Tamoxifen or Estradiol Limited to the Induction Phase of Nicotine Sensitization Enhances the Expression of Locomotor Sensitization in Ovariectomized and in Intact Female Rats

Abstract

In both humans and rodents, females are more vulnerable to addiction than males, which has been linked to higher concentrations of the hormone estradiol in females. In rats, nicotine injections produce greater sensitization (neurological changes responsible for drug cravings) in females than in males, which could contribute to sex differences in susceptibility to addiction. The purpose of these experiments was to investigate the effects of estradiol during three nicotine injections (two consecutive days and a third injection nine days later). Results from these experiments indicate that depletion of estradiol via ovariectomy attenuates nicotine sensitization in females, which can be rescued by estradiol injection limited to the induction phase of sensitization. Administration of tamoxifen (antagonist at nuclear estradiol receptors, agonist of the membrane-bound estradiol receptor GPER1) did not alter sensitization in gonadally intact rats, and was sufficient to restore expression of sensitization in ovariectomized females (similar to estradiol). Findings from these experiments indicate that the enhancing effects of estradiol on nicotine sensitization occur during the induction phase, and may be mediated by membrane bound estrogen receptors (e.g., GPER1).