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