A) Effects of LM-4131 and Lumiracoxib (LMX) in the EPM in ~4-month-old mice under non-stressed conditions. (B) Effects of LM-4131 and LMX in the EPM in 4-month old mice tested 8 hr after foot-shock stress exposure. Significant F and P values for one-way ANOVA shown above figures. *p<0.05, ** p<0.01, ***p<0.001, ****p<0.0001 by Holm-Sidak multiple comparisons post-hoc test.DOI:http://dx.doi.org/10.7554/eLife.14137.010
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Related In: Results  -  Collection

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fig2s1: Effects of COX-2 inhibition in the EPM in ~4-month-old mice.(A) Effects of LM-4131 and Lumiracoxib (LMX) in the EPM in ~4-month-old mice under non-stressed conditions. (B) Effects of LM-4131 and LMX in the EPM in 4-month old mice tested 8 hr after foot-shock stress exposure. Significant F and P values for one-way ANOVA shown above figures. *p<0.05, ** p<0.01, ***p<0.001, ****p<0.0001 by Holm-Sidak multiple comparisons post-hoc test.DOI:http://dx.doi.org/10.7554/eLife.14137.010
Mentions: We also examined the effects of COX-2 inhibition in a well-established test for anxiety-like behavior, the elevated-plus maze (EPM). In non-stressed mice, drug treatment increased open arm entries and closed arm latency, without affecting other measures (Figure 2A). In mice stressed 8 hr earlier, treatment with either LM-4131 or LMX reduced the latency to enter an open arm and increased the latency to enter closed arm and to freeze, but did not alter open arm time or entries or total distance traveled (Figure 2B). In a separate cohort of 4-month-old mice, LM-4131 and LMX reduced open-arm latency and latency to freeze regardless of prior stress exposure (Figure 2—figure supplement 1). These data demonstrate the effects of COX-2 inhibition are evident across behavioral assays, and are not restricted to appetitive motivated behavioral tests such as the NIH assay.10.7554/eLife.14137.009Figure 2.Effects of COX-2 inhibition in the elevated-plus maze.

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