Anxiolytic-Like Effects of κ-Opioid Receptor Antagonists in Models of Unlearned and Learned Fear in Rats

Abstract

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

Corticotropin-Releasing Factor (CRF)-Induced Disruption of Attention in Rats Is Blocked by the κ-Opioid Receptor Antagonist JDTic

“…Interactions between these systems have been thoroughly characterized within the raphe nucleus (Bruchas et al, 2011) but may also occur in other brain regions (Pliakas et al, 2001;Newton et al, 2002;Shirayama et al, 2004;Muschamp et al, 2011b;Knoll et al, 2011). The notion that KOR antagonists block the effects of stress fits well with other evidence that these agents have antidepressant-like (Pliakas et al, 2001;Newton et al, 2002;Mague et al, 2003;Shirayama et al, 2004) and anxiolytic-like effects, including the ability to block acquisition of fear-potentiated startle (Knoll et al, 2007(Knoll et al, , 2011, a procedure often used to study PTSD (Mahan and Ressler, 2012). In addition, KOR agonists can produce key behavioral signs of stress (McLaughlin et al, 2003(McLaughlin et al, , 2006Mague et al, 2003;Todtenkopf et al, 2004).…”

“…Although some of the JDTic effects might be suggestive of behavioral activation, stimulant effects have not been observed with this class of drugs. For example, we did not observe any effects of KOR antagonists on locomotor activity at doses that produce antidepressant-like or anxiolytic-like effects (Mague et al, 2003;Knoll et al, 2007), or alterations in reward-driven behavior or response capabilities at doses that block the prodepressive-like effects of KOR agonists on motivation (Todtenkopf et al, 2004). JDTic also blocks (rather than primes) stress-induced reinstatement of cocaine self-administration in rats (Beardsley et al, 2005), another indicator of a lack of effects that would raise concerns about stimulant effects or abuse potential of this class of drugs.…”

“…JDTic was synthesized at Research Triangle Institute (Research Triangle Park, NC) and dissolved in 0.9% saline; 10 mg/kg (based on the salt form of the drug) was selected because this dose produces strong anxiolytic-like effects in rats (Knoll et al, 2007). Rats first received an infusion of aCSF to ensure the infusion procedure did not affect performance, and to obtain data to serve as baseline.…”

“…After 48 h, the rats received an injection of either JDTic (10 mg/kg, IP; n ¼ 7) or vehicle (1.0 ml/kg, IP, n ¼ 7). A 24-h pretreatment period was used before beginning behavioral testing to optimize KOR selectivity (Carroll et al, 2004;Knoll et al, 2007). Rats were subsequently tested with CRF in the following order: 0 (aCSF), 0.5, 1.0, and 0.25 mg.…”

“…Stress is known to degrade performance in tasks requiring attention or concentration in humans (Campeau et al, 2011), and poor concentration is one of the diagnostic criteria for stress-related psychiatric illnesses such as PTSD (American Psychiatric Association, 2000). Previous work has demonstrated that JDTic produces long-lasting (414 days) disruptions of KOR function (Carroll et al, 2004) and that the behavioral effects of JDTic and nor-BNI are virtually identical (Knoll et al, 2007;Knoll and Carlezon, 2010). To confirm that a single injection of JDTic produced disruption of KOR function for the duration of our tests in the 5CSRTT, we examined the ability of the KOR agonist U50,488 to produce antinociceptive effects in the tail immersion assay (Smith and French, 2002).…”