Abstract
Women become addicted sooner after initiating cocaine use as compared to men. Preclinical studies reveal a similar vulnerability in females, with findings from ovariectomized rats suggesting that estradiol mediates the enhanced vulnerability. However, since ovariectomy depletes not only estradiol, but all ovarian hormones, its role in a physiological context is not clear. Thus, the goal of this study was to determine the role of estradiol in the development of an addiction-like phenotype in ovary-intact females treated chronically with the selective estrogen receptor (ER) modulator tamoxifen. We hypothesized that tamoxifen, by antagonizing ERs, would block the development of an addiction-like phenotype as defined by an enhanced motivation for cocaine (assessed under a progressive-ratio schedule), and a heightened vulnerability to relapse (assessed under an extinction/cue-induced reinstatement procedure). Effects were examined following extended access cocaine self-administration (24-h/day; 4-discrete trials/h; 1.5 mg/kg/infusion) and 14-days of abstinence, conditions optimized for inducing an addiction-like phenotype. As predicted, motivation for cocaine was increased following extended-access self-administration and protracted abstinence in the vehicle (sesame oil) and no-injection control groups, but not in the tamoxifen group indicating that ER signaling is critical for the development of this feature of an addiction-like phenotype. Surprisingly, the increase in motivation for cocaine following abstinence was also attenuated in the vehicle group as compared to no-injection controls suggesting that oil/injections also affected its development. Contrary to our hypothesis, tamoxifen did not decrease vulnerability to relapse as this group responded at similar levels during initial extinction sessions and cue-induced reinstatement testing as compared to controls. Tamoxifen did, however, impair extinction learning as this group took longer to extinguish as compared to controls. Taken together, these findings indicate that estradiol is critical for the extinction of drug-associated cues and the development of motivational features of addiction.
Highlights
Cocaine use is a leading cause of overdose deaths in the U.S, second only to opioids (Hedegaard et al, 2018)
A significant effect of group was observed for cocaine intake (F(2,59) = 3.190, P = 0.048; Figure 1), this effect appears to be due to a non-significant trend for higher intake in the NO INJ group as compared to VEH (P = 0.07); no differences were observed between the VEH and TAM groups
Tamoxifen prevented the increase in motivation for cocaine following extended access (ExA) self-administration and protracted abstinence, suggesting that estrogen receptor (ER) signaling is critical for the development of this feature of an addiction-like phenotype
Summary
Cocaine use is a leading cause of overdose deaths in the U.S, second only to opioids (Hedegaard et al, 2018). Female rats given extended access (ExA) to cocaine (6–24 h/day) take more cocaine and display a greater disruption of diurnal control over intake as compared to males (Lynch and Taylor, 2004, 2005; Roth and Carroll, 2004; Kawa and Robinson, 2019; Nicolas et al, 2019). When conditions are optimized (i.e., 10 days of ExA self-administration and 14 days of abstinence), both males and females show an enhanced motivation for cocaine (Ramôa et al, 2013). These findings are consistent with humans and indicate that the enhanced time-course for the development of cocaine addiction in females is biologically-based
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