Abstracts

Glutamatergic receptors may play a significant role in epileptogenesis in the amygdala. The role of GluR receptor subtypes has not been elucidated. Agents such as kainic acid (KA) activate multiple glutamatergic receptors. Preliminary studies with amygdalar infusion of the specific KAr GluR5 agonist ATPA ((RS-2-amino-3-(3-hydroxy-5-tert-butylisoxazole-4-yl)propanoic acid) led to prolonged limbic seizures (10 mins [ndash] 4hrs ) monitored behaviorally (Racine stages 1 [ndash] 5 ) and by EEG, suggesting that the KAr GluR5 receptor subtype could mediate ictal activity. In order to evaluate the physiologic effects of specific GluR5 activation, we used KA, AMPA and ATPA, and functional MRI to map the cerebral blood flow (CBF) response to seizures induced by amygdalar injection in rats. Rats were anesthetized with ketamine / xylazine and an MR-compatible cannula was placed stereotactically in basolateral amygdala. After several days rest, they were intubated under isoflurane anesthesia. Body core temperature was maintained at 37 degrees with a heated water pad. Lines were placed in femoral artery to monitor blood pressure, and femoral vein for drug and fluid administration. Blood gases were analyzed at frequent intervals. MRI was performed on a horizontal 7T Bruker Avance scanner using a 72mm diameter transmit-receive coil. A 2mm axial slice containing the cannula was scanned for 10 minutes before and for approximately two hours after 10 nanomoles (5uL) infusion of each convulsant. Regional cerebral perfusion was measured using arterial spin labeling techniques. MRI parameters: matrix size : 64x64, TR : 2 s, TE: 6.5 ms, 2 ms labeling pulse with power of 81 mG/cm. Field of View= 3.2 cm, Time per scan : 4.5 min. T2 weighted and Diffusion weighted images (in read) were acquired for five 1mm slices centered around the cannula. Parameters: 128x128, TR = 3000 ms, TE = 10 (T2) and 20 ms, (DWI), [Delta] = 20 ms, FOV = 3.2 cm. The perfusion images for each drug showed bilateral cortical and subcortical increases in CBF beginning approximately 10 minutes after infusion, peaking at approximately 60 minutes, and lasting up to 2 hours. There was no significant difference in the intensity of CBF activation among the three agents. The time course of activation was similar in widely separated brain regions. Normal saline had no effect. Focal Amgydalar infusion of glutamatergic agonists leads to rapid widespread bilateral cerebral activation. Selective GluR5 activation is sufficient to produce this response. The spread of activation is unlikely to have been due to physical diffusion of the infused agent. (Supported by NINDS Division of Intramural Research)