Corticotropin-Releasing Factor-Dopamine Interactions in