There is growing evidence that kappa opioid receptor (KOR) antagonists could be a useful class of therapeutics for treating depression and anxiety. However, the overwhelming majority of preclinical investigations examining the behavioral effects of KOR antagonists have been in male rodents. Here, we examined the effects of the long-acting KOR antagonist nor-binaltophimine (norBNI) on immobility in the forced swim test in males and females of two different rodent species (C57Bl/6J and California mice). Consistent with previous reports, norBNI (10 mg/kg) decreased immobility in the forced swim test for male C57Bl/6J and California mice. Surprisingly, dose–response studies in female C57Bl/6J and California mice showed that norBNI did not reduce immobility. Pharmacokinetic analyses showed that metabolism and brain concentrations of norBNI were similar in male and female C57Bl/6J. In the nucleus accumbens of male but not female C57Bl/6J, norBNI increased phosphorylation of c-Jun N-terminal kinase (pJNK), a putative mechanism for norBNI action. However, no differences in pJNK were observed in male or female California mice. Together, these results suggest that immobility in the forced swim test is less dependent on endogenous KOR signaling in female rodents and highlight the importance of examining the effects of possible therapeutic agents in both males and females.

Psychosocial stress leads to the activation of kappa opioid receptors (KORs), which induce dysphoria and facilitate depression-like behaviors. However, less is known about the long-term effects of stress and KORs in females. We examined the long-term effects of social defeat stress on the aversive properties of KOR activation in male and female California mice (Peromyscus californicus) using a conditioned place aversion paradigm. Female California mice naïve to social defeat, formed a place aversion following treatment with 2.5 mg/kg of the KOR agonist U50,488, but females exposed to defeat did not form a place aversion to this dose. This supports the finding by others that social defeat weakens the aversive properties of KOR agonists. In contrast, both control and stressed males formed an aversion to 10 mg/kg of U50,488. We also examined EGR1 immunoreactivity, an indirect marker of neuronal activity, in the nucleus accumbens (NAc) and found that stress and treatment with 10 mg/kg of U50,488 increased EGR1 immunoreactivity in the NAc core in females but reduced activation in males. The effects of stress and U50,488 on EGR1 were specific to the NAc, as we found no differences in the bed nucleus of the stria terminalis. In summary, our data indicate important sex differences in the long-term effects of stress and indicate the need for further study of the molecular mechanisms mediating the behavioral effects of KOR in both males and females.

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Atrial fibrillation (AF) leads to remodeling of the left atrium (LA) and left atrial appendage (LAA), resulting in atrial myopathy. Reduced LA and LAA function in chronic AF leads to thrombus formation and spontaneous echo contrast (SEC). The effect of inotropic stimulation on LAA function in patients with chronic AF is unknown. LAA emptying velocity (LAAEV) and maximal LAA area at baseline and after dobutamine were measured by transesophageal echocardiography in 14 subjects in normal sinus rhythm (NSR) and 6 subjects in AF. SEC in the LA was assessed before and after dobutamine. LAAEV increased significantly in both groups. However, the LAAEV at peak dobutamine in patients with AF remained significantly lower than the baseline LAAEV in patients who were in NSR (P = 0.009). Maximal LAA area decreased significantly with dobutamine in both groups, but LAA area at peak dose of dobutamine in patients with AF remained greater than baseline area in those in NSR (P = 0.01). Despite the increase in LAAEV, SEC improved in only two of five patients. We conclude that during AF, the LAA responds to inotropic stimulation with only a modest improvement in function.