Studies have demonstrated that exercise decreases the symptoms of a variety of neurological disorders, but the mechanism through which exercise provides this protection is unknown. Excitotoxicity is a common cause of cell death underlying a number of brain disorders. Neuronal hyperexcitability is reduced by the neuropeptide galanin, and galanin mRNA is up-regulated by 3 weeks of activity wheel running. The following studies tested whether activity wheel running can reduce excitability and seizure behaviors induced by kainic acid. The importance of exercise-induced up-regulation of galanin was determined by injecting the galanin antagonist M-40 prior to administration of kainic acid. Seizure-induced behaviors and excitability were decreased in exercising animals following intraperitoneal and intracerebroventricular (ICV) administration of kainic acid. This effect was significantly attenuated when M-40 was injected prior to ICV kainic acid. These findings indicate that exercise induced up-regulation of galanin is a necessary factor in exercise-induced neuroprotection against excitotoxicity.