17β-Estradiol is necessary for extinction of cocaine seeking in female rats

Abstract

Human and preclinical models of addiction demonstrate that gonadal hormones modulate acquisition of drug seeking. Little is known, however, about the effects of these hormones on extinction of drug-seeking behavior. Here, we investigated how 17b-estradiol (E 2 ) affects expression and extinction of cocaine seeking in female rats. Using a conditioned place preference (CPP) paradigm, ovariectomized rats were maintained throughout conditioning with 2 d of E 2 treatment followed by 2 d of vehicle treatment, or were injected with E 2 daily. Hormone injections were paired or explicitly unpaired with place conditioning sessions. Expression of a cocaine CPP was of equal magnitude regardless of conditioning protocol, suggesting that E 2 levels during conditioning did not affect subsequent CPP expression. During extinction, daily E 2 administration initially enhanced expression of the cocaine CPP, but resulted in significantly faster extinction compared to controls. Whereas E 2 -treated rats were extinguished within 8 d, vehicle-treated rats maintained CPP expression for more than a month, indicative of perseveration. To determine whether E 2 could rescue extinction in these rats, half were given daily E 2 treatment and half were given vehicle. E 2 -treated rats showed rapid extinction, whereas vehicle-treated rats continued to perseverate. These data demonstrate for the first time that E 2 is necessary for extinction of cocaine seeking in female rats, and that it promotes rapid extinction when administered daily. Clinically, these findings suggest that monitoring and maintaining optimal E 2 levels during exposure therapy would facilitate therapeutic interventions for female cocaine addicts.Gonadal hormones render women more susceptible than men to developing compulsive patterns of psychostimulant use. Natural fluctuations in levels of the primary ovarian hormones, estrogens and progesterone, account for this increased abuse liability. Higher levels of estrogens, and lower levels of progesterone, are associated with greater sensitivity to the euphorigenic properties of cocaine in women (Evans 2007). This increased sensitivity may contribute to why women, compared with men, start using cocaine regularly at a younger age (Chen and Kandel 2002), transition from use to abuse more quickly (McCance-Katz et al. 1999), experience greater craving in response to drug-associated cues (Robbins et al. 1999) and stress (Potenza et al. 2012;Waldrop et al. 2012), and exhibit more severe drug-seeking behavior upon relapse (Gallop et al. 2007). In contrast, more women than men remain abstinent after treatment (Weiss et al. 1997). Thus, women are both more susceptible to cocaine abuse and, paradoxically, more responsive to treatment.A substantial literature supports that estrogens mediate the enhancement of drug seeking observed in females (Febo et al. 2002;Larson et al. 2007;Segarra et al. 2010; Kerstetter and Kippin 2011), but little is known regarding the role of estrogens during treatment. Preclinically, treatment is modeled through ext...

Sex differences in cocaine conditioned place preference in C57BL/6J mice

“…Progesterone attenuates cocaine reward in humans and rats [6,20] and estrogen also plays an important role in cocaine reward. In ovariectomized rats, estradiol itself can induce CPP [21], increase the sensitivity of the brain to reward as measured by intracranial self-stimulation [22], and enhance cocaine CPP [23,24]. The ability of estradiol to enhance cocaine reward may be due to the expression of estrogen receptor alpha (ERα) in the nucleus accumbens, since administration of antisense oligonucleotides targeting ERα into the nucleus accumbens can reduce estradiol-induced CPP [25].…”

“…Hormonal effects in the brain may account for this difference. Estradiol has been shown to facilitate extinction of cocaine CPP in female rats [24] and may be one factor that can account for the sex difference in extinction of cocaine CPP in mice. No sex differences in extinction of cocaine CPP were observed with 5 and 10 mg/kg cocaine, perhaps because lower doses of cocaine are needed to reveal differences or estrous cycle phase effects are masked due to testing in cycling females.…”

17β-Estradiol Potentiates the Reinstatement of Cocaine Seeking in Female Rats: Role of the Prelimbic Prefrontal Cortex and Cannabinoid Type-1 Receptors

“…Bilateral surgical OVXs were conducted using a dorsal approach as previously described (Twining et al, 2013). See Supplementary Methods for more information.…”

“…One caveat of the present study was that rats were surgically ovariectomized to permit precise control over E2 levels during reinstatement testing. Importantly, to avoid effects on cocaine self-administration (Zhao and Becker, 2010;Lynch and Taylor, 2005) and extinction (Twining et al, 2013) that could later confound reinstatement, rats underwent OVX after selfadministration and extinction and just before reinstatement testing. The purpose of the experiment was to reproduce proestrus-level E2 and assess effects on cocaine seeking.…”

Effects of cocaine on aggression and associated central ERα and oxytocin expression in ovariectomized and intact mandarin voles

“…Circulating levels of ovarian hormones, especially estrogen, are a key biological substrate mediating female responses to drugs (Becker & Hu 2008;Segarra et al 2010;Anker & Carroll 2011). For example, estradiol exacerbates the cocaine-induced locomotor response and affects the expression of cocaine-induced conditioned place preference (CPP) in female rats (Segarra et al 2010;Twining et al 2013;Bobzean et al 2014). Effects of ovarian hormone on cocaine-induced behavioral sensitization have been widely researched in female rats (Rattus norvegicus Berkenhout, 1769) (Roberts et al 1987;Sircar & Kim 1999;Quiñones-Jenab et al 2000;Perrotti et al 2001).…”