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. 2016 May 10:5:e14137.
doi: 10.7554/eLife.14137.

Cyclooxygenase-2 inhibition reduces stress-induced affective pathology

Joyonna Carrie Gamble-George  1   2 , Rita Baldi  1 , Lindsay Halladay  3 , Adrina Kocharian  3 , Nolan Hartley  1   2 , Carolyn Grace Silva  1 , Holly Roberts  1 , Andre Haymer  1 , Lawrence J Marnett  4 , Andrew Holmes  3 , Sachin Patel  1   2   5   6
Affiliations

Cyclooxygenase-2 inhibition reduces stress-induced affective pathology

Joyonna Carrie Gamble-George et al. Elife. .

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.

Keywords: COX-2; PTSD; amygdala; anxiety; cannabinoid; mouse; neuroscience; stress.

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Conflict of interest statement

The other authors declare that no competing interests exist.

LJM: LJM is a co-inventor on a patent #US20150183737 entitled "Composition and method of Substrate-Selective COX-2 inhibition". LJM has a collaborative research contract with Lundbeck Pharmaceuticals.

SP: SP is a co-inventor on a patent #US20150183737 entitled "Composition and method of Substrate-Selective COX-2 inhibition". SP has a collaborative research contract with Lundbeck Pharmaceuticals.

