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

Abstract

Stress often disrupts behavior and can lead to psychiatric illness. Considerable evidence suggests that corticotropin-releasing factor (CRF) plays an important role in regulating the effects of stress. CRF administration produces stress-like effects in humans and laboratory animals, and CRF levels are elevated in individuals with stress-related illness. Recent work indicates that k-opioid receptor (KOR) antagonists can block CRF effects, raising the possibility that at least some of the effects of stress are mediated via KORs. Here we examined the effects of CRF on performance in the 5-choice serial reaction time task (5CSRTT), a test used to quantify attention in rodents, as well as functional interactions between CRF and KORs. Male Sprague-Dawley rats were trained in the 5CSRTT and then each was implanted with an intracerebroventricular (ICV) cannula. After recovery and restabilization of performance, they received a single intraperitoneal (IP) injection of vehicle or JDTic (10 mg/kg), a KOR antagonist with long-lasting (414 days) effects. In subsequent sessions, rats received ICV infusions of CRF (0.25-1.0 mg) or vehicle and were tested 60 min later. CRF dose-dependently disrupted performance as reflected by decreases in correct responding, increases in omission errors, increases in latencies to respond correctly, and increases in time to complete the session. JDTic attenuated each of these CRF-induced deficits while having no effects on its own. The persistent ability of JDTic to disrupt KOR function was confirmed using the tail immersion assay. These findings indicate that KOR antagonists can prevent acute stress-related effects that degrade performance in tasks requiring attention.

The role of the dynorphin/κ opioid receptor system in anxiety

“…Recent work further showed that the anxiogenic-like effects of CRF were triggered by CRF1-R activation of the dynorphin/ κ opioid receptor system [59] . These results reveal a connection between CRF and the dynorphin/κ opioid receptor system [70] and support that the CRF-induced dynorphin/κ opioid receptor-dependent pathway is involved in the modulation of anxiety-like behaviors [62] .…”

Perturbations in Effort-Related Decision-Making Driven by Acute Stress and Corticotropin-Releasing Factor

“…In this latter instance, these manipulations did not affect choice behavior, suggesting that the mechanisms through which increased CRF transmission alters choice latencies may be dissociable from those involved in biasing the direction of choice. Notably central CRF infusions have been reported to increase choice latencies during tests of attention ( Van't Veer et al, 2012;Beard et al, 2015). These findings suggest that the ability of acute stress to induce 'indecisiveness' and increase processing times for action selection is also mediated in part by increased central CRF transmission.…”

“…An initial study investigated the effects of ICV infusions of three different doses of CRF (rat/human; Tocris Bioscience; 0.25, 1, and 3 μg) on effort discounting. Previous experiments have seen alterations in behavior following ICV infusions ranging from doses as low as 0.1 to 10 μg infused into the ventricular system (Dunn and Berridge, 1990;Cador et al, 1992;Adamec and McKay, 1993;Campbell et al, 2004;Van't Veer et al, 2012). As the maximum solubility of CRF in artificial cerebrospinal fluid is 1 μg/1 μl, the infusion volume for the 3 μg dose was set to 3 μl, whereas for the other two doses, the volume was 1 μl.…”

Ablation of Kappa-Opioid Receptors from Brain Dopamine Neurons has Anxiolytic-Like Effects and Enhances Cocaine-Induced Plasticity

“…It has been suggested that KOR antagonists might have a wide range of indications, including the treatment of depressive-, anxiety-, and addictive disorders (for review, see Carlezon et al, 2009;Wee and Koob, 2010;Tejeda et al, 2012;Carlezon and Carroll, 2013). A general ability to reduce the impact of stress may explain how KOR antagonists can have efficacy in such a wide variety of animal models that would appear to represent different disease states Knoll and Carlezon, 2010;Van't Veer et al, 2012;Carlezon and Carroll, 2013). Partial KOR agonists, which activate KORs with a lower efficacy than DYN and thus may lack the dysphoric effects produced by full agonists, could be useful for the treatment of conditions characterized by elevated motivation (Carlezon et al, 2009).…”