Two short-acting kappa opioid receptor antagonists (zyklophin and LY2444296) exhibited different behavioral effects from the long-acting antagonist norbinaltorphimine in mouse anxiety tests

Abstract Prototypical long-acting kappa opioid receptor (KOPR) antagonists [e.g., norbinaltorphimine (norBNI)] have been reported to exert anxiolytic-like effects in several commonly used anxiety tests in rodents including the novelty-induced hypophagia (NIH) and elevated plus maze (EPM) tests. It remains unknown if the short-acting KOPR antagonists (e.g., zyklophin and LY2444296) have similar effects. In this study effects of zyklophin and LY2444296 (s.c.) were investigated in the NIH and EPM tests in mice 1 h post-injection and compared with norBNI (i.p.) 48 h post-administration. In the NIH test, zyklophin at 3 and 1 mg/kg, but not 0.3 mg/kg, or LY2444296 at 30 mg/kg decreased the latency of palatable food consumption in novel cages, but had no effect in training cages, similar to norBNI (10 mg/kg). Zyklophin at 3 or 1 mg/kg increased or had a trend of increasing the amount of palatable food consumption in novel cages, with no effects in training cages, further indicating its anxiolytic-like effect, but norBNI (10 mg/kg) and LY2444296 (30 mg/kg) did not. In the EPM test, norBNI (10 mg/kg) increased open arm time and % open arm entries or time, but zyklophin at all three doses and LY2444296 (30 mg/kg) had no effects. In addition, zyklophin at 3 mg/kg increased numbers of close and total arm entries on EPM, suggesting increased activity; however, norBNI and LY2444296 had no effects on close and total arm entries. Thus, all three KOPR antagonists had anxiolytic-like effects in the NIH test. However, only the long-acting one (norBNI), but not the short-acting ones (zyklophin and LY2444296), demonstrated anti-anxiety like effects in the EPM test. It remains to be investigated if the differences are due to the differences in their durations of action and/or pharmacodynamic properties.