Novel neurotransmitters and their neuropsychiatric relevance

Objective: The purpose of this review is to integrate insights regarding no vel neurotransmitters or neuromodulators of neuropsychiatric significance. Method: Evolving concepts of neurotransmitter criteria are reviewed in ligh t of the unexpected properties displayed by recently identified transmitter s. Results: Classic criteria for transmitters were based on the properties of acetylcholine but were markedly revised with the recognition of the catecho lamines, serotonin, gamma -aminobutyric acid (GABA), and other amino acid t ransmitters 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-S erine, recently appreciated as the endogenous ligand for the glycine site o f 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 glut amate acts on receptors on the protoplasmic astrocytes closely apposed to t he synapse to release L-serine, which coactivates postsynaptic NMDA recepto rs together with glutamate. D-Serine is formed by serine racemase, which di rectly converts L-serine to D-serine. Inhibitors of this enzyme should redu ce NMDA neurotransmission and might be therapeutic in stroke and other cond itions associated with glutamate excitotoxicity. Conclusions: The diversity of novel neurotransmitters and venues of their a ctivity afford multiple opportunities for therapeutic intervention.