Involvement of nitric oxide in learning and memory processes

Your brain makes nitric oxide from the amino acid L-arginine using an enzyme called neuronal nitric oxide synthase. Because nitric oxide is a gas that diffuses freely across cell membranes, it acts as an unusual kind of neurotransmitter — one that does not sit in vesicles waiting for release, but is made on demand at the moment a nerve cell needs it. The moment usually comes when the excitatory neurotransmitter glutamate activates NMDA receptors and calcium floods into the cell.

This 2011 review pulls together roughly two decades of animal experiments testing whether nitric oxide is actually needed for learning and for storing memories. The consistent pattern: increasing brain nitric oxide (with L-arginine or with drugs that release nitric oxide) tends to improve performance on learning tasks in rats, mice, chicks, and even invertebrates like octopus and honeybees. Blocking nitric oxide synthesis with L-NAME, 7-nitroindazole, or similar inhibitors tends to impair learning and memory across the same range of species. Most of this evidence is in animals rather than humans.

The review also examines conditions in which brain nitric oxide is thought to be low — ageing, diabetes, chronic stress, epilepsy, and Alzheimer's disease. In each case, animal models show cognitive deficits alongside reduced nitric oxide activity. In rodent models of ageing, L-arginine and nitric oxide donors have partially reversed those deficits. The authors argue this preclinical pattern supports investigating L-arginine and nitric oxide donors for age-related cognitive decline in humans, though direct clinical trial evidence is not the focus of this review.