Enhanced sensitivity to behavioral effects of naltrexone in rats.

Rats were trained on a fixed-ratio schedule under which every 30th response produced food reinforcement. Five 3-min periods of fixed-ratio reinforcement were each preceded by a 10-min time-out in which responding had no scheduled consequence. Cumulative dose-effect functions for naltrexone were determined once per week by administering increasing doses during each successive time-out. Initially, only a dose of 100 mg/kg suppressed fixed-ratio responding. After eight exposures to cumulative naltrexone, however, a dose of 10 mg/kg suppressed responding. This shift to the left of the dose-effect function, or supersensitivity, persisted for at least 10-wk when naltrexone was not injected. Pretreatment with either morphine (3.0 mg/kg) or ethylketocyclazocine (0.1 and 1.0 mg/kg) partially prevented the naltrexone-induced decreases in response rates. Neither chlordiazepoxide nor [D-pen2, D-pen5]enkephalin pretreatments appreciably altered the effects of naltrexone. When cumulative doses of 1.0-10.0 mg/kg naltrexone were followed by two saline injections instead of the higher doses of naltrexone, over 8 wk, the naltrexone dose-effect function shifted back to the right. The return to normal naltrexone sensitivity after elimination of the two highest doses suggests that a reliable association between the lower and higher doses in a cumulative dosing procedure can result in conditioned effects to the lower doses. Similar observations of salivation elicited by cumulative naltrexone injections further support the hypothesis that the present naltrexone supersensitivity may involve conditioning processes.