Differential effects of allopregnanolone on the escalation of cocaine self-administration and sucrose intake in female rats

Anker, Justin J.; Zlebnik, Natalie E.; Carroll, Marilyn E.

doi:10.1007/s00213-010-1968-7

Cited by 30 publications

(27 citation statements)

References 91 publications

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“…Our finding that E 2 treatment enhanced extinction of cocaine seeking even in ovariectomized rats that were perseverating for up to 5 wk suggests a potentially vital role for E 2 in the recovery from cocaine abuse. The importance of E 2 is underscored by our finding that female rats in the absence of E 2 failed to suppress cocaine seeking during extinction, and may explain why gonadally intact female rats in estrus (low E 2 levels) are more resistant to extinction of drug seeking than are male rats (Kerstetter et al 2008;Anker et al 2010). Therefore, low E 2 levels may increase the risk of relapse in some women, and this risk may be exacerbated by cocaine-induced menstrual cycle disorders (Mello and Mendelson 1997).…”

Section: Discussionmentioning

confidence: 93%

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

et al. 2013

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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...

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Section: Discussionmentioning

confidence: 93%

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

et al. 2013

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“…For example, acute progesterone pretreatment reversed the effects of estradiol on the acquisition of cocaine self-administration (Jackson et al 2006) and cocaine-primed reinstatement (Anker et al 2007) in ovariectomized rats. In addition, the progesterone metabolite, allopregnanolone, blocked the escalation of cocaine self-administration (Anker et al 2010), cocaine-primed reinstatement (Anker et al 2009), and stress-induced reinstatement (Anker and Carroll 2010) in female rats. Taken together, these studies provide strong evidence for the role of gonadal hormones in cocaine abuse vulnerability, with estradiol increasing susceptibility and progesterone decreasing susceptibility.…”

Section: Discussionmentioning

confidence: 99%

The effects of sex, estrous cycle, and social contact on cocaine and heroin self-administration in rats

et al. 2016

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Rationale Preclinical studies indicate that gonadal hormones are important determinants of drug self-administration. To date, little is known about the influence of sex and estrous cycle on drug self-administration in ecologically relevant social contexts. Objective Examine the role of sex and estrous cycle in a rat model during cocaine and heroin self-administration with male-female and female-female social dyads. Methods Male and female virgin rats were trained to self-administer cocaine and heroin in operant conditioning chambers that permitted two rats to self-administer concurrently but prevented physical contact. Experiment 1 examined cocaine self-administration on a progressive-ratio schedule in male-female dyads. Experiments 2 and 3 examined heroin self-administration on a fixed-ratio schedule in male-female dyads at constant and varying doses, respectively. Experiment 4 examined heroin self-administration in female-female dyads on a fixed-ratio schedule. Results Cocaine-maintained breakpoints increased by ~17% in females during estrus but remained consistent in males. Heroin self-administration decreased by ~70% during proestrus in females whether they were isolated, housed with males, or housed with females. Heroin self-administration was lower in males than females under some conditions and was not consistently associated with the responding of females. Conclusions Cocaine and heroin self-administration is influenced by the estrous cycle in females when in the presence of a male partner. As a novel finding, these data illustrate that heroin self-administration is reduced in females during proestrus regardless of the social context tested. Finally, these data suggest that drug self-administration in males is only minimally influenced by the hormonal status of a female partner.

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“…Additionally, the lack of an effect on days 1-3 may have been the result of the change in session length from 2 to 6 hr. Results from several studies indicate that treatment effects and individual differences in LgA cocaine intake often emerge following several days of cocaine self-administration (Anker et al 2011; Gipson et al 2011; Larson et al 2007; Mantsch et al 2008). In contrast to the results in the LgA condition, progesterone enhanced cocaine intake at the lowest cocaine concentration in the LoS rats following the LgA period, thus illustrating a complex interaction between phenotype, treatment, phase, and dose.…”

Section: Discussionmentioning

confidence: 99%

Effects of progesterone on escalation of intravenous cocaine self-administration in rats selectively bred for high or low saccharin intake

Anker

Holtz

Carroll

2012

Behavioural Pharmacology

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Progesterone decreases cocaine self-administration in women and in female rats. In a previous study using rats selectively bred for high (HiS) and low (LoS) saccharin intake, HiS rats escalated their cocaine intake compared to LoS rats. Our goal was to examine the effects of progesterone on the escalation of cocaine self-administration in HiS and LoS rats. Four groups of female rats were compared: HiS P (progesterone-treated), LoS P, HiS VEH (vehicle-treated), and LoS VEH. Rats were trained to self-administer 0.8 mg/kg cocaine i.v. under a fixed-ratio 1 (FR 1) schedule during daily short-access (ShA) 2-h sessions. Rats then self-administered 3 randomly-presented doses of cocaine (0.2, 0.4, 1.6 mg/kg) and then had daily 6-h long-access (LgA) sessions with 0.4 mg/kg cocaine for 21 days. Cocaine intake was then reassessed with the 4 doses under the ShA condition. Throughout the experiment, rats were treated with daily s.c. injections of P (0.5 mg/kg) or an equal volume of VEH 30 min prior to each session. During the initial ShA condition, HiS rats earned more cocaine infusions than LoS rats at all doses, and during the subsequent LgA condition, HiS rats escalated cocaine intake, while the LoS rats maintained a steady rate. Progesterone treatment potentiated escalation of cocaine intake in the HiS rats but had an opposite effect on LoS rats, attenuating their cocaine self-administration. Results from the post-LgA dose-response ShA condition, indicated that both LoS and HiS VEH and P-treated rats earned more infusions than pre-LgA, but mainly at low doses. These results suggest that genetic differences in drug abuse vulnerability contribute differentially to treatment outcomes during escalation, a critical phase of the drug abuse process.

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Differential effects of allopregnanolone on the escalation of cocaine self-administration and sucrose intake in female rats

Cited by 30 publications

References 91 publications

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

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

The effects of sex, estrous cycle, and social contact on cocaine and heroin self-administration in rats

Effects of progesterone on escalation of intravenous cocaine self-administration in rats selectively bred for high or low saccharin intake

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