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Journal of Neuroscience, Vol 5, 1228-1232, Copyright © 1985 by Society for Neuroscience
A mechanism for glucocorticoid toxicity in the hippocampus: increased neuronal vulnerability to metabolic insults
RM Sapolsky
Glucocorticoids appear capable of damaging or destroying hippocampal
neurons. There is a progressive loss of such neurons with age, and the
process can be prevented by adrenalectomy at mid-age or accelerated by
prolonged exposure to high circulating titers of glucocorticoids. The
present study examines possible mechanisms for this steroid action. Rats
were either adrenalectomized, intact, or treated with corticosterone (CORT)
sufficient to produce prolonged elevations of titers in the high
physiological range. After 1 week, unilateral hippocampal microinfusions
were made with either kainic acid (KA) or 3- acetylpyridine (3-AP). Doses
of these hippocampal neurotoxins were chosen to produce small-sized
lesions. Treatment with CORT exacerbated the extent of damage following
neurotoxin infusion, whereas adrenalectomy attenuated the damage.
Additional studies eliminated some potential mechanisms for this
phenomenon. CORT did not directly alter the intrinsic toxicity of the
compounds but, rather, altered the sensitivity of target cells to them. As
evidence, no potentiation of damage in CORT-treated animals occurred in
KA-sensitive brain regions lacking CORT receptors. Since CORT did not
increase the diffusion or binding of [3H]KA in the hippocampus, it appears
unlikely that CORT potentiated toxin-induced damage by influencing the
specific mechanism of action of any toxin. Finally, the general nature of
the CORT potentiation of damage was supported by the markedly different
postulated mechanisms of toxicity of KA and 3-AP. We hypothesize that CORT
exerts its extensive catabolic effects upon target cells to produce
generalized metabolic vulnerability in hippocampal neurons possessing high
concentrations of CORT receptors, thereby sensitizing them to varied
metabolic insults.
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