Role of the α subunit in the modulation of GABA A receptors by anabolic androgenic steroids

Abstract

Neural transmission mediated by circuits expressing α 2 subunit-containing γ-aminobutyric acid type A (GABA A) receptors is critical for the expression of behaviors known to be altered by anabolic androgenic steroids (AAS). Here we show that micromolar concentrations of AAS, which reflect levels found in steroid abusers, induce positive modulation of currents from α 2β 3γ 2L recombinant receptors elicited by pulses of GABA that mimic synaptic conditions in a manner that is mechanistically distinct from modulation induced at α 1β 3γ 2L receptors. Specifically, at α 2-containing receptors, the AAS, 17α-methyltestosterone (17α-MeT) enhanced peak current, slowed deactivation, diminished desensitization, and promoted entry of receptors into more distal states along the activation pathway. Analysis of GABA A receptor-mediated synaptic currents in primary cortical neurons followed by single cell real-time RT-PCR demonstrated that 17α-MeT enhancement of synaptic currents is proportional to the ratio of α 2 to α 1 subunit mRNA. Finally, we show that the modulation elicited by AAS is not comparable to that produced by micromolar concentrations of other positive allosteric modulators at α 2-containing receptors. In sum, these data indicate that AAS elicit effects on GABA A receptor function that depend significantly on α subunit composition and that the mechanism of AAS modulation of GABA A receptors is distinct from that of other positive allosteric modulators.