Figures

Figure 1.
Figure 1.. Effects of COX-2 inhibition in the NIH assay.
Effects of vehicle, LM-4131, Lumiracoxib, and Celecoxib administered 2 hr prior to behavioral testing on feeding latency under non-stressed (control conditions) (A), and 4 hr (B), 8 hr (C), 24 hr (D), and 72 hr (E) after foot-shock stress (experimental design shown above). Cumulative distribution curves depict percentage of mice feeding at each latency time point (sec), while bar graphs represent mean ± S.E.M feeding latency for each group and individual data points. Each point represents 1 mouse. (F) Re-plotted data from A-E in time-course format depicting effects of drugs on feeding latency over time. Significant F and P values from one-way ANOVA noted above bar graphs; *p<0.05, **p<0.01, ****p<0.0001 by Holm-Sidak post hoc multiple comparisons test in bar graphs. For cumulative frequency distributions, *p<0.05, ****p<0.0001 by K-S test. DOI: http://dx.doi.org/10.7554/eLife.14137.003
Figure 1—figure supplement 1.
Figure 1—figure supplement 1.. Effects of COX-2 inhibition on feeding latency in the NIH assay in 4-month-old male mice.
(A) Effects of LM-4131 and Lumiracoxib (LMX) on feeding latency in control, non-stressed mice. (B) Effects of LM-4131, LMX, and Celecoxib on feeding latency tested 8 hr after acute foot-shock exposure. Significant F and P values for one-way ANOVA shown above figures. **p<0.01 by Holm-Sidak post hoc multiple comparisons test. For cumulative distribution curves, **p<0.01, ****p<0.0001 by K-S test. DOI: http://dx.doi.org/10.7554/eLife.14137.004
Figure 1—figure supplement 2.
Figure 1—figure supplement 2.. Effects of COX-2 inhibition on feeding latency in the NIH test in female mice.
(A) Effects of LM-4131 on feeding latency in the NIH assay under control, non-stressed conditions in female mice. (B) Effects of LM-4131 on feeding latency 8 hr after foot-shock exposure. (C) Effects of Rimonabant + vehicle, or Rimonabant + LM-4131 co-treatment, on feeding latency tested 8 hr after foot-shock exposure. *p<0.05 by two-tailed unaired t-test. For cumulative distribution curves, **p<0.01 by K-S test. DOI: http://dx.doi.org/10.7554/eLife.14137.005
Figure 1—figure supplement 3.
Figure 1—figure supplement 3.. Effects of COX-2 inhibition on feeding latency in the NIH test after sub-chronic stress.
(A) Effects of LM-4131 and Lumiracoxib (LMX) on feeding latency in the NIH assay under control, non-stressed conditions. (B) Effects of LM-4131 and LMX on feeding latency in the NIH assay 8 hr after the last of 5 daily foot-shock exposures. Significant F and P values by one-way ANOVA shown above figures. **p<0.01 by Holm-Sidak post hoc multiple comparisons test. For cumulative distribution curves, ****p<0.0001 by K-S test. DOI: http://dx.doi.org/10.7554/eLife.14137.006
Figure 1—figure supplement 4.
Figure 1—figure supplement 4.. Effects of subchronic COX-2 inhibition on feeding latency in the NIH test.
(A) Effects of 5 consecutive daily administrations of Lumiracoxib (LMX) on feeding latency and food consumption in the NIH test, and body weight, in control non-stressed mice. (B) Effects of 5 consecutive daily administrations of LMX on feeding latency and food consumption in the NIH test 8 hr after foot-shock exposure. *p<0.05 by two-tailed unpaired t-test. For cumulative distribution curves, ****p<0.0001 by K-S test. DOI: http://dx.doi.org/10.7554/eLife.14137.007
Figure 1—figure supplement 5.
Figure 1—figure supplement 5.. Effects of COX-2 inhibition on locomotor activity in the open field test.
(A) Effects of LM-4131 on total distance travelled. (B) Effects of Lumiracoxib on total distance travelled. DOI: http://dx.doi.org/10.7554/eLife.14137.008
Figure 2.
Figure 2.. Effects of COX-2 inhibition in the elevated-plus maze.
(A) Effects of LM-4131 (10 mg/kg) and Lumiracoxib (experimental design shown above) under basal non-stressed conditions. (B) Effects of LM-4131 and Lumiracoxib 8 hr after acute foot-shock exposure. Significant F and P values for one-way ANOVA shown above bar graphs. *p<0.05, ****p<0.0001 by Holm-Sidak multiple comparisons post hoc test. DOI: http://dx.doi.org/10.7554/eLife.14137.009
Figure 2—figure supplement 1.
Figure 2—figure supplement 1.. 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
Figure 3.
Figure 3.. Effects of COX-2 inhibition on contextual fear conditioning.
(A) Timeline for contextual fear conditioning. Data from each time point shown in correspondingly labeled panel (B–D). (B) No differences in freezing behavior between groups were observed during conditioning. Drugs were administered 6 hr after conditioning (2 hr before fear retrieval). (C) Time course and summary of effects of LM-4131, Lumiracoxib (LMX), or Celecoxib on conditioned fear expression during context re-exposure. (D) Effects of LM-4131, LMX, and Celecoxib on contextual freezing on a second context re-exposure. Significant F and P values for two-way ANOVA (C) and one-way ANOVA (D) shown above figure. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 by Holm-Sidak post hoc analysis. Color of * indicates significance level of comparison between each drug and vehicle; red, LM-4131; blue, LMX; green, Celecoxib. DOI: http://dx.doi.org/10.7554/eLife.14137.011
Figure 4.
Figure 4.. Effects of COX-2 inhibition in the TST.
(A) Effects of LM-4131, LMX, and Celecoxib on immobility duration under non-stressed conditions. (B–C) Effects of LM-4131 on immobility duration 8 and 24 hr after foot-shock exposure. DOI: http://dx.doi.org/10.7554/eLife.14137.012
