Down-regulation of AMPA glutamate receptors reduces cerebrocortical metabolic response to stimulation

We tested the hypothesis that chronic stimulation of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate) glutamate receptors with an agonist causes down-regulation of the receptor protein and a decrement in basal and/or stimulated cerebral O-2 consumption. Male Wistar rats were intradurally infused with 10 muM AMPA by an osmotic pump at a rate of 1 mul/h for 6 days. As a result, the specific binding of (S)-[H-3]-5-fluorowillardiine to AMPA receptors in the cerebral cortex decreased 46% from 2.7 +/- 0.3 to 1.5 +/- 0.6 (density units). Under isoflurane anesthesia and after topical stimulation to the right cerebral cortex with 10(-3) M AMPA, cerebral blood flow (C-14-iodoantipyrine method) and O-2 consumption (cryomicrospectrophotometrically determined) were determined in control and down-regulated rats. Down-regulation of AMPA receptors did not alter basal O-2 consumption. In control, after agonist stimulation, the O-2 consumption in the ipsilateral cortex increased by 34%, (4.7 +/- 0.5 ml O-2 . min(-1) . 100 g(-1) compared to 3.5 +/- 0.4 in the contralateral cortex). In the down-regulated rats, the O-2 consumption did not significantly increase (4.0 +/- 1.5 ml O-2 . min(-1) . 100 g(-1) compared to 3.3 +/- 1.7 in the contralateral cortex) after AMPA. In conclusion, following chronic simulation, AMPA receptors underwent down-regulation, but such down-regulation did not alter basal cerebrocortical blood flow or O-2 consumption. AMPA down-regulation reduced the agonist stimulated increase in cortical O-2 consumption.