Estradiol impacts the endocannabinoid system in female rats to influence behavioral and structural responses to cocaine
Introduction
There are sex differences in the etiology of drug addiction, with women progressing more rapidly to an addicted state. This is particularly true for psychostimulants, but applies to multiple classes of abused drugs (Becker and Hu, 2008, Carroll et al., 2004). The ovarian hormone estradiol is a key biological factor contributing to this vulnerability in females (Hedges et al., 2010). Clinical research demonstrates that women are more sensitive to the rewarding properties of psychostimulants when endogenous estradiol levels are elevated, and administration of exogenous estradiol further enhances these properties (Justice and de Wit, 1999, Maria et al., 2014, McCance-Katz et al., 2005). Animal models of addiction parallel human reports, in that high estradiol concentrations correspond with greater locomotor responses to psychostimulants, a more rapid acquisition of psychostimulant self-administration, enhanced motivation for psychostimulants, and increased total psychostimulant consumption (Anker and Carroll, 2011, Becker and Hu, 2008, Festa and Quinones-Jenab, 2004, Segarra et al., 2010) Yet, despite the abundance of behavioral observations of the effects of estradiol in females on responsiveness to psychostimulants, little is known regarding the cellular mechanisms underlying these phenomena.
While estradiol was once thought to act solely through a single nuclear estrogen receptor (Couse and Korach, 1999, Klinge, 2001), recent studies have established that estradiol can affect cellular function through multiple receptors, many localized to the surface membrane (Micevych and Kelly, 2012). In addition to GPER-1 (GPR30) and the putative ER-X, and the STX-sensitive receptors (Barton, 2016, Filardo and Thomas, 2012, Qiu et al., 2003, Toran-Allerand et al., 2002), palmitoylation of both ERα and ERβ promotes receptor trafficking to the surface membrane (Meitzen et al., 2013, Pedram et al., 2007). Within the nervous system, these two estrogen receptors functionally couple to metabotropic glutamate receptors (mGluRs) leading to glutamate-independent mGluR signaling (Boulware et al., 2007, Boulware et al., 2005).
Recent work from our lab has identified a putative signaling mechanism through which estradiol can impact structural and behavioral substrates of drug addiction, which in turn may promote a greater vulnerability for female drug abuse. Within medium spiny neurons (MSNs) of the striatum and nucleus accumbens (NAc), estradiol activates ERα coupled to mGluR subtype 5 (mGluR5) (Grove-Strawser et al., 2010). Specific to the NAc core, estradiol induces synaptic plasticity via decreases in dendritic spine density through transactivation of mGluR5 (Peterson et al., 2014). In general, synaptic plasticity within the NAc core is thought to be a neurobiological substrate of drug addiction, and to underlie psychostimulant behavioral sensitization (Dumitriu et al., 2012, Li et al., 2004, Robinson and Kolb, 2004, Waselus et al., 2013). Related, estradiol enhances psychostimulant locomotor sensitization through membrane ER coupling to mGluR5 (Martinez et al., 2014).
Activation of group I mGluRs leads to a variety of other cellular responses, one of which is the release of endogenous cannabinoids (endoCBs) (Alger and Kim, 2011, Wilson and Nicoll, 2002). Upon release from post-synaptic membranes, endoCBs within the CNS retrogradely bind to presynaptic type 1 cannabinoid receptors (CB1Rs). Interestingly, multiple lines of research demonstrate that estradiol enhances endoCB activity in the nervous system of both women and female rodents (Bradshaw et al., 2006, El-Talatini et al., 2010, Gorzalka and Dang, 2012, Huang and Woolley, 2012, Rodríguez de Fonseca et al., 1994, Scorticati et al., 2004). Moreover, similar to estradiol, both endoCBs and CB1Rs have emerged as key endogenous moderators of drug addiction (Olière et al., 2013). Although these lines of evidence were developed independently, an intriguing possibility is that within females, estradiol and endoCBs may act through a common pathway to exert effects on structural plasticity and addiction. At least in male animals, activation of mGluR5 leads to mobilization of endoCBs in the NAc (Jung et al., 2005, Robbe et al., 2002, Uchigashima et al., 2007). Based on these observations, we hypothesized that estradiol activates ERs to initiate mGluR5-dependent endoCB signaling, and that it is the endoCB system that is ultimately responsible for the effects of estradiol on structural and behavioral substrates of drug addiction.
Section snippets
Animals
Female Sprague Dawley rats 12 weeks of age (175–200 g) were ovariectomized at Harlan labs (Indianapolis, IN). Upon arrival at our animal facility animals were housed in pairs, handled daily, and allowed to habituate for one week prior to experimentation. Animals were maintained on a 12 h light-dark cycle (lights on at 6:00 a.m.) with all behavioral testing occurring between 8:30 a.m. and 1:30 p.m. Food and water were available ad libitum. Animal procedures were in accordance with the National
Estradiol-facilitated psychostimulant locomotor sensitization depends on CB1R
Several laboratories have demonstrated that estradiol treatment in females facilitates cocaine-induced sensitization of locomotor responses (Segarra et al., 2010, Sircar and Kim, 1999) More recently, we demonstrated that this effect of estradiol is dependent on activation of mGluR5 (Martinez et al., 2014). As the endoCB system lies downstream of mGluR5 signaling (Jung et al., 2005, Robbe et al., 2002, Uchigashima et al., 2007), we sought to determine whether this effect of estradiol depends on
Discussion
For women, estradiol is a key biological factor contributing to the etiology of addiction. Yet, our understanding of the underlying neural mechanisms through which estradiol acts is still in its infancy. Recent findings indicate that estradiol, through activation of metabotropic glutamate receptor type 5 (mGluR5), structurally remodels nucleus accumbens (NAc) reward circuits (Peterson et al., 2014) and imparts a greater sensitivity to psychostimulants (Martinez et al., 2014). Here we extend
Acknowledgements
This material is based upon work supported by the National Institutes of Health DA035008 (PGM and RLM) and DA040345-01 (BMP) a National Science Foundation Grant No. 00006595 (BMP). We would like to thank Ambrosia Smith, Sonal Napgal and Holly Korthas for assistance with data collection.
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