Acquisition of cocaine self-administration in ovariectomized female rats: Effect of estradiol dose or chronic estradiol administration

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Abstract

This study was conducted to investigate whether the dose of estradiol (E) administered acutely, or chronic delivery of one dose of E impacts acquisition and subsequent cocaine self-administration in ovariectomized (OVX) female rats. Five groups of female rats were compared: OVX females treated with 0, 1, 2, or 5 μg 17β-E, 30 min prior to the self-administration session, and OVX rats that received a 1.5 mg E pellet (designed to chronically release 25 μg E/day X 60 days) implanted 1 week before cocaine self-administration initiation. Rats were tested in 1 h sessions on a FR1 schedule with the dose of cocaine increasing every week (testing occurred 5 day/week; doses: 0.2, 0.3, 0.4, 0.5 and 0.75 mg/(kg infusion)). We report that OVX rats treated with 2 μg E acquired self-administration more rapidly than all of the other groups, and animals that received 1 or 2 μg E self-administered significantly more cocaine compared to OVX + vehicle at 0.3 and 0.4 mg/(kg infusion). In contrast, OVX rats given 5 μg E acutely, or chronic E via slow-release pellets did not take more cocaine than the OVX + vehicle group at any time point. Physiological serum concentrations of E were seen with 1 or 2 μg E, but 5 μg E and the E pellet produced supra-physiological concentrations. These results suggest an inverted U-shaped dose–response curve for the effect of E on acquisition of cocaine self-administration.

Introduction

Cocaine abuse by women has increased rapidly in the last decade, and it is estimated that approximately 600,000 of the 2 million estimated cocaine users are now women (Substance Abuse and Mental Health Service Administration, 2007). Women are more likely to use cocaine at an earlier age and with a greater frequency (Lynch et al., 2002, Johnston et al., 2006). After their first use of cocaine, women tend to take less time to become addicted, they enter treatment sooner and when they enter treatment their cocaine habit is more severe than is usually seen in men seeking treatment (Griffin et al., 1989, Kosten et al., 1993, Mendelson et al., 1999, Carroll et al., 2004). Women also reported stronger cravings in response to cocaine cues than do men (Robbins et al., 1999), and the hormones of the menstrual cycle modulate the subjective value of psychomotor stimulants (Justice and de Wit, 1999, Justice and de Wit, 2000).

Similar to women, female rats are more sensitive to the psychomotor activating effects of psychostimulants than are males. Female rats show greater behavioral sensitization after repeated cocaine injections than do male rats (Glick and Hinds, 1984, van Haaren and Meyer, 1991, Chin et al., 2002, Hu and Becker, 2003). They also acquire cocaine self-administration more readily than male rats (Lynch and Carroll, 1999, Lynch et al., 2001, Carroll et al., 2002, Hu et al., 2004).

Estradiol (E) is thought to modulate the reinforcing effects of cocaine (Roberts et al., 1989, Grimm and See, 1997, Lynch et al., 2000, Lynch et al., 2001, Carroll et al., 2002, Hu et al., 2004, Jackson et al., 2006). For example, female rats will work harder for cocaine during estrus than during other phases of the estrous cycle (Roberts et al., 1989, Carroll et al., 2002) and E treatment given to ovariectomized (OVX) rats enhances the motivation to self-administer cocaine (Becker and Hu, 2007). When various doses of cocaine are available, female rats choose higher doses of cocaine during estrus than during other phases of the estrous cycle (Lynch et al., 2000). OVX females given E replacement acquire cocaine self-administration faster, and at lower doses of cocaine, than do OVX females or male rats treated with vehicle (Hu et al., 2004). Finally, E does not enhance cocaine self-administration in male rats (Jackson et al., 2006).

In most previous studies, only a single dose of E has typically been used, and the doses of E used by various laboratories can be quite different. The current study was conducted to investigate whether the dose of E given acutely vs. chronic E delivery impacts acquisition of cocaine self-administration and subsequent cocaine taking behavior in OVX female rats.

Section snippets

Subjects

Adult female Sprague–Dawley rats weighed 250–300 g at the beginning of the experiment (Harlan Sprague–Dawley, Indianapolis, IN). Animals were housed individually under a 14:10 reverse light:dark cycle at a constant temperature of 20–21 °C, and received a phytoestrogen-free rodent chow (2014 Teklad global 14% protein rodent maintenance diet, Harlan Teklad, Madison, WI); carbon filtered tap water (to remove environmental contaminants) was continuously available. All the procedures were carried out

Serum E concentrations

As shown in Table 1, the injections of E induced a dose-dependent increase in serum E concentrations. The serum E concentrations achieved 1 h after one s.c. injection with 1 or 2 μg E were in the physiological range for the proestrus rat (Butcher et al., 1974, Henderson et al., 1977a, Henderson et al., 1977b), and returned to OVX levels within 24 h. There was no difference in the serum E concentration seen 1 h after the fifth injection of 1 or 2 μg E (over 5 consecutive days) when compared with

Discussion

In the present study, we replicated our earlier observation that acute E facilitates the acquisition of cocaine self-administration behavior in OVX rats (Hu et al., 2004). More importantly, we find that the effect of acute E on acquisition of cocaine self-administration has an inverted U-shaped dose–response curve with an apparent peak effect around 400 pg/ml E in serum (estimated from serum concentrations in separate groups of rats). In contrast, OVX rats with E pellets that deliver a high dose

Conflict of interest

There are no conflicts of interest to report.

Acknowledgements

Funding for this study was provided by NIDA grant 012677; the NIDA had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.

Contributors: Hu and Becker designed the study and wrote the protocol, managed the literature searches and summaries of previous related work, and conducted the statistical analysis. Hu wrote the first draft of the manuscript. All authors contributed to

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