Influence of preoptic estradiol on behavioral and neural response
to cocaine in female Sprague-Dawley rats
Christopher L. Robison
Julia R. Martz
Juan M. Dominguez
Received: 27 March 2017 / Accepted: 1 November 2017 / Published online: 4 December 2017
Springer-Verlag GmbH Germany, part of Springer Nature 2017
Rationale Systemic estradiol (E2) increases the behavioral and neural response to cocaine. Where in the brain E2 acts to modulate
cocaine response is not entirely clear. Evidence supports a role in this modulation for several candidate regions, including the
medial preoptic area (mPOA).
Objectives This study examined whether manipulation of E2 in the mPOA modulates differing behavioral responses to cocaine
and whether this is reflected in differing levels of c-Fos in the NAc following cocaine administration.
Methods Female rats received ovariectomies and bilateral cannulations of the mPOA. They then received either artificial
cerebrospinal fluid (aCSF) or E2 microinjections into the mPOA the day before receiving systemic injections of saline or cocaine
(5 or 10 mg/kg). Conditioned-place preference (CPP) to cocaine and locomotor activation were then obtained.
Results Animals receiving 10 mg/kg, but not 5 mg/kg, cocaine developed significant CPP, and those receiving E2 into the mPOA
expressed greater CPP than those receiving microinjections of only aCSF at both doses (p <0.05,d > 0.80). Cocaine also caused
significant psychomotor activation, but this was not dependent on microinjection of E2 in the mPOA. Finally, animals that
received cocaine had increased NAc core and shell c-Fos relative to animals that received saline, with animals receiving both E2
microinjections and systemic cocaine expressing the highest activation in the caudal NAc, compared to rats receiving aCSF
microinjections and systemic cocaine (p = 0.05, d =0.70).
Conclusions These results indicate that E2 in the mPOA facilitates the behavioral response and neural activation that follows
cocaine administration. Furthermore, they confirm the close relationship between the mPOA and cocaine response.
Medial preoptic area
The medial preoptic area (mPOA) is a region at the rostral end
of the hypothalamus most widely recognized for its vital role
in the regulation of male sexual behavior (Hull and
Dominguez 2015), female sexual behavior (Graham and
Pfaus 2010), and parental behaviors (Lee and Brown 2007).
Recent evidence indicates that the mPOA also has a more
generalized role in motivated behaviors, such as the response
to drugs of abuse, namely cocaine. Bilateral lesions of the
mPOA significantly increased cocaine-induced c-Fos within
the nucleus accumbens (NAc) without affecting baseline ex-
pression and enhanced cocaine-induced conditioned place
preference (CPP) in female rats (Tobiansky et al. 2013).
Lesions of the mPOA also potentiate the cocaine-induced in-
crease of dopamine in the NAc, as evidenced by microdialysis
experiments performed following lesions (Tobiansky et al.
Sex steroids are potent regulators of the cocaine response.
In both human and rodent studies, estradiol (E2) has been
shown to potentiate the psychoactive effects of cocaine
(Carroll et al. 2004; Festa and Quinones-Jenab 2004). In
humans and non-human primates, sex steroids are a
* Juan M. Dominguez
Department of Psychology, The University of Texas at Austin, 108 E
Dean Keeton, Mail Stop A8000, Austin, TX 78712-1043, USA
Waggoner Center for Alcohol and Addiction Research, The
University of Texas at Austin, Austin, TX, USA
Institute for Neuroscience, The University of Texas at Austin,
Austin, TX, USA
Department of Pharmacology & Toxicology, The University of Texas
at Austin, Austin, TX, USA
Psychopharmacology (2018) 235:663–672