Kappa opioid receptor mediated operant performance in male and female rats.

Anhedonia and avolition are emotions frequently endorsed by individuals with stress related disorders. Kappa opioid receptor (KOR) activation can induce negative emotions and recent clinical evidence suggests that KOR antagonism can alleviate anhedonia in a transdiagnostic cohort of patients. However, the behavioral consequences of KOR activation and antagonism in modulating motivation, as assessed by schedule-controlled behavioral performance without preexisting conditions (stress or substance use), have not been formally assessed. To address this gap in the literature, this report utilized male and female Sprague Dawley rats to (1) evaluate the impact of the selective KOR agonist U50,488, on the performance of animals responding for sucrose pellets under a progressive ratio (PR) schedule and (2) determine the effects of the short-acting KOR antagonist LY2444296 alone and on U50,488 mediated reductions in PR performance. Overall, U50,488 5 mg/kg significantly reduced the breakpoint and number of rewards obtained by animals. This occurred in the absence of motor impairment and independent of evidence for satiation. LY2444296 did not alter PR performance when administered alone but effectively blocked the deficits induced by U50,488. To further delineate the behavioral alterations that underlie these reductions in responding, a more detailed analysis was conducted on PR performance in the first 15 min of the session, the period of time when animals obtained the most reinforcers. During this period, U50,488 increased the length of the post-reinforcement pause and reduced the running rate on PR schedules. These changes in behavior produced by acute activation of KORs are consistent with a reduction of effort-related motivation in rodents. These data contribute to the understanding of how KORs modulate motivation, which is critical to future efforts to evaluate performance in the context of stress and assess how KOR antagonists alleviate anhedonic behaviors associated with stress.

LY2444296, a κ-opioid receptor antagonist, selectively reduces alcohol drinking in male and female Wistar rats with a history of alcohol dependence.

Alcohol use disorder (AUD) remains a major public health concern. The dynorphin (DYN)/κ-opioid receptor (KOP) system is involved in actions of alcohol, particularly its withdrawal-associated negative affective states. This study tested the ability of LY2444296, a selective, short-acting, KOP antagonist, to decrease alcohol self-administration in dependent male and female Wistar rats at 8 h abstinence. Animals were trained to orally self-administer 10% alcohol (30 min/day for 21 sessions) and were made dependent via chronic intermittent alcohol vapor exposure for 6 weeks or exposed to air (nondependent). After 6 weeks, the effect of LY2444296 (0, 3, and 10 mg/kg, p.o.) was tested on alcohol self-administration at 8 h of abstinence. A separate cohort of rats was prepared in parallel, and their somatic withdrawal signs and alcohol self-administration were measured after LY2444296 administration at 8 h, 2 weeks, and 4 weeks abstinence. LY2444296 at 3 and 10 mg/kg significantly reduced physical signs of withdrawal in dependent rats at 8 h abstinence, only. Furthermore, 3 and 10 mg/kg selectively decreased alcohol self-administration in dependent rats at only 8 h abstinence. These results highlight the DYN/KOP system in actions of alcohol during acute abstinence, suggesting KOP antagonism could be beneficial for mitigating acute withdrawal signs and, in turn, significantly reduce excessive alcohol consumption associated with AUD.