Impact of pubertal and adult estradiol treatments on cocaine self-administration
Introduction
Men and women are differentially vulnerable to drugs of abuse. Even though more men than women use cocaine and psychotherapeutics, more women show dependence for these substances (Back et al., 2010, Cotto et al., 2010, Elman et al., 2001). The subjective effects of psychostimulants, like euphoria, desire, increased energy and intellectual efficiency, vary across the menstrual cycle. Thus, women report effects that are comparable to those of men when they are in the follicular phase and reduced during the luteal phase (Justice and de Wit, 1999, Justice and de Wit, 2000a, Justice and de Wit, 2000b). During the follicular phase, estradiol administration enhances, whereas progesterone attenuates, the subjective effects of psychostimulants (Justice and de Wit, 2000b). In men, the effects of estradiol on psychostimulant responses have not been examined and the effects of progesterone are ambiguous (Evans and Foltin, 2005, Evans, 2007, Fox et al., 2013, Sofuoglu et al., 2004). Furthermore, it is unclear whether the effects of ovarian hormones on subjective effects of drugs translate into different patterns of psychostimulant use between men and women (Reed et al., 2011, Sofuoglu et al., 2004).
In contrast, estradiol has been shown to have significant effects on drug self-administration in preclinical models, with the majority occurring selectively in females. Estradiol treatment facilitates acquisition of cocaine self-administration, increases cocaine intake and enhances motivation for cocaine in ovariectomized female rats, but has no apparent effects in males (Hu and Becker, 2008, Jackson et al., 2006, Lynch and Carroll, 2001). Male rats are quite capable of responding to estradiol, as it is one of the primary signals required for both the organization and activation of their reproductive behavior (McCarthy, 2008, Ogawa et al., 2000). Current views on sexual differentiation of the brain are largely based on the differentiation of reproductive behavior in males and females, which is driven in large part by perinatal testosterone exposure in males (but not females) and further refinement by sex-specific gonadal hormone profiles during puberty (McCarthy, 2008, Mccarthy and Arnold, 2011, Sisk and Zehr, 2005). During the perinatal period, estradiol primarily functions as a masculinizing hormone, whereas it becomes crucial for female differentiation during puberty (McCarthy, 2008, Stewart and Cygan, 1980).
We have previously proposed that the expression of sex differences in motivated behaviors in adulthood are at least partly mediated by ovarian hormones secreted during puberty, which are essential for feminizing the mesocorticolimbic dopamine system (Becker, 2009). The current experiment was conducted to test whether pubertal estradiol exposure is necessary and/or sufficient for the subsequent feminization of cocaine self-administration behavior in adult rats. We predicted that the self-administration behavior of females would only be sensitive to adult estradiol treatment if they had also been exposed to estradiol during puberty. Conversely, we predicted that pubertal estradiol would not be sufficient to feminize behavior in males, possibly due to the prior masculinizing effects of perinatal testosterone/estradiol.
Section snippets
Animals
Sprague–Dawley rats purchased from Charles Rivers (Portage, MI) were gonadectomized (OVX/CAST) at postnatal day (PD) 22, or remained intact through puberty (pINTACT) (N = 51 per sex). Animals were housed in same-sex groups in standard laboratory cages (2–3 per cage) and maintained on a 14:10 (light:dark) reversed light cycle (lights off at 08:00) and provided free access to rat chow (Teklad Global 14% protein rodent maintenance diet) and carbon-filtered water in a temperature- and
Acquisition of cocaine self-administration on FR1 schedule
Adult EB treatment enhanced acquisition of cocaine self-administration in all female groups irrespective of hormone treatment during puberty (Fig. 1A). Therefore, data were combined into four groups based on sex and adult hormone treatment for survival analyses. Females treated with EB as adults (aEB) acquired cocaine self-administration significantly earlier than aOIL females (χ2 = 4.53, p = 0.033, Cohen's d = 0.67, r = 0.32), whereas there was no effect of adult EB treatment in males. The mean
Discussion
The results of this experiment confirm that estradiol treatment only affects cocaine self-administration in adult females and that pubertal estradiol may be necessary, but is not sufficient, for this subsequent sensitivity to estradiol. Furthermore, the effects of adult estradiol treatment on acquisition, intake and the motivation to self-administer cocaine were differentially sensitive to pubertal estradiol manipulations in females. Our initial hypothesis was based on the assumption that
Acknowledgments
This research was supported by NIDA grants DA012677 (JBB) and DA007268 (T32 Training Grant). The authors thank Brandon Luma for technical assistance.
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These authors contributed equally to this work.