PMID- 10848550
OWN - NLM
STAT- MEDLINE
DCOM- 20000712
LR  - 20171213
IS  - 0022-3077 (Print)
IS  - 0022-3077 (Linking)
VI  - 83
IP  - 6
DP  - 2000 Jun
TI  - Anabolic steroids induce region- and subunit-specific rapid modulation of GABA(A) 
      receptor-mediated currents in the rat forebrain.
PG  - 3299-309
AB  - 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.
FAU - Jorge-Rivera, J C
AU  - Jorge-Rivera JC
AD  - Department of Physiology, Dartmouth Medical School, Hanover, New Hampshire 03755, 
      USA.
FAU - McIntyre, K L
AU  - McIntyre KL
FAU - Henderson, L P
AU  - Henderson LP
LA  - eng
GR  - NS-28668/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PT  - Retracted Publication
PL  - United States
TA  - J Neurophysiol
JT  - Journal of neurophysiology
JID - 0375404
RN  - 0 (Anabolic Agents)
RN  - 0 (Ion Channels)
RN  - 0 (Receptors, GABA-A)
RN  - 4R1VB9P8V3 (Stanozolol)
RN  - 56-12-2 (gamma-Aminobutyric Acid)
RN  - 6PG9VR430D (Nandrolone)
RN  - V9EFU16ZIF (Methyltestosterone)
SB  - IM
CIN - NIH Guide Grants Contracts. 2007 Aug 17;:NOT-OD-07-086. PMID: 17715513
RIN - J Neurophysiol. 2007 Sep;98(3):1841. PMID: 17846256
MH  - Anabolic Agents/*pharmacology
MH  - Animals
MH  - Cell Line
MH  - Dose-Response Relationship, Drug
MH  - Excitatory Postsynaptic Potentials/drug effects/physiology
MH  - Female
MH  - Humans
MH  - In Vitro Techniques
MH  - Ion Channels/*drug effects
MH  - Kinetics
MH  - Methyltestosterone/pharmacology
MH  - Nandrolone/pharmacology
MH  - Preoptic Area/cytology/drug effects
MH  - Prosencephalon/*drug effects
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, GABA-A/*drug effects
MH  - Stanozolol/pharmacology
MH  - Synapses/drug effects
MH  - Ventromedial Hypothalamic Nucleus/cytology/drug effects
MH  - gamma-Aminobutyric Acid/physiology
EDAT- 2000/06/10 09:00
MHDA- 2000/07/15 11:00
CRDT- 2000/06/10 09:00
PHST- 2000/06/10 09:00 [pubmed]
PHST- 2000/07/15 11:00 [medline]
PHST- 2000/06/10 09:00 [entrez]
AID - 10.1152/jn.2000.83.6.3299 [doi]
PST - ppublish
SO  - J Neurophysiol. 2000 Jun;83(6):3299-309. doi: 10.1152/jn.2000.83.6.3299.