This study investigated whether the aging process in dogs is associated with an increased sensitivity to inhalation anesthesia and whether age-related changes in glutamate receptors are related to the increased sensitivity. The mean minimum alveolar concentration (MAC) of isoflurane was 1.82 +/- .08% for 2-3 year olds and 1.45 +/- .06% for 11 years olds, indicating that there was an increased potency of isoflurane in the older dogs as compared to the young. These older animals also showed a significant decrease in binding of [3H]glutamate and [3H]dizocilpine ([3H]MK801) to N-methyl-D-aspartate (NMDA) receptors in multiple cortical and hippocampal regions. The density of binding to NMDA receptors in the cortex, using a single concentration of ligand, correlated significantly with individual MAC values. These results demonstrate that dogs experience an increase in anesthetic potency with increased age, similar to humans, and that age-related changes in the NMDA receptor may represent one mechanism underlying this increased sensitivity to anesthesia.