Novel Neurotransmitters and Their Neuropsychiatric Relevance

OBJECTIVE: The purpose of this review is to integrate insights regarding novel neurotransmitters or neuromodulators of neuropsychiatric significance. METHOD: Evolving concepts of neurotransmitter criteria are reviewed in light of the unexpected properties displayed by recently identified transmitters. RESULTS: Classic criteria for transmitters were based on the properties of acetylcholine but were markedly revised with the recognition of the catecholamines, serotonin, γ-aminobutyric acid (GABA), and other amino acid transmitters and neuropeptides. Nitric oxide and carbon monoxide are notably atypical, as they are not stored in synaptic vesicles, are not released by exocytosis, and do not act at postsynaptic membrane receptor proteins. d-Serine, recently appreciated as the endogenous ligand for the glycine site of the glutamate N-methyl-d-aspartate (NMDA) receptor, overturns fundamental axioms of biology as well as those of neuroscience. It is a d-amino acid, and it is synthesized and stored in glia rather than neurons. Released glutamate acts on receptors on the protoplasmic astrocytes closely apposed to the synapse to release d-serine, which coactivates postsynaptic NMDA receptors together with glutamate. d-Serine is formed by serine racemase, which directly converts l-serine to d-serine. Inhibitors of this enzyme should reduce NMDA neurotransmission and might be therapeutic in stroke and other conditions associated with glutamate excitotoxicity. CONCLUSIONS: The diversity of novel neurotransmitters and venues of their activity afford multiple opportunities for therapeutic intervention.