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 i n recent years with the highest increase reported in adolescent girls. In s pite of the increased use of AAS, the CNS effects of these steroids are poo rly understood. We report that in prepubertal female rats, three commonly a bused AAS, 17 alpha-methyltestosterone, stanozolol, and nandrolone, induced rapid and reversible modulation of GABAergic currents in neurons of two br ain regions known to be critical for the expression of reproductive behavio rs: the ventromedial nucleus of the hypothalamus (VMN) and the medial preop tic area (mPOA). All three AAS significantly enhanced peak synaptic current amplitudes and prolonged synaptic current decays in neurons of the VMN. Co nversely all three AAS significantly diminished peak current amplitudes of synaptic currents from neurons of the mPOA. The endogenous neuroactive ster oids, 3 alpha-hydroxy-5 alpha-pregnan-20-one and 5 alpha-androstane-3 alpha ,17 beta-diol, potentiated currents in the VMN as did the AAS. In contrast to the negative modulation induced by AAS in the mPOA, the endogenous stero ids potentiated responses in this region. To determine the concentration re sponse relationships, modulation by the AAS, 17 alpha-methyltestosterone (1 7 alpha-meT), was assessed for currents evoked by ultrafast perfusion of br ief pulses of GABA to acutely isolated neurons. Half-maximal effects on cur rents elicited by 1 mM GABA were elicited by submicromolar concentrations o f AAS for neurons from both brain regions. In addition, the efficacy of 10( -5) to 10(-2) M GABA was significantly increased by 1 mM 17 alpha-meT. Prev ious studies have demonstrated a striking dichotomy in receptor composition between the VMN and the mPOA with regard to gamma subunit expression. To d etermine if the preferential expression of gamma(2) subunit-containing rece ptors in the VMN and of gamma(1) subunit-containing receptors in the mPOA c ould account for the region-specific effects of AAS in the two regions, res ponses elicited by ultrafast perfusion of GABA to human embryonic kidney 29 3 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, p ositive 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 modulatio n of GABAergic transmission in brain regions essential for neuroendocrine f unction. In addition, the effects of these steroids can vary significantly between brain regions in a manner that appears to depend on the subunit com position of GABA(A) receptors expressed.