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ANESTHETIC PHARMACOLOGY

Nitrous Oxide Decreases Cortical Methionine Synthase Transiently but Produces Lasting Memory Impairment in Aged Rats

Deborah J. Culley, MD^*, Sumati V. Raghavan, MD, Mostafa Waly, PhD, Mark G. Baxter, PhD, Rustam Yukhananov, MD, PhD^*, Richard C. Deth, PhD, and Gregory Crosby, MD^*

From the *Department of Anesthesiology Harvard Medical School, Brigham and Women’s Hospital, Boston; Department of Psychology, Harvard University, Cambridge; Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts; and Department of Experimental Psychology, Oxford University, Oxford, United Kingdom.

Address correspondence and reprint requests to Gregory Crosby, MD, Department of Anesthesiology, Aging Neuroscience Laboratory, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115. Address e-mail to gcrosby{at}zeus.bwh.harvard.edu.

BACKGROUND: Nitrous oxide is a commonly used anesthetic that inhibits the activity of methionine synthase, an enzyme involved in methylation reactions and DNA synthesis and repair. This inhibition triggers vacuole formation and degeneration of neurons in areas of the developing and mature brain that are important for spatial memory, raising the possibility that nitrous oxide might have sustained effects on learning.

METHODS: To test this possibility, we randomized 18-month-old Fischer 344 rats (n = 13 per group) to 4 h of 70% nitrous oxide + 30% oxygen or 70% nitrogen + 30% oxygen (control) and assessed memory using a 12-arm radial maze for 14 days beginning 2 days after nitrous oxide inhalation. In separate, identically treated groups of rats, we measured methionine synthase activity in the cortex and liver at the end of nitrous oxide exposure and 2 days later (n = 3 rats per group per time point) using a standard assay.

RESULTS: Liver and cortical methionine synthase was inhibited during nitrous oxide inhalation (6% and 23% of control in liver and cortex, respectively; P < 0.01). Liver enzyme activity remained depressed 2 days later, whereas cortical enzyme activity recovered. There was no difference in error rate between control and nitrous oxide treated rats. However, those exposed to nitrous oxide took more time to complete the maze and made fewer correct choices before first error (P < 0.05).

CONCLUSIONS: Sedation with 70% nitrous oxide profoundly, but transiently, reduces the activity of cortical methionine synthase but produces lasting impairment in spatial working memory in aged rats.

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