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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 sucrose preference test.(A–C) 2 hr cumulative sucrose preference, sucrose consumption, and water consumption after vehicle or LM-4131 treatment in non-stressed mice and 8 hr after foot-shock exposure. Testing was conducted during the light phase of the circadian cycle. (D–F) Effects of LM-4131 or vehicle on sucrose preference, sucrose consumption, and water consumption during the light and dark phases of the circadian cycle. Mice were treated with LM-4131 or vehicle 8 hr after foot-shock exposure and tested for 16 hr (4 hr during the light cycle and 12 hr during the dark cycle).DOI:http://dx.doi.org/10.7554/eLife.14137.013
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fig5: Effects of COX-2 inhibition in the sucrose preference test.(A–C) 2 hr cumulative sucrose preference, sucrose consumption, and water consumption after vehicle or LM-4131 treatment in non-stressed mice and 8 hr after foot-shock exposure. Testing was conducted during the light phase of the circadian cycle. (D–F) Effects of LM-4131 or vehicle on sucrose preference, sucrose consumption, and water consumption during the light and dark phases of the circadian cycle. Mice were treated with LM-4131 or vehicle 8 hr after foot-shock exposure and tested for 16 hr (4 hr during the light cycle and 12 hr during the dark cycle).DOI:http://dx.doi.org/10.7554/eLife.14137.013

Mentions: The effects of COX-2 inhibition were next tested in two assays sensitive to monoamine antidepressant treatment, the tail suspension test (TST) and the sucrose preference test (Cryan and Holmes, 2005). Interestingly, we found that neither LM-4131, LMX, nor Celecoxib altered TST immobility time in non-stressed mice (Figure 4A) and that LM-4131 also had no effect on this behavior in mice given foot-shock stress 8 or 24 hr previously (Figure 4B–C). In a similar vein, LM-4131 had no effect on sucrose consumption or preference, either under non-stressed conditions or 8 hr following foot-shock (Figure 5). These data highlight a degree of specificity in the behavioral effects of acute COX-2 inhibition.10.7554/eLife.14137.013Figure 5.Effects of COX-2 inhibition in the sucrose preference test.


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 sucrose preference test.(A–C) 2 hr cumulative sucrose preference, sucrose consumption, and water consumption after vehicle or LM-4131 treatment in non-stressed mice and 8 hr after foot-shock exposure. Testing was conducted during the light phase of the circadian cycle. (D–F) Effects of LM-4131 or vehicle on sucrose preference, sucrose consumption, and water consumption during the light and dark phases of the circadian cycle. Mice were treated with LM-4131 or vehicle 8 hr after foot-shock exposure and tested for 16 hr (4 hr during the light cycle and 12 hr during the dark cycle).DOI:http://dx.doi.org/10.7554/eLife.14137.013
© Copyright Policy
Related In: Results  -  Collection

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

fig5: Effects of COX-2 inhibition in the sucrose preference test.(A–C) 2 hr cumulative sucrose preference, sucrose consumption, and water consumption after vehicle or LM-4131 treatment in non-stressed mice and 8 hr after foot-shock exposure. Testing was conducted during the light phase of the circadian cycle. (D–F) Effects of LM-4131 or vehicle on sucrose preference, sucrose consumption, and water consumption during the light and dark phases of the circadian cycle. Mice were treated with LM-4131 or vehicle 8 hr after foot-shock exposure and tested for 16 hr (4 hr during the light cycle and 12 hr during the dark cycle).DOI:http://dx.doi.org/10.7554/eLife.14137.013
Mentions: The effects of COX-2 inhibition were next tested in two assays sensitive to monoamine antidepressant treatment, the tail suspension test (TST) and the sucrose preference test (Cryan and Holmes, 2005). Interestingly, we found that neither LM-4131, LMX, nor Celecoxib altered TST immobility time in non-stressed mice (Figure 4A) and that LM-4131 also had no effect on this behavior in mice given foot-shock stress 8 or 24 hr previously (Figure 4B–C). In a similar vein, LM-4131 had no effect on sucrose consumption or preference, either under non-stressed conditions or 8 hr following foot-shock (Figure 5). These data highlight a degree of specificity in the behavioral effects of acute COX-2 inhibition.10.7554/eLife.14137.013Figure 5.Effects of COX-2 inhibition in the sucrose preference test.

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