Anabolic androgenic steroid (AAS) abuse, once largely limited to elite athletes, has spread to a wider population that includes adolescents along with adults, and girls as well as boys. While the psychological and behavioral consequences of AAS use presumably reflect its impact on a number of brain areas, a NIDA-funded study at Dartmouth Medical School has identified one neurobiological effect that has potentially important implications for the emotional stability and well-being of adolescent girls in particular.
Principal investigator Dr. Leslie Henderson and colleagues studied the effect of the AAS, 17α-methyltestosterone (17α-MeT), on the activity of the neurotransmitter gamma-aminobutyric acid (GABA) in adolescent mice. Loosely speaking, GABA acts as a calming agent throughout the nervous system: It dampens activity of the neurons to which they are connected. Specifically, the researchers focused on the steroid's impact on GABA functioning in the medial preoptic area (MPOA) of the basal forebrain, a region that participates in the regulation of sexual behavior, anxiety, and aggression. They found that in female, but not male, animals the AAS interfered with GABA transmission in the area. Theoretically, this effect would reduce GABA's inhibitory influence and thus potentially contribute to the excessive emotions and behaviors seen in AAS abuse. Various studies have linked increased anxiety and aggression, and both increased and decreased libido to AAS use.
"The GABA system isn't the only target for the effects of AAS, but it is likely an important one," Dr. Henderson says. "Going into the experiment, we assumed we'd see an anabolic steroid effect on the GABA system in the MPOA and expected there would be differences between males and females." This area of the brain, particularly the cluster of neurons within it called the medial preoptic nucleus (MPN), is structurally different in the sexes.
Drug Targets Receptors
The researchers injected mice with a solution of 17α-MeT in sesame oil, in doses (7.5 mg/kg/d) that would correspond to those taken by humans who are abusing the drug heavily. They injected a control group of mice with the sesame oil vehicle alone. The researchers examined brain tissue from half the mice in each group after 3 weeks of treatment and from the other half after 6 weeks. They focused on the subunits that make up GABA type A receptors (GABAA) in cells of the MPN and on the way that AAS exposure affected the function of these receptors. Each receptor contains five of these subunits, proteins that determine the receptor's sensitivity to drugs and hormones.
To test how the reduction in α2 subunit production might affect GABAA receptor function, the researchers measured the amplitude and frequency of inhibitory postsynaptic currents (IPSCs)—a measure of the receptor's efficacy in inhibiting the activity of neurons—in the MPN. Here, too, they found sex-based differences that were magnified by AAS. In untreated mice, the IPSCs were smaller in amplitude in females than in males. Female mice that received 3 to 4 weeks of AAS displayed smaller and less frequent currents than controls, suggesting that exposure to the drug had reduced GABAA receptor function, thereby widening the gender gap. There was no comparable change in males.
The researchers concentrated on the α2 subunit family, which earlier studies had shown that 17α-MeT alters. Before treatment, levels of messenger RNA (mRNA) for the α2 subunit were lower in female than in male mice in cells of the MPN. After 6 weeks, α2 subunit mRNA—an indicator of the quantity of the subunit being produced—had declined by 37 percent in female mice treated with the AAS compared with controls, but was essentially unchanged in males. When the researchers measured the actual protein that makes up the α2 subunit in female mice, they found a small but significant reduction (8 percent) in the number of neurons containing α2 protein.
Chronic exposure to of the AAS augmented gender differences in both the structure and function of certain GABA receptors, Dr. Henderson says. "Overall, the effect was to decrease GABA transmission in the MPN of female, but not male, adolescent mice. This would presumably increase the level of activity or change the pattern of activity in postsynaptic neurons of the female mice."
A Closer Look
How do these neurobiological changes contribute to the behavioral manifestations of AAS abuse? "It could be that an AAS that promotes aggression in males would promote it more in females, or have different effects on the expression of sexual behaviors, but this is something we are just beginning to explore," Dr. Henderson says. "What's more, there are 60 to 100 AAS, and their neurobiological effects are unlikely to be uniform. In time, we may be able to start parsing out whether certain commonly abused steroids are likely to amplify aggression and libido in women or in men while others affect both genders equally."
Dr. Henderson notes that alterations in GABAA receptor function could have other important effects as well. "The GABAA receptor is a major target of many drugs, including alcohol and benzodiazepines. Changing the subunit composition could alter the brain's sensitivity to these chemicals."
"Although this is a basic research study, its potential translation to humans, even if speculative, is striking," says Dr. Pushpa Thadani, formerly of NIDA's Division of Basic Neuroscience and Behavioral Research. "It demonstrates that AAS exposure in the adolescent period produces gender-specific changes at the molecular level that may be correlated with known behavioral outcomes."
Although applying findings from this and similar studies in actual interventions remains a distant goal, "these studies advance our understanding of the actions of AAS on the brain and behavior, which can empower us to better educate the lay public on the harmful effects associated with abuse," Dr. Thadani says. "The research is still in its infancy," she observes. Other studies, now under way, are seeking to clarify the links between aggression in female mice and AAS-associated neurobiological changes. "When these findings are available, we'll probably be in a better position to translate this information into the human arena."
Penatti, C.A.A., et al. Sex-specific effects of chronic anabolic androgenic steroid treatment on GABAA receptor expression and function in adolescent mice. Neuroscience 135(2):533-543, 2005. [Abstract]