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 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.

Keywords: cocaine; estradiol; extended access; self-administration; sex differences.

Figure 1

Effect of tamoxifen on ExA cocaine self-administration. (A) Mean (±SEM) cocaine intake (mg/kg) for the no-injection (NO INJ; n = 18), vehicle (VEH; n = 24) and tamoxifen (TAM; n = 20) groups for each of the 10 ExA cocaine self-administration sessions. *Significant group effect (P = 0.048); ^#Significant effect of session (1–2 vs. 3–10, P < 0.0001) (B) Scatterplot of each individual rat’s mean cocaine intake across the 10 days of ExA cocaine self-administration. Solid bars represent the average values within each group (±SEM).

Figure 2

Tamoxifen blocked the development of an enhanced motivation for cocaine. (A) Mean (±SEM) number of cocaine infusions obtained under the progressive-ratio (PR) schedule during each of the three sessions at baseline (PRE) and retest following ExA self-administration and abstinence (POST) for the no-injection (NO INJ; n = 10), vehicle (VEH; n = 16) and tamoxifen (TAM; n = 13) groups. *Significant group effect (P = 0.022); ⁺Significant increase from baseline within the VEH (P = 0.042) and NO INJ groups (P < 0.001). (B) Percent change (±SEM) in the number of infusions obtained at retest following ExA self-administration relative to baseline (PRE) averaged across the three sessions. *Significant difference between the NO INJ and VEH groups (P = 0.044) and the VEH and TAM groups (P = 0.019). (C) Scatterplot of each individual rats’ data for percent change in the number of infusions from baseline to retest. Solid bars represent the average values within each group (±SEM). ⁺Significant increase from zero within each group (NO INJ, P = 0.003; VEH, P = 0.036).

Figure 3

Tamoxifen impaired extinction learning. (A) Mean (±SEM) active-lever responses made during the nine extinction sessions for the no-injection (NO INJ; n = 8), vehicle (VEH; n = 8) and tamoxifen (TAM; n = 7) groups. The dotted line indicates that additional extinction sessions were run for rats that did not meet the extinction criterion within the first six sessions (≤15 responses; one of the eight rats in the NO INJ and VEH groups and six of the seven rats in the TAM group). *Significant difference between the VEH and TAM groups (session 5, P = 0.017; session 6, P = 0.029; session 7, P = 0.035; session 8, P = 0.007; session 9, P = 0.02); ^#Significant effect of session (1 vs. 2–9, P < 0.0001). (B) Number of sessions required to extinguish responding (≤15 responses). *Unequal distribution across groups. (C) Mean (±SEM) active-lever responses made during the last extinction session and reinstatement test session.

Figure 4

Tamoxifen was associated with an increased ratio of serum estradiol to serum progesterone. (A) Mean (±SEM) serum estradiol concentration in the no-injection (NO INJ, n = 14), vehicle (VEH, n = 12), and tamoxifen (TAM, n = 11) groups. (B) Mean (±SEM) serum progesterone concentration. Despite a significant overall effect of group (P = 0.006), Dunnett-corrected pair-wise comparisons to the VEH group were not significant due to a high level of variability in this group. (C) Mean (±SEM) ratio of estradiol to progesterone. *Significant difference between the VEH and TAM groups (P < 0.0001).

Figure 5

Tamoxifen decreased body weight. Mean (±SEM) body weight across 10 phases of study for the no-injection (NO INJ, n = 18), vehicle (VEH, n = 24), and tamoxifen (TAM, n = 20) groups. *Significant difference between the VEH and TAM groups (P’s < 0.0001). FR, fixed ratio; PR, progressive-ratio; ExA, extended-access; WD, withdrawal/abstinence.