Stress is most often associated with aversive states. It rapidly induces the release of hormones and neuropeptides including dynorphin, which activates kappa opioid receptors (KORs) in the central and peripheral nervous systems. In animal models, many aversive effects of stress are mimicked or exacerbated by stimulation of KORs in limbic brain regions. Although KOR signaling during acute stress may increase physical ability (by producing analgesia) and motivation to escape a threat (by producing aversion), prolonged KOR signaling in response to chronic or uncontrollable stress can lead to persistent expression of behavioral signs that are characteristic of human depressive disorders (i.e., "prodepressive-like" signs). Accumulating evidence suggests that KORs contribute to the progressive amplification (sensitization) of stress-induced behaviors that occurs with repeated exposure to stress. Many of the aversive effects of stress are blocked by KOR antagonists, suggesting that these agents may have potential as therapeutics for stress-related conditions such as depression and anxiety disorders. This review summarizes current data on how KOR systems contribute to the acute (rapid), delayed, and cumulative molecular and behavioral effects of stress. We focus on behavioral paradigms that provide insight on interactions between stress and KOR function within each of these temporal categories. Using a simplified model, we consider the time course and mechanism of KOR-mediated effects in stress and suggest future directions that may be useful in determining whether KOR antagonists exert their therapeutic effects by preventing the development of stress-induced behaviors, the expression of stress-induced behaviors, or both.

Endogenous opioid systems regulate neurobiological responses to threatening stimuli. Stimulation of -opioid receptors (KORs) produces analgesia but induces prodepressive-like effects in a variety of animal models. In contrast, KOR antagonists have antidepressant-like effects. KORs and their endogenous ligand dynorphin are expressed throughout brain areas involved in fear and anxiety, including the extended amygdala. Here, we examined whether KOR antagonists would affect unlearned fear (anxiety) in the elevated plus maze (EPM) and open field (OF) paradigms and learned fear in the fear-potentiated startle (FPS) paradigm. These studies were designed to accommodate the slow onset (ϳ24 h) and extended time course (Ͼ3 weeks) of the prototypical KOR antagonists nor-binaltorphimine hydrochloride (norBNI) and JDTicRats received an i.p. injection of norBNI (3.0 -30 mg/kg) or JDTic (1.0 -10 mg/kg) 48 h before EPM testing. One day later, they were tested in the OF, and 5 and 7 days later, they were trained and tested in the FPS paradigm. Both KOR antagonists dose-dependently increased open arm exploration in the EPM without affecting OF behavior. They also decreased conditioned fear in the FPS paradigm. The anxiolytic-like effects of KOR antagonists were qualitatively similar to those of the benzodiazepine chlordiazepoxide in the EPM. The selective serotonin reuptake inhibitor fluoxetine had no effect in the EPM and anxiogenic-like effects in the OF. Our results indicate that KOR antagonists produce a unique combination of antidepressant-and anxiolytic-like effects and suggest that this class of drugs may be particularly effective for the treatment of comorbid depressive and anxiety disorders.Although the neurobiology of depression and anxiety disorders is not well understood, evidence suggests that these disorders share common genetic and neuroanatomic components. Depression and anxiety disorders are highly comorbid; more than half of individuals with anxiety disorders also co-present with a lifetime history of depression (Kaufman

SUMMARY Vocalizations play a significant role in social communication across species. Analyses in rodents have used a limited number of spectro-temporal measures to compare ultrasonic vocalizations (USVs), which limits the ability to address repertoire complexity in the context of behavioral states. Using an automated and unsupervised signal processing approach, we report the development of MUPET (Mouse Ultrasonic Profile ExTraction) software, an open access MATLAB® tool that provides data-driven, high-throughput analyses of USVs. MUPET measures, learns, and compares syllable types and provides an automated time-stamp of syllable events. Using USV data from a large mouse genetic reference panel and open source datasets produced in different social contexts, MUPET analyzes the fine details of syllable production and repertoire use. MUPET thus serves as a new tool for USV repertoire analyses, with the capability to be adapted for use with other species.

Background The kappa opioid receptor (KOR) system contributes to the prodepressive and aversive consequences of stress, and is implicated in the facilitation of conditioned fear and anxiety in rodents. Here we sought to identify neural circuits that mediate KOR system effects on fear and anxiety in rats. Methods We assessed whether fear conditioning induces plasticity in KOR or dynorphin (the endogenous KOR ligand) mRNA expression in the basolateral (BLA) and central (CeA) nuclei of the amygdala, hippocampus (HIP), or striatum (STR). We then assessed whether microinfusions of the KOR antagonist JDTic (0–10.0 μg/side) into the BLA or CeA affect the expression of conditioned fear or anxiety. Finally, we examined whether fear extinction induces plasticity in KOR mRNA expression that relates to the quality of fear extinction. Results Fear conditioning upregulated KOR mRNA in the BLA by 65%, and downregulated it in the STR by 22%, without affecting KOR levels in the CeA or HIP, or dynorphin levels in any region. KOR antagonism in either the BLA or CeA decreased conditioned fear in the fear-potentiated startle paradigm, whereas KOR antagonism in the BLA but not the CeA produced anxiolytic-like effects in the elevated plus maze. Effective fear extinction was associated with a 67% reduction in KOR mRNA in the BLA. Conclusions These findings suggest that fear conditioning and extinction dynamically regulate KOR expression in the BLA, and provide evidence that the BLA and CeA are important neural substrates mediating the anxiolytic-like effects of KOR antagonists in models of fear and anxiety.