Anabolic androgenic steroids and forebrain GABAergic transmission
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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