Glucocorticoids Exacerbate Kainic Acid–Induced Extracellular Accumulation of Excitatory Amino Acids in the Rat Hippocampus

Abstract

Glucocorticoids (GCs) compromise the ability of hippocampal neurons to survive various insults, and do so, at least in part, by exacerbating steps in the glutamate/N-methyl-D-aspartate (NMDA)/calcium cascade of damage. As evidence, GCs impair uptake of glutamate by hippocampal astrocytes, the GC endangerment of the hippocampus is NMDA receptor dependent, and GCs exacerbate kainic acid (KA)-induced calcium mobilization. These observations predict that GCs should also exacerbate KA-induced accumulation of extracellular glutamate and aspartate. To test this, adrenalectomized rats were given replacement GCs in either the low or high physiological range. Three days later, rats were anesthetized and 1 mM KA was infused through a dialysis probe placed in the dorsal hippocampus. Extracellular amino acid concentrations in the dialysate were then assessed by HPLC. After KA infusion, high-GC rats (30 +/- 3 micrograms/dl) had significantly elevated concentrations of glutamate and aspartate compared with low-GC rats (all less than 0.95 micrograms/dl). The glutamate accumulation was due to GCs raising pre-KA concentrations, whereas the aspartate accumulation was due to GCs exacerbating the KA-induced rise. Glutamine concentrations were unaffected by KA, whereas the high-GC regimen elevated glutamine concentrations both before and after KA. Taurine concentrations rose after infusion of KA, but were unaffected by GC regime, whereas alanine concentrations were unaffected by either manipulation. Serine concentrations were unaffected by KA, but were depressed both before and after KA in high-GC rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic stress enhances methamphetamine‐induced extracellular glutamate and excitotoxicity in the rat striatum

“…This finding extends previous reports of an augmentation of kainic acid-induced increases in extracellular GLU by glucocorticoids in the rat hippocampus (Stein-Behrens et al, 1992). The mechanism by which CUS enhances GLU levels in the striatum during METH administration is unknown, but it is likely mediated by stress-associated elevations in glucocorticoids.…”

“…Exposure to elevated glucocorticoids or stress has been shown to exacerbate kainic acidinduced GLU accumulation and spectrin proteolysis (Stein-Behrens et al, 1992, 1994a. Therefore, the current study examined how chronic stress enhances METH toxicity, and tested the hypothesis that prior exposure to stress will augment the acute METH-induced increases in GLU and the production of spectrin proteolysis.…”

“…Furthermore, the increases in extracellular GLU in various brain areas after exposure to acute or chronic stressors (Broom and Yamamoto, 2005;Lowy et al, 1995;Moghaddam, 1993) are attenuated by adrenalectomy (Lowy et al, 1993;Moghaddam et al, 1994). Moreover, elevations in glucocorticoids or psychological stress exacerbate the increase in extracellular GLU, neuron loss, and spectrin proteolysis in the hippocampus produced by kainic acid (Stein-Behrens et al, 1992, 1994b.…”

Interleukin-1β Biosynthesis Inhibition Reduces Acute Seizures and Drug Resistant Chronic Epileptic Activity in Mice

“…Besides its established anti-inflammatory properties, dexamethasone anticonvulsant effect may be mediated by its ability to reverse the increased serum corticosterone concentrations, which are elicited by elevated IL-1β brain levels via activation of the hypothalamic-pituitary adrenal axis (HPA) axis [47,48]. Thus, chronic high levels of glucorticoids can produce proinflammatory effects in the brain [49] and increase neuronal vulnerability to injury [50,51]. This mechanism, although still speculative, may also play a role in the anticonvulsant activity of VX-765.…”

Mineralocorticoid and glucocorticoid receptors in the brain. Implications for ion permeability and transmitter systems

“…Additional administration of energy sources, such as glucose or mannose, effectively protected against the deleterious effects of glucocorucolos (Sapolsky, 1986). Considering the implication of increased excitatory amino acid transmission, particularly through NMDA receptors, and a :~teady elevation of intracellular [Ca] in neuronal damage due to energy shortage, it is not surprising that the glucocorticoid-induced exacerbatmn of neurotoxic agents shows NMDA and Ca dependenc~,: !l) Corticosterone enhanced 3AP toxicity was reduced by a NMDA antagonist (Armanini cz al., 1990): rapid changes in glucose utilization after mild stress are also NMDA-dependent (Schasfoort <: al.. 1988) (2) Kainic acid-evoked rises in [Ca]~ in a hippocampal neuronal culture are enhanced alter 24 hr incubation with 1 #M corticosterone (Elliot and Sapolsky, 1992), at least partly due t~ an impaired Ca-extrtlsion mechanism (Elliot and Sapolsky, 1993).…”