Anabolic steroids induce region- and subunit-specific rapid modulation of GABA(A) receptor-mediated currents in the rat forebrain.

Anabolic-androgenic steroids (AAS) have become significant drugs of abuse in recent years with the highest increase reported in adolescent girls. In spite of the increased use of AAS, the CNS effects of these steroids are poorly understood. We report that in prepubertal female rats, three commonly abused AAS, 17alpha-methyltestosterone, stanozolol, and nandrolone, induced rapid and reversible modulation of GABAergic currents in neurons of two brain regions known to be critical for the expression of reproductive behaviors: the ventromedial nucleus of the hypothalamus (VMN) and the medial preoptic area (mPOA). All three AAS significantly enhanced peak synaptic current amplitudes and prolonged synaptic current decays in neurons of the VMN. Conversely all three AAS significantly diminished peak current amplitudes of synaptic currents from neurons of the mPOA. The endogenous neuroactive steroids, 3alpha-hydroxy-5alpha-pregnan-20-one and 5alpha-androstane-3alpha,17beta-diol, potentiated currents in the VMN as did the AAS. In contrast to the negative modulation induced by AAS in the mPOA, the endogenous steroids potentiated responses in this region. To determine the concentration response relationships, modulation by the AAS, 17alpha-methyltestosterone (17alpha-meT), was assessed for currents evoked by ultrafast perfusion of brief pulses of GABA to acutely isolated neurons. Half-maximal effects on currents elicited by 1 mM GABA were elicited by submicromolar concentrations of AAS for neurons from both brain regions. In addition, the efficacy of 10(-5) to 10(-2) M GABA was significantly increased by 1 microM 17alpha-meT. Previous studies have demonstrated a striking dichotomy in receptor composition between the VMN and the mPOA with regard to gamma subunit expression. To determine if the preferential expression of gamma(2) subunit-containing receptors in the VMN and of gamma(1) subunit-containing receptors in the mPOA could account for the region-specific effects of AAS in the two regions, responses elicited by ultrafast perfusion of GABA to human embryonic kidney 293 cells transfected with alpha(2), beta(3), and gamma(2) or alpha(2), beta(3), and gamma(1) subunit cDNAs were analyzed. As with native VMN neurons, positive modulation of GABA responses was elicited for alpha(2)beta(3)gamma(2) recombinant receptors, while negative modulation was induced at alpha(2)beta(3)gamma(1) receptors as in the mPOA. Our data demonstrate that AAS in doses believed to occur in steroid abusers can induce significant modulation of GABAergic transmission in brain regions essential for neuroendocrine function. In addition, the effects of these steroids can vary significantly between brain regions in a manner that appears to depend on the subunit composition of GABA(A) receptors expressed.