Tamoxifen Blocks the Development of Motivational Features of an Addiction-Like Phenotype in Female Rats

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 ovaryintact 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; 4discrete 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.

Sex differences in the neuroadaptations associated with incubated cocaine-craving: A focus on the dorsomedial prefrontal cortex

“…However, future studies are necessary to determine whether the phase of the estrous cycle impacts cocaine-craving following 2 days of withdrawal and whether ovarian hormones contribute to the modestly accelerated time-course for the incubation of cocaine craving in females. This question is important considering evidence indicating that estradiol underlies the accelerated course in females for the development of other key addiction-like features, such as an enhanced motivation for cocaine (Ramôa et al, 2013(Ramôa et al, , 2014Bakhti-Suroosh et al, 2019).…”

Effects of Sex and Estrous Cycle on the Time Course of Incubation of Cue-Induced Craving following Extended-Access Cocaine Self-Administration

“…Tamoxifen is an estrogen receptor modulator that antagonizes both estrogen receptor alpha and beta and has been shown to inhibit estradiol-dependent behaviors such as mating behavior (e.g., Wilson et al, 2003). While chronic tamoxifen treatment prevented the increase in motivation for cocaine normally observed in female rats following cocaine self-administration, it did not reduce cocaine seeking behavior during extinction and cue-induced reinstatement tests (Bakhti-Suroosh et al, 2019), in support of findings that other hormones such as progesterone may instead play a critical role (e.g., Feltenstein and See, 2007;Sinha et al, 2007). However, these studies involved chronic suppression of estradiol-dependent signaling, making it difficult to assess how changes in estradiol fluctuations across the estrous cycle influence relapse vulnerability.…”

Estradiol Enhances the Development of Addiction-Like Features in a Female Rat Model of Opioid Use Disorder

“…Additionally, estradiol is critical for the development of key features of an addiction-like phenotype such as an enhanced motivation for the drug and a preference for the drug over other reward alternatives. For example, our previous studies with cocaine show that both OVX and pharmacological blockade of estradiol via treatment with the selective estrogen receptor modular tamoxifen in ovary-intact females effectively block the development of an enhanced motivation for cocaine following extended-access self-administration and 14 days of withdrawal, which are optimal conditions for inducing this addiction-like phenotype [26, 27, 33]. Additionally, as with effects on drug intake, this phenotype can be rescued in OVX females with estradiol replacement [26, 27].…”

“…We also used an extended (24 h/day), IntA fentanyl self-administration procedure (2, 5-min trials/h, 10 days) that mimics patterns of drug use observed in humans (i.e., bingeabstinent patterns of use and repeated spiking drug levels; [35]) and has been buprenorphine-validated to induce an addiction-like phenotype in both females and males [i.e., vulnerability to relapse is attenuated following buprenorphine treatment during a 14-day withdrawal period; [36]). Based on previous reports of estradiol increasing extended-access drug self-administration and the subsequent development of an addiction-like phenotype with psychostimulants and alcohol [25][26][27][28][29][30][31][32][33][34], we predicted that estradiol would increase fentanyl intake and subsequent vulnerability to developing addiction-like features with fentanyl.…”