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

Abstract

Increased anxiety is commonly observed in individuals who illicitly administer anabolic androgenic steroids (AAS). Behavioral effects of steroid abuse have become an increasing concern in adults and adolescents of both sexes. The dorsolateral bed nucleus of the stria terminalis (dlBnST) has a critical role in the expression of diffuse anxiety and is a key site of action for the anxiogenic neuromodulator, corticotropin releasing factor (CRF). Here we demonstrate that chronic, but not acute, exposure of female mice during adolescence to AAS augments anxiety-like behaviors; effects that were blocked by central infusion of the CRF receptor type 1 antagonist, antalarmin. AAS treatment selectively increased action potential (AP) firing in neurons of the central amygdala (CeA) that project to the dlBnST, increased the frequency of GABA(A) receptor-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) in dlBnST target neurons, and decreased both c-FOS immunoreactivity (IR) and AP frequency in these postsynaptic cells. Acute application of antalarmin abrogated the enhancement of GABAergic inhibition induced by chronic AAS exposure whereas application of CRF to brain slices of naïve mice mimicked the actions of this treatment. These results, in concert with previous data demonstrating that chronic AAS treatment results in enhanced levels of CRF mRNA in the CeA and increased CRF-IR in the dlBnST neuropil, are consistent with a mechanism in which the enhanced anxiety elicited by chronic AAS exposure involves augmented inhibitory activity of CeA afferents to the dlBnST and CRF-dependent enhancement of GABAergic inhibition in this brain region.

Maternal testosterone exposure increases anxiety-like behavior and impacts the limbic system in the offspring

“…Supraphysiological doses of androgens cause anxiety-like behavior in female mice and enhance presynaptic release of GABA (37). Anxiety-related behavior has also been associated with altered GABAergic transmission in the amygdala, including altered expression of GABA-synthesizing enzymes GAD65 (Gad2), GAD67 (Gad1), and GABA receptors.…”

Contrasting distribution of physiological cell types in different regions of the bed nucleus of the stria terminalis

“…Indeed, most electrophysiological studies have focused on other aspects of BNST physiology such as the influence of various peptides/transmitters (Grueter et al 2005;Krawczyk et al 2011a;Li et al 2012;Lungwitz et al 2012;McElligott and Winder 2008;Nobis et al 2011;Puente et al 2010;Shields et al 2009), particularly corticotropin releasing factor (Gafford et al 2012;Ide et al 2013;Kash and Winder 2006;Oberlander and Henderson 2012;Silberman et al 2013), mechanisms of addiction and relapse to drug seeking (Conrad et al 2012;Davis et al 2008;Dumont and Williams 2004;Dumont et al 2005Dumont et al , 2008Grueter et al 2008;Kash et al 2008aKash et al ,b, 2009Krawczyk et al 2011b), synaptic plasticity (Weitlauf et al 2005), and the impact of stress (Conrad et al 2011).…”

Mad men, women and steroid cocktails: a review of the impact of sex and other factors on anabolic androgenic steroids effects on affective behaviors

“…Chronic treatment (4 weeks) of female mice during adolescence with a mixture of AAS elicits a consistent increase in anxiety-like behaviors as measured by the acoustic startle response and marble burying assays (Costine et al 2010; Oberlander and Henderson 2012b; Onakomaiya et al 2014), reminiscent of results obtained with prolonged treatment of adult female mice with a mixture of AAS and tested in the open field test (Bronson et al 1996; Table 1). In contrast, a briefer (16 day) treatment of adult female mice with a high dose of a single AAS (17α-methyltestosterone) was reported to have no effect on anxiety-like behaviors as measured on the EPM, light-dark transitions, or defensive behavior tests (Barreto-Estrada et al 2004; Table 1).…”

“…All AAS [and some of their metabolites] have biological activity at nuclear ARs, albeit with varying degrees of efficacy and potency. Additionally, their ability to act via other members of the nuclear hormone receptor family and through non-genomic mechanisms depends on both their synthetic chemical signatures and the high concentrations at which they are consumed (Clark et al, 2003, Henderson, 2007; Penatti and Henderson 2009; Oberlander and Henderson, 2012a; Oberlander 2012a,b; Figure 1). Taken with the fact that the expression and function of both nuclear hormone receptors and the targets of non-genomic AAS actions (e.g., the molecules that comprise GABAergic, glutamatergic, peptidergic and serotonergic signaling pathways) show significant developmental and sex-specific differences, these variables alone provide an expansive template upon which the AAS may impose age- and sex-specific actions (Jorge and Henderson, 2004; Clark et al, 2006; Henderson, 2007; Oberlander et al, 2012a,b).…”

“…While expression of anxiety arises from the coordinate actions of many signaling systems, the CRF family of ligands and receptors in the extended amygdala (Walker et al 2009; Davis et al 2010) and their interaction with the GABAergic projection from the CeA to the BnST have a prominent role in AAS-induced anxiety and in sex-specific differences in AAS-induced anxiety (Costine et al 2010; Oberlander and Henderson 2012a,b; Onakomaiya et al 2014). Elevated levels of CRF in extrahypothalamic areas of the CNS are a hallmark of anxiety and stress disorders in humans (Nemeroff 1988; 1992; Arborelius et al 1999; Holsboer 1999; Reul and Holsboer 2002; Hauger et al 2006, 2009; Holsboer and Ising 2008); central infusion of CRF in rodents stimulates anxiety-like behaviors (Bale and Vale 2004); the BnST is the primary site of the anxiogenic action of CRF; and CRF-dependent enhancement of anxiety-like behaviors in rodents is observed in a wide variety of testing paradigms (Bale and Vale 2004; Davis et al 2010).…”