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.