Converging research efforts over the last 4 decades have established beyond a doubt that many, if not most, neurons release more than 1 neurotransmitter. Although much attention has been paid to the co-release of small-molecule neurotransmitters with neuropeptides, a number of examples of co-release of 2 small-molecule neurotransmitters have now been described. It has been suggested recently that monoamine neurons use glutamate as a co-transmitter. First, both serotonin (5-HT) and dopamine (DA) neurons in culture establish functional glutamatergic synapses in addition to classic terminals that release 5-HT or DA. Second, immunocytochemical work has provided evidence for the presence of neurotransmitter pools of glutamate in DA, 5-HT and noradrenergic neurons. Third, the recent cloning of 3 vesicular glutamate transporters (VGLUT1–3) has led to the discovery that noradrenergic neurons contain VGLUT2 mRNA, whereas 5-HT neurons contain VGLUT3 mRNA. Finally, although VGLUT2 mRNA does not appear to be abundant in DA neurons in the adult brain, DA neurons cultured from neonatal animals express VGLUT2, suggesting that these neurons may have the capacity to express this protein under specific conditions. Taken together with recent work describing the capacity of neurons to change neurotransmitter phenotype during development or in an activity-dependent manner, the finding of glutamate co-transmission in monoamine neurons may lead to significant revisions of current physiologic models of monoamine neuron function. In addition, the possible role of glutamate co-release in physiopathologic models of diseases that implicate central monoamine pathways, such as schizophrenia, must now be seriously considered.
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