Ultrastructural localization of the serotonin 2A receptor in dopaminergic neurons in the ventral tegmental area

Serotonin (5-hydroxytryptamine, 5-HT) 2A receptor antagonists are clinically effective antipsychotics that may differentially target mesocortical and mesolimbic dopaminergic neurons having partially segregated distribution in the parabrachial (PB) and paranigral (PN) ventral tegmental area (VTA). We examined the ultrastructural immunocytochemical localization of the 5-HT2A receptor in these subdivisions of rat VTA, to determine (1) the functional sites for receptor activation, and (2) cellular associations between the receptor and dopaminergic neurons identified by their content of tyrosine hydroxylase (TH). The mean area density of neuronal profiles containing 5-HT2A receptor labeling was not significantly different in the PB and PN VTA. In each region approximately 44% of the 5-HT2A labeled profiles were dendrites while the remainder were mainly axons. Dendritic 5-HT2A-immunoreactivity was often localized to membranous cytoplasmic organelles resembling smooth endoplasmic reticulum, and to more rarely to segments of the plasma membrane beneath contacts from unlabeled axon terminals. 5-HT2A labeling was also seen within the cytoplasm of a few axon initial segments and many small unmyelinated axons. Approximately 40% of the 5-HT2A-labeled dendritic profiles contained TH in either PB or PN VTA. Our results suggest that 5-HT2A receptors in VTA are largely cytoplasmic and play an equally important role in modulating dopaminergic neurons in PB and PN VTA. These results also implicate 5-HT2A receptors in the postsynaptic activation of non-dopaminergic neurons and possibly the presynaptic release from terminals of axons originating in, or passing through, these regions.