Mesoaccumbens dopamine neuron synapses reconstructed in vitro are glutamatergic

The mesoaccumbens projection, formed by ventral tegmental area dopamine neu rons synapsing on nucleus accumbens gamma-aminobutyl ic acid neurons, has b een implicated in the pathogenesis of schizophrenia and drug addiction. Des pite intensive study, the nature of the signal conveyed by dopamine neurons has not been fully resolved. In addition to several slower, dopamine-media ted, modulatory actions, several lines of evidence suggest that dopamine ne urons have fast excitatory actions. To rest this, we placed dopamine neuron s together with accumbens neurons in microcultures. Surprisingly, most dopa mine neurons made excitatory recurrent connections (autapses), which provid ed a basis for their identification; accumbens gamma-aminobutyric acid neur ons were identified by their distinctive size. In 75% of mesoaccumbens cell pairs, stimulation of the dopamine neuron evoked a glutamate mediated, exc itatory synaptic response in the accumbens neuron. Immunostaining revealed dopamine neuron varicosities that were predominantly dopaminergic, ones tha t were predominantly glutamatergic, and ones that were both dopaminergic an d glutamatergic. Despite close appositions of both glutamatergic and dopami nergic varicosities to the dendrites of accumbens neurons, only glutamaterg ic synaptic responses were seen. In the majority of cell pairs, pharmacolog ic activation of D2-type dopamine receptors inhibited glutamatergic respons es, presumably via immunocytochemically-visualized presynaptic D2 receptors . In some cell pairs, the evoked autaptic and synaptic responses were disco rdant, suggesting that D2 receptors may be differentially trafficked to dif ferent presynaptic varicosities. Thus, dopamine neurons appear to mediate both slow dopaminergic and fast gl utamatergic actions via separate sets of synapses. Together with evidence f or glutamate cotransmission in serotonergic raphe neurons and noradrenergic locus coeruleus neurons, these results add a new dimension to monoamine ne uron signaling that may have important implications for neuropsychiatric di sorders. (C) 2000 IBRO. Published by Elsevier Science Ltd. All rights reser ved.