Development of conditioned place aversion to spontaneous morphine withdrawal during estradiol replacement

Abstract

Opiate withdrawal syndrome works as negative reinforcement contributing to the maintenance of drug seeking behavior and consequently relapse. In animal research, withdrawal‐induced conditioned place aversion (CPA) has been widely used to investigate the negative associations formed during drug withdrawal. Studies using it's counterpart (CPP) have reported sex differences with females developing CPP to lower doses of psychostimulants than males, an effect highly dependent on ovarian hormones. It is still unknown how ovarian hormones might affect CPA during spontaneous opiate withdrawal. We hypothesized that in females, estrogen is necessary to develop CPA during spontaneous withdrawal from chronic morphine. Adult ovariectomized female rats (n=27) were exposed to chronic morphine regimen and somatic signs of spontaneous morphine withdrawal were assessed at 14 and 84 hours after morphine cesation. Estradiol replacement (10μg/0.2mL, s.c.) or vehicle (sesame oil) started with the last injection of morphine until sacrifice. At 14 hours following morphine cesation (early withdrawal), we confined them to one side of a dual choice box where the compartments differ in the floor and wall cues. In contrast to our previous observations in normal cycling female rats, morphine treated females with estradiol replacement did not show CPA. These findings suggest that estradiol must be present during the acquisition of dependence and not only during the withdrawal phase for avoidance responses to happen. Supported by 2G12MD007579‐29.