N-methyl-D-aspartate (NMDA) receptors in the ventral tegmental area: Subcellular distribution and colocalization with 5-hydroxytryptamine(2A) receptors

Glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype have been im plicated in behavioral sensitization to psychostimulants and in psychotic b ehaviors involving excitation of ventral tegmental area (VTA) dopaminergic neurons. Antagonists of serotonin (5-hydroxytryptamine, 5-HT) receptors of the 5-HT2A subtype are potent antipsychotics that attenuate these NMDA-evok ed responses. We examined the electron microscopic immunocytochemical local ization of antisera against the NMDA R1 subunit (NMDAR1) and 5-HT2A recepto rs to determine potential sites for their dual activation in the rat parani gral and parabrachial VTA subdivisions that are distinguished, in part, by their respective striatolimbic and cortical projections. In both regions, N MDAR1 immunoreactivity was localized mainly to the cytoplasm of somata and dendrites, and was only occasionally seen near or within excitatory-type as ymmetric synapses. Many of the NMDAR1-labeled somata and dendrites also exp ressed 5-HT2A receptors, having a similar, but largely non-overlapping, neu ronal distribution. The mean area density of NMDAR1 and dually labeled dend ritic profiles was significantly greater in the paranigral than in the para brachial VTA. NMDAR1 was also present in small axons showing a similar regi onal difference in area density. No regional difference in area density was seen in dendrites or small axons containing only 5-HT2A receptors. Our res ults indicate that NMDA and 5-HT2A receptors in the VTA are transiently exp ressed on synaptic plasma membranes of single neurons showing widespread cy toplasmic distributions of each of the receptors. They also suggest a major role for NMDA receptors in modulating the output of paranigral neurons and the release of transmitters from axons passing through this region. (C) 20 00 Wiley-Liss, Inc.