Sex-linked loss of motivation to eat by morphine.

Decreased food intake and poor nutritional status are key clinical features of substance use disorders (SUD). Recent evidence suggests a sex-linked role for the corticotropin-releasing factor (CRF) system in the effects of substances of abuse. However, CRF role in substance-induced impairment of eating behaviour is poorly understood. CRF signalling is transmitted by two receptor types, named CRF1 and CRF2. The present studies examined the influence of sex and the role for the CRF1 receptor in opiate-induced loss of motivation to eat. For this purpose, female and male mice were trained to acquire palatable food-driven operant behaviour. Then, using a counterbalanced within-subject experimental design, they were treated per os with the CRF1 receptor-preferring antagonist antalarmin (20 mg/kg) and intraperitoneally with morphine (2.5 mg/kg). Substance-naïve female mice showed higher food-driven operant behaviour than male mice, indicating elevated motivation for palatable food. Moreover, female and male mice showed similar discrimination index, ruling out a role for learning processes in the sex-linked motivation for food. Morphine decreased food-driven behaviour in either sex. Notably, morphine-induced motivation deficits were greater in female than in male mice, indicating sex-linked effects of opiate substances. However, antalarmin did not affect motivation deficits by morphine, suggesting no role for the CRF1 receptor in opiate-induced loss of interest for food. Nevertheless, antalarmin attenuated the locomotor-suppressing effects of morphine, indicating independency of motivation from locomotion. The present findings demonstrate sex-linked deleterious effects of morphine upon motivation to eat, highlighting the need for sex-customized approaches in the management of opiate-related disorders.