Sex differences in alcohol and amphetamine-like compound consumption and their relationship with mu opioid receptor density in the pallidal-mesolimbic system

Excessive alcohol (ETOH) consumption is associated with alterations in the opioid system, including β-endorphin deficiency and differential expression of the mu opioid receptor (MOR) in brain areas involved in reward. This system also contributes to the rewarding properties of psychostimulants, such as cocaine and amphetamines; however, its role in this regard has been little studied, particularly with respect to sex differences. The aim of this study was to determine whether male and female Wistar rats with high ETOH consumption also exhibit higher intake of the psychostimulant phentermine (PHEN), and to analyze its relationship with MOR expression in the nucleus accumbens (Acb), ventral pallidum (VP), and ventral tegmental area (VTA). Rats of both sexes were classified as high or low consumers after a period of voluntary ingestion of 10% ethanol. Subsequently, self-administration of PHEN solution (0.1 mg/ml) was recorded. The results showed that females showed higher ETOH consumption, whereas males had higher PHEN consumption. High ETOH consumers did not show higher stimulant consumption. When MOR expression was examined, males showed higher density in the Acb and VP, while females showed higher density in the VTA. High ETOH consumers showed higher MOR expression in Acb than low consumers, regardless of sex. Taken together, these findings suggest that sex differences, such as MOR distribution, modulate the consumption of different drugs, which appear to be intrinsic differences that are not linked to a specific psychoactive substance use. Additionally, it was observed that high ETOH consumption does not necessarily indicate greater vulnerability to psychostimulant use.