Elsevier

Neuroscience

Volume 138, Issue 3, 27 March 2006, Pages 793-799
Neuroscience

Anabolic androgenic steroids and forebrain GABAergic transmission

https://doi.org/10.1016/j.neuroscience.2005.08.039Get rights and content

Abstract

Anabolic androgenic steroids are synthetic derivatives of testosterone designed for therapeutic purposes, but now taken predominantly as drugs of abuse. The most common behavioral effects associated with anabolic androgenic steroid use are changes in anxiety, aggression and reproductive behaviors, including the onset of puberty and sexual receptivity. GABAergic circuits in the forebrain underlie these behaviors and are regulated by gonadal steroids. Work from our laboratories has shown that the expression and function of GABAA receptors in the rat and mouse forebrain varies between the sexes and across the estrous cycle. We have also shown that there are significant changes in GABAA receptor expression that occur with the progression through puberty to adulthood. Because GABAergic systems are both steroid-sensitive and critical for the expression of behaviors altered with anabolic androgenic steroid use, forebrain GABAA receptors are an attractive candidate to assess how molecular actions of anabolic androgenic steroids may be translated to known behavioral outcomes. Our studies demonstrate that anabolic androgenic steroids elicit both acute modulation of GABAA receptor-mediated currents, as well as chronic regulation of GABAA receptor expression and forebrain GABAergic transmission. Because anabolic androgenic steroid use has now become prevalent not only among adolescent boys, but in an increasing number of adolescent girls, we have also been particularly interested in determining age- and sex-specific effects of anabolic androgenic steroids. Our data show that the effects of chronic anabolic androgenic steroid exposure can be greater for adolescent than adult animals and are more marked in females than in males. These data have particularly important implications with respect to studies we have done demonstrating that chronic anabolic androgenic steroid exposure alters the onset of puberty, estrous cyclicity and sexual receptivity.

Section snippets

GABAA receptors in the mammalian forebrain

In both human abusers and animal models, the most prominent behavioral effects associated with AAS use are changes in aggression, anxiety and reproductive behaviors; all behaviors for which neural transmission mediated by GABA type A (GABAA) receptors in the basal forebrain play a pivotal role. In particular, GABAergic transmission in the medial preoptic area (mPOA), ventromedial nucleus (VMN) and the medial amygdala (MeA) are implicated in the expression of reproductive behaviors, aggression

GABAA receptor subunit gene expression during adolescence

While the popular press has highlighted AAS use by adult body builders and professional athletes, the more insidious use of AAS is among adolescents. Current assessments of children between 12 and 18 years of age indicate a usage prevalence of 2–4%; which is comparable to that for crack cocaine (Johnston et al., 2004). Adolescents are also reported to exhibit a heightened sensitivity to the effects of AAS (for review, Clark and Henderson, 2003). In spite of these facts, nearly all studies to

Regulation of GABAA receptor expression and function by gonadal steroids

The possibility that the AAS may elicit many of their behavioral effects via modulation of forebrain GABAergic transmission is strongly supported by extensive literature demonstrating that natural, gonadal steroids and their derivatives regulate GABAA receptor expression and function (for review, Henderson and Jorge, 2004). In particular, work from our laboratory has shown that GABAA receptor expression and function in the rodent forebrain are dependent upon hormonal state in adult animals.

Chronic AAS exposure alters GABAA receptor subunit expression and function

To determine if chronic exposure to AAS altered GABAA receptor expression and if the effects of AAS depended upon the dose of the steroid or on the age or sex of the animal, we performed semiquantitative RT-PCR analysis for α1, α2, α5, γ1, γ2, and ε subunit mRNAs in the MeA, VMN and mPOA for male and female C57Bl/6J mice given doses of the AAS, 17α-MeT (17α-methyl-4-androsten-17β-ol-3-one), that correspond to either a moderate (0.75mg/kg/day) or high (7.5mg/kg/day) human use regimen (Clark et

AAS-dependent changes in GABAA receptor expression: implications for receptor function

A wide range of psychoactive agents, including the benzodiazepines, ethanol, endogenous neurosteroids, and the AAS, shares, as an important mechanism of action, allosteric modulation of the GABAA receptor. The ability of these compounds to elicit acute changes in receptor function depends upon subunit composition (for review, Clark et al 2004, Henderson and Jorge 2004). Three commonly abused AAS, 17α-MeT, stanozolol and nandrolone, were found to allosterically modulate sIPSCs in a

AAS-dependent changes in GABAA receptor expression: implications for behavior

In adult rats, the AAS, dihydrotestosterone propionate, 17α-MeT, stanozolol, and nandrolone decanoate all inhibit estrogen-induced female sexual behavior at doses that reflect high abuse concentrations in human subjects (Blasberg et al., 1998). The effects of these AAS on estrogen-induced sexual behavior require activity at the AR, since their actions can be blocked by the AR antagonist, flutamide. The neural basis for these effects is not known, but GABAergic transmission in the basal

Conclusions

Despite two decades of well-documented studies of the influence of AAS on behavior, the effects of these synthetic steroids on brain function are only beginning to be explored. The GABAergic system is an attractive candidate for mediating many of the behavioral effects of the AAS, and data from our laboratories indicate that the AAS elicit both acute and chronic changes in this signaling system. It will be of interest to determine if some of the immediate effects noted by AAS users, such as

Acknowledgments

Work from the Henderson and Clark laboratories was supported by the NIH (DA/NS14137 and DA14216 to L.P.H., DA08574 to ASC, and DA06079 to P.Y.).

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