Chronic Exposure to Anabolic Androgenic Steroids Alters Neuronal Function in the Mammalian Forebrain via Androgen Receptor- and Estrogen Receptor-Mediated Mechanisms

Abstract

Anabolic androgenic steroids (AAS) can promote detrimental effects on social behaviors for which GABA type A (GABA A ) receptormediated circuits in the forebrain play a critical role. While all AAS bind to androgen receptors (AR), they may also be aromatized to estrogens and thus potentially impart effects via estrogen receptors (ER). Chronic exposure of wild-type male mice to a combination of chemically distinct AAS increased action potential (AP) frequency, selective GABA A receptor subunit mRNAs, and GABAergic synaptic current decay in the medial preoptic area (mPOA). Experiments performed with pharmacological agents and in AR-deficient Tfm mutant mice suggest that the AAS-dependent enhancement of GABAergic transmission in wild-type mice is AR-mediated. In AR-deficient mice, the AAS elicited dramatically different effects, decreasing AP frequency, spontaneous IPSC amplitude and frequency and the expression of selective GABA A receptor subunit mRNAs. Surprisingly, in the absence of AR signaling, the data indicate that the AAS do not act as ER agonists, but rather suggest a novel in vivo action in which the AAS inhibit aromatase and impair endogenous ER signaling. These results show that the AAS have the capacity to alter neuronal function in the forebrain via multiple steroid signaling mechanisms and suggest that effects of these steroids in the brain will depend not only on the balance of AR-versus ER-mediated regulation for different target genes, but also on the ability of these drugs to alter steroid metabolism and thus the endogenous steroid milieu.

Intratumoral Localization of Aromatase and Interaction between Stromal and Parenchymal Cells in the Non–Small Cell Lung Carcinoma Microenvironment

“…In our present study, we also showed that the AR blocker flutamide also exerted inhibitory effects on estradiol production as a result of conversion from testosterone. Androgens were reported to stimulate aromatase expression/activity through an AR-dependent pathway in rodent brains (32,33). Therefore, aromatase expression was inhibited by blocking of AR-dependent transcription in lung carcinoma cell lines.…”

The Sturm und Drang of anabolic steroid use: angst, anxiety, and aggression

“…These studies suggest that both AR-dependent and AR-independent signaling are important in the ability of AAS to increase aggression in mice. AAS can also have important effects by indirectly altering signaling via ER by their ability to allosterically inhibit aromatase, thus limiting the availability of endogenous estrogens[77]. Furthermore, they may havekey non-receptor-mediated effects on both aggression and anxiety through their ability to decrease the biosynthesis of endogenous neurosteroids [66,68,77].…”

Corticotropin-Releasing Factor Modulation of Forebrain GABAergic Transmission has a Pivotal Role in the Expression of Anabolic Steroid-Induced Anxiety in the Female Mouse

“…Behavioral testing commenced at BPN55, and treatment with either AAS or oil was continued during testing. AAS treatment imposes an anestrous state characterized by diestras-like profiles (Blasberg and Clark, 1997;Penatti et al, 2009aPenatti et al, , 2011, and control mice were assessed in diestras (Cooper et al, 1993). In some experiments, PN55 diestras female mice that had not received any injections (naïve) were used.…”

“…In some experiments, either 100 mM picrotoxin or 1 mM strychnine (Sigma) were added to the recording bath to block GABA A or glycine receptors, respectively. All physiological data was acquired and stored using a HEKA-EPC9 amplifier (HEKA Instruments, Bellmore, NY, USA) (Penatti et al, 2005(Penatti et al, , 2009a(Penatti et al, , b, 2010(Penatti et al, , 2011.…”

“…Patterning was determined using autocorrelation analysis and classified as regular, irregular, or 'bursty' (Penatti et al, 2009a(Penatti et al, , b, 2010(Penatti et al, , 2011. Autocorrelational profiles correlated with the coefficient of variation (CV) of AP firing: the bursty pattern with high CVs (X4), the irregular pattern with CVs between 0.5 and 2.5, and the regular pattern with CVs o0.5.…”