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 κ-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 (>14 days) effects. In subsequent sessions, rats received ICV infusions of CRF (0.25-1.0 μg) 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.

Figure 1

Representative micrograph of ICV cannula track in cresyl violet-stained tissue. Rats were excluded if the tip of the cannula was embedded in the brain tissue surrounding the lateral ventricle (LV).

Figure 2

Effects of JDTic pretreatment on the ability of CRF to affect performance in the 5CSRTT. Left panel represents effects of pretreatment alone on baseline (a) percent correct responses, (b) percent omissions, (c) latency to correct responses (in seconds), and (d) latency to complete the task (in seconds); right panel represents effects after various doses of CRF. ^*P<0.05, ^**P<0.01 within-group comparisons, ^P<0.05, ^^P<0.01 between-group comparisons, Newman–Keuls post-hoc t-tests.

Figure 3

Effects of JDTic pretreatment on latency to withdraw the tail (in seconds) in the tail immersion assay at baseline or 60 min after administration of the KOR-selective agonist U50,488 (15 mg/kg, IP). ^**P<0.01 within-group comparisons, ^^P<0.01 between-group comparisons, Newman–Keuls post-hoc t-tests.