Intracerebroventricular (ICV) administration of creatine increased cerebral phosphocreatine in normal rats by 67%, the highest increase so far reported in an in vivo model. We used osmotic minipumps (Alzet, Palo Alto, CA, USA) to administer creatine, 0.5 mM, to the lateral ventricle at the rate of 10 microl/h for 3 days. Brain phosphocreatine in saline-treated controls was 33 +/- 17 microM/g protein (mean +/- SD, N = 9). In creatine-treated rats (0.5 mM for 3 days) such content was 55 +/- 17 microM/g protein (mean +/- SD, N = 7). This difference is statistically significant (p = 0.02, t-test). The increase we found in cerebral phosphocreatine is of an order of magnitude comparable to the increase previously found in in vitro experiments, and may be effective in protecting brain tissue from ischemic damage.