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

J Neurophysiol. 2000 Jun;83(6):3299-309.

Comment in:
    NIH Guide Grants Contracts. 2007 Aug 17;:NOT-OD-07-086.

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

Jorge-Rivera JC, McIntyre KL, Henderson LP.

Department of Physiology, Dartmouth Medical School, Hanover, New Hampshire 03755,
USA.

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.