Acute ovarian hormone treatment in freely cycling female rats regulates distinct aspects of heroin seeking

Abstract

Females are at higher risk for certain opioid addictive behaviors, but the influence of ovarian hormones is unknown. In our rat model of heroin self-administration, females exhibited higher relapse rates that correlated with rates of heroin seeking on the first extinction session. We administered estradiol alone, or in combination with progesterone, 30 min prior to the first extinction session in freely cycling, heroin-seeking female rats. Although neither treatment produced long-term effects on relapse, each treatment regulated distinct aspects of heroin seeking. Estradiol treatment enhanced extinction memory retention, whereas the combination treatment acutely reduced expression of heroin seeking.

Figure 1.

Heroin seeking in females versus males. (A) Heroin seeking over the course of heroin self-administration, extinction, and cued reinstatement in female and male rats (Charles River Laboratories). n = 7/group (n = 1 catheter failure/group eliminated). Sidak's post-hoc active versus inactive lever (*) P < 0.05 females, (+) P < 0.05 males. (B) Number of heroin infusions consumed in females and males over the course of self-administration. (C) Heroin seeking on the first day of extinction was higher in females. Sidak's post-hoc males versus females (*) P < 0.05. (D) The extinction index did not differ between sexes. (E) Females relapsed at higher rates on the cued reinstatement test. Sidak's post-hoc males versus females (**) P < 0.0001. (F) Heroin seeking on extinction day 1 correlated with cued relapse rates in females, but not males. All data are mean ± SEM, except data from individual rats shown in (F). Gray bars = inactive presses nested within active presses.

Figure 2.

Estradiol selectively enhances extinction memory retention without altering heroin seeking. (A) Heroin seeking over the course of heroin self-administration, extinction, and cued reinstatement did not differ between groups prior to treatment. n = 7 vehicle (n = 1 statistical outlier excluded, >2 standard deviations from mean); n = 8 estradiol. Sidak's post-hoc active versus inactive lever (*) P < 0.01 vehicle, (+) P < 0.0001 estradiol. (B) Number of heroin infusions over the course of self-administration also did not differ. (C) Heroin seeking on the first day of extinction was not altered by estradiol treatment (15 µg/kg, s.c.; Sigma-Aldrich, E8875) 30 min prior. (D) The extinction index was significantly higher (indicating better extinction) in the estradiol group. Unpaired, two-tailed t-test (*) P < 0.05. (E) Heroin seeking on the second day of extinction was reduced by estradiol treatment the previous day. Unpaired, two-tailed t-test (**) P < 0.01. (F) Estradiol treatment on extinction day 1 did not alter relapse rates on the cued reinstatement test. All data are mean ± SEM. Gray bars = inactive presses nested within active presses.

Figure 3.

Combination treatment with estradiol + progesterone acutely reduces heroin seeking. (A) Heroin seeking over the course of heroin self-administration, extinction, and cued reinstatement did not differ between groups prior to treatment. n = 8 estradiol; n = 7 estradiol + progesterone (n = 1 statistical outlier excluded, >2 standard deviations from mean). Sidak's post-hoc active versus inactive lever (+) P < 0.001 estradiol, (*) P < 0.05 estradiol + progesterone. (B) Number of heroin infusions over the course of self-administration also did not differ. (C) Heroin seeking on the first day of extinction was reduced by estradiol + progesterone treatment (15 µg/kg estradiol + 2 mg/kg progesterone, s.c.; Sigma-Aldrich, P0130) 30 min prior. Sidak's post-hoc estradiol versus estradiol + progesterone (**) P < 0.0001 (Unpaired, two-tailed t-test P < 0.05). (D) The extinction index did not differ between the combination treatment group versus estradiol alone. (E) Heroin seeking on the second day of extinction was not significantly different between treatments (P = 0.098). (F) Neither treatment on extinction day 1 altered relapse rates on the cued reinstatement test. All data are mean ± SEM. Gray bars = inactive presses nested within active presses.