Acute inhibition of kappa opioid receptors before stress blocks depression-like behaviors in California mice

Abstract

Kappa opioid receptors (KOR) are considered to be a promising therapeutic target for stress-induced psychiatric disorders such as anxiety and depression. Preclinical data show that KOR antagonists have greater efficacy if administered before stressful experiences as opposed to afterwards. However, almost all of these studies use long-acting antagonists, leaving it unclear whether inhibition of KOR after stress is required for efficacy. Here we show that administration of the short-acting KOR antagonist AZ-MTAB before episodes of social defeat stress block the induction of anhedonia (both males and females) and social avoidance responses (females) that persist two weeks after stress. In both males and females pre-stress AZ-MTAB treatment also blunted anticipatory autogrooming behavior immediately prior to the third episode of defeat. In contrast when AZ-MTAB was administered two weeks after defeat (immediately before behavior testing) in female California mice, it was ineffective at reversing anhedonia and social avoidance. These results suggest that short-acting KOR antagonists may have greater therapeutic potential if administered before exposure to psychosocial stressors.

Keywords: Anhedonia; Depression; Kappa opioid receptor; Social defeat stress; Social interaction.

Figure 1. Effects of 10 mg/kg U50,488 and 10 mg/kg AZ-MTAB on immobility in control and stressed female California mice in Experiment 1

Experimental timeline (Fig. 1A). Average immobility during the FST (Fig. 2B). Locomotor behavior in a novel environment (Fig. 2C). † p < 0.05, †† p < 0.01 compared to vehicle (26% DMSO in saline). Group N’s: control/vehicle n=6, control/U50,488 n=6, control/AZ-MTAB+U50,488 n = 7; stress/vehicle n=6, stress/U50,488 n =6, stress/AZ-MTAB+U50,488 n=6. Error bars are SEM.

Fig. 2. Autogrooming behavior in male and female California mice in Experiment 2

Experimental timeline (Fig. 2A). Time spent displaying autogrooming behavior prior to defeat (day 1, Fig. 2B and 2C), and prior to the last episode of defeat (day 3, Fig. 2D and 2E). ***p<0.0001 compared to controls; **p<0.01, main effect of stress; † p<0.0001 compared to vehicle. Group N’s: Males: control/vehicle: 14, control/AZ-MTAB: 14, stress/vehicle: 14, stress/AZ-TAB: 14. Females: control/vehicle: 8, control/AZ-MTAB: 8, stress/vehicle: 8, stress/AZ-MTAB: 8. All error bars are SEM.

Fig. 3. Sucrose preference in male and female California mice in Experiment 2

Experimental timeline (Fig. 3A). Baseline levels of preference for sucrose water over tap water prior to social defeat stress (Fig. 3B and 3C) and following social defeat stress (Fig. 3D and 3E). ***p<0.0001 compared to control; † p<0.0001 compared to vehicle. Group N’s: Males: control/vehicle: 14, control/AZ-MTAB: 18, stress/vehicle: 18, stress/AZ-MTAB: 14. Females: control/vehicle: 10, control/AZ-MTAB: 10, stress/vehicle: 10, stress/AZ-MTAB: 10. All error bars are SEM.

Fig 4. Social interaction behavior in female California mice in Experiment 2

Experimental timeline (Fig. 4A). Time spent near the interaction zone while a novel mouse was present (Fig. 4B). Head orientation towards the target mouse during the interaction phase (Fig. 4C). Time spent near the cage during an acclimation phase (Fig. 4D). Time spent in the center during the open field phase (Fig. 4E). Locomotor behavior during open field testing (Fig. 4F). ***p<0.0001 compared to controls; † p< 0.0001 compared to vehicle. Groups N’s: control/vehicle: 10, control/AZ-MTAB: 10, stress/vehicle: 9, stress/AZ-MTAB: 10. All error bars are SEM.

Fig. 5. Effects of post-stress AZ-MTAB treatment on sucrose preference and social interaction behavior in female California mice in Experiment 3

Experimental timeline (Fig. 5A). Time spent in the interaction zone while a novel mouse was present (Fig. 5B) Head orientation towards the target mouse during the interaction phase (Fig. 5C). Time spent near the cage during an acclimation phase (Fig. 5D). Locomotor behavior during open field testing (Fig. 5E). Baseline levels of preference for sucrose water over tap water prior to social defeat stress (Fig. 5F) and following social defeat stress (Fig. 5G). ***p<0.0001, **p<0.001 compared to controls. Groups N’s: control/vehicle: 8, control/AZ-MTAB: 7, stress/vehicle: 6, stress/AZ-MTAB: 9. All error bars are SEM.