Ultrastructural interactions between terminals expressing the norepinephrine transporter and dopamine neurons in the...

The norepinephrine (NE) system is implicated in the etiology and treatment of depression and drugs blocking the NE transporter (NET) are effective antidepressants. It is possible that dopamine (DA) also plays a role in depression and the action of antidepressant drugs, although the mechanisms whereby NE and DA interact have not been fully elaborated. We examined whether NE neurons might alter DA transmission via synaptic projections to cells in the ventral tegmental area (VTA) by using electron microscopic dual labeling immunocytochemistry in the rat and monkey. NET was used as a marker for NE axons, whereas the catecholamine synthetic enzyme, tyrosine hydroxylase (TH), served as a label for DA neurons. We observed three types of spatial relationships between these profiles that were similar in type but varied in frequency between rodent and primate. The most common arrangement involved nonsynaptic appositions between NET-immunoreactive (-ir) axons and TH-ir dendrites. Such relationships may facilitate extrasynaptic actions of NE on DA cell activity. The other commonly observed arrangement involved adjacent profiles that were otherwise separated by glia. These relationships may represent regions where NE is prevented from reaching DA cells. In only a few cases were synapses observed between NET-ir axons and TH-ir dendrites. This finding suggests that NE can synaptically regulate DA neurons, although functional interactions are more likely to involve extrasynaptic mechanisms. Finally, in the VTA of both species the majority of NET-ir axons exhibited no detectable TH immunoreactivity. The latter finding agrees with observations in cortical regions and represents the first report of its type in a subcortical structure.