Sex Differences in Kappa Opioid Receptor Modulation of Nest Building Behavior in Mice

Abstract

Kappa opioid receptor (KOR) activation produces aversion and negative affect. Blockade of KORs consistently exerts anti‐stress and antidepressant‐like effects in preclinical studies, and KOR antagonists are now under clinical investigation for the treatment of major depressive disorder (MDD). Emerging evidence suggests that females are less sensitive than males to the effects of KOR ligands. Although women are twice as likely to be diagnosed with depression than men, the majority of preclinical studies neglect the evaluation of females. Specifically, there is a substantial gap in the literature regarding the behavioral effects of KOR antagonists in female rodents. In these experiments, we investigated sex differences in response to the KOR agonist U50,488 (U50) and the KOR antagonist CERC‐501 in mice. In order to study behavioral effects in response to these KOR ligands, we employed an ethologically relevant indicator of overall well‐being, nest building, which is an innate spontaneously performed behavior in the mouse. We examined the following hypotheses; 1) KOR activation by U50 will suppress nesting; 2) CERC‐501, a selective KOR antagonist, will block U50‐induced suppression of nesting and 3) Females will require higher doses of these KOR ligands to affect nesting. Nest building behavior was assessed in adult male and female C57BL/6J mice by providing individual mice with compressed square cotton nestlet material. Nesting was scored using a scale of 1 to 5 every half hour for five hours. The primary measures included the time it took to reach a nest criterion score of 2.5, in addition to the final average score of the last two hours, when score values plateau. First, intraperitoneal injections of U50 (5 or 10 mg/kg) were administered immediately prior to testing. Second, CERC‐501 (1, 3, or 10 mg/kg) was administered 24 hours prior to vehicle or U50 (10 mg/kg), and nesting was assessed. U50 dose‐dependently suppressed nesting at both doses in males, but females only exhibited the full suppression of nesting behavior when administered the highest dose of U50. U50‐induced suppression of nesting in males was reduced by CERC‐501 at both 3 and 10 mg/kg. In females, the effects of U50 were blocked by CERC‐501 only at 10 mg/kg. Our results confirm that nesting is sensitive to alterations by KOR ligands and is an ideal test to assess compounds that engage with KOR/dynorphin signaling. Importantly, our data encourage further clinical development of CERC‐501 as a novel therapeutic for MDD. Our results also support the existence of sex differences in KOR activation and sensitivity. Overall, these findings agree with earlier preclinical investigations that demonstrated sex differences in response to KOR agonists. Together, these data indicate that females will potentially require a different dosing regimen than men. Our ongoing studies are addressing the role of dynorphin secretion, KOR availability and signaling in mediating these sex‐dependent responses to KOR ligands, particularly in the context of stress, where KOR/dynorphin signaling is upregulated. A more thorough understanding of sex‐biased mechanisms in response to KOR ligands is crucial to developing more effective, sex‐specific treatments for MDD.Support or Funding InformationR01 MH92412, R01 MH105623This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.