Prolonged exposure to hypobaric hypoxia transiently reduces GABA(A) receptor number in mice cerebral cortex.
The central nervous system is severely affected by hypoxic conditions, which produce alterations in neural cytoarchitecture and neurotransmission, resulting in a variety of neuropathological conditions such as convulsive states, neurobehavioral impairment and motor CNS alterations. Some of the neuropathologies observed in hypobaric hypoxia, corresponding to high altitude conditions, have been correlated with a loss of balance between excitatory and inhibitory neurotransmission, produced by alterations in glutamatergic and GABAergic receptors. In the present work, we have studied the effect of chronic hypobaric hypoxia (506 hPa, 18 h/day x 21 days) applied to adult male mice on GABA(A) receptors from cerebral cortex, to determine whether hypoxic exposure may irreversibly affect central inhibitory neurotransmission. Saturation curves for [3H]GABA specifically bound to GABA(A) receptors in isolated synaptic membranes showed a 30% decrease in maximal binding capacity after hypoxic exposure (Bmax control, 4.70+/-0.19, hypoxic, 3.33+/-0.10 pmol/mg protein), with no effect on GABA binding sites affinity (Kd control: 159.3+/-13.3 nM, hypoxic: 164.2+/-15.1 nM). Decreased B(max) values were observed up to the 10th post-hypoxic day, returning to control values by the 15th post-hypoxic day. Pharmacological properties of GABA(A) receptor were also affected by hypoxic exposure, with a 45 to 51% increase in the maximal effect by positive allosteric modulators (pentobarbital and 5alpha-pregnan-3alpha-ol-20-one). We conclude that long-term hypoxia produces a significant but reversible reduction on GABA binding to GABA(A) receptor sites in cerebral cortex, which may reflect an adaptive response to this sustained pathophysiological state.
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, FMRP-USP, 3900 Bandeirantes Ave., 14049-900 Ribeirão Preto, São Paulo, Brazil. viapiano@rfa.fmrp.usp.br
M S
MS
Viapiano
A M
AM
Mitridate de Novara
S
S
Fiszer de Plazas
C E
CE
Bozzini
D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism; D001640:Bicuculline / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism*; D003900:Desoxycorticosterone / Q000031:analogs & derivatives* / Q000378:metabolism; D018756:GABA Antagonists / Q000378:metabolism; D018757:GABA Modulators / Q000378:metabolism; D002534:Hypoxia, Brain / Q000378:metabolism*; D008297:Male; D051379:Mice; D010424:Pentobarbital / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism*
D014151:Anti-Anxiety Agents; D018756:GABA Antagonists; D018757:GABA Modulators; D011963:Receptors, GABA-A; D003900:Desoxycorticosterone; C009413:tetrahydrodeoxycorticosterone; D010424:Pentobarbital; D001640:Bicuculline