Figure 5.
Figure 5.. 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
Figure 6.
Figure 6.. Receptor mechanisms mediating anxiolytic-like effects of COX-2 inhibition.
(A) Cumulative feeding latency distribution curves for vehicle, LM-4131, and Lumiracoxib treated mice in the presence of vehicle, or the CB1R antagonist Rimonabant (2 or 5 mg/kg) co-treatment. (B) Mean feeding latency for each group tested 8 hr after stress exposure. (C) Effects of the CB2R antagonist, SR144528 (3 mg/kg), or the TRPV1 antagonist, Capsazapine (10 mg/kg), on LM-4131-induced reductions in feeding latency tested 8 hr after stress exposure. (D) Effects of the SK channel inhibitor, Apamin (0.4 or 0.8 mg/kg; combined data shown), on LM-4131, LMX, and Celecoxib-induced reductions in feeding latency tested 8 hr after stress exposure. (E) Effects of the SK channel activator, 1-EBIO (5 mg/kg), on feeding latency in the presence and absence of LM-4131 tested 8 hr after stress exposure. Significant F and P values from one-way ANOVA noted above bar graphs; *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 by Holm-Sidak post hoc comparisons test in bar graphs. For cumulative frequency distributions, ****p<0.0001 by K-S test. DOI: http://dx.doi.org/10.7554/eLife.14137.014
Figure 6—figure supplement 1.
Figure 6—figure supplement 1.. Effects of CB1R antagonism on LM-4131-induced reductions in feeding latency in the NIH test.
(A) Under non-stressed conditions, LM-4131 produces a small but significant reduction in feeding latency in the NIH test. (B) In the presence of the CB1R antagonist, Rimonabant (Rim) LM-4131 has no effect on feeding latency relative to Rimonabant alone. DOI: http://dx.doi.org/10.7554/eLife.14137.015
Figure 6—figure supplement 2.
Figure 6—figure supplement 2.. Effects of Apamin and 1-EBIO on locomotor activity.
(A) Effects of Apamin (0.2–1 mg/kg) on locomotor activity. (B) Effects of 1-EBIO 1–10 mg/kg on locomotor activity. DOI: http://dx.doi.org/10.7554/eLife.14137.016
Figure 7.
Figure 7.. Effects of COX-2 inhibition on food consumption in the NIH test.
(A) Cumulative distribution curves depicting proportion of mice consuming a given amount of food, and mean consumption amounts in the home cage and novel cage setting. (B–F) Effects of LM-4131 on Ensure consumption compared to vehicle treatment under control (non-stressed) conditions (B), 4 hr (C), 8 hr (D), 24 hr (E), and 72 hr (F) after foot-shock stress. (G–H) Effects of Vehicle, LM-4131 or Lumiracoxib on consumption in the presence of vehicle or Rimonabant (2 or 5 mg/kg) co-treatment. In bar graphs *p<0.05, **p<0.01, ***p<0.001 by unpaired two-tailed t-test (B–F) or by Holm-Sidak multiple comparisons test (G). For cumulative frequency distributions, ***p<0.001, ****p<0.0001 by K-S test. DOI: http://dx.doi.org/10.7554/eLife.14137.017
Figure 8.
Figure 8.. Effects of COX-2 inhibition on ex vivo BLA neuronal excitability.
(A–B) Effects of LM-4131 (10 μM) on BLA neuron excitability, (C) I/V relationship, (D) resting membrane potential (Vm), input resistance (Ri), and action potential (AP) threshold in non-stressed mice. (E–F) Effects of LM-4131 on BLA neuron excitability, (G) I/V relationship, (H) resting membrane potential (Vm), input resistance (Ri), and action potential (AP) threshold in mice 24 hr after foot-shock stress. F and P values for drug effects by two-way ANOVA shown in (A and E), *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 by post hoc Holm-Sidak test in (A) and (E). DOI: http://dx.doi.org/10.7554/eLife.14137.018
Figure 8—figure supplement 1.
Figure 8—figure supplement 1.. Effects of Rimonabant, Apamin, and Capsazepine on LM-4131-induced reductions in BLA neuron excitability.
(A) Effects of Rimonabant (Rim; 5 μM) on LM-4131 (10 μM) induced reductions in BLA neuronal excitability ex vivo. (A) Effects of Capsazepine (CPZ; 10 μM) on LM-4131 induced reductions in BLA neuronal excitability ex vivo. (A) Effects of Apamin (500 nM) on LM-4131 induced reductions in BLA neuronal excitability ex vivo. Drug effect F and P values by two-way ANOVA shown in figures. DOI: http://dx.doi.org/10.7554/eLife.14137.019
Figure 8—figure supplement 2.
Figure 8—figure supplement 2.. 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
Figure 9.
Figure 9.. Effects of COX-2 inhibition on in vivo activity of BLA neuronal activity.
(A) LM-4131 decreases latency to enter and increases entries into and time spent in the open arms of the EPM 8 hr following stress exposure. (B) Representative heat maps of time spent in the closed (vertical) versus open (horizontal) arms of the EPM. (C) Percentage of total cells recorded that were responsive upon exiting a closed arm. (D) LM-4131 reduced the maximum firing rate of cells responsive to closed arm exit, but had no effect on cells inhibited by closed-arm exit. (E) LM-4131 reduced the increase in average firing rate following closed arm exit in responsive cells. *p<0.05, **p<0.01 by two-tailed unpaired t-test. F and P values for two-way ANOVA shown in (E). DOI: http://dx.doi.org/10.7554/eLife.14137.021
Figure 9—figure supplement 1.
Figure 9—figure supplement 1.. Schematic diagram of in vivo electrophysiological recording sites.
Black dots represent cannula tip locations for vehicle and grey dots represent cannula tip locations for LM-4131 treated mice. Numbers refer to coordinates lateral to bregma for each sagittal brain section. DOI: http://dx.doi.org/10.7554/eLife.14137.022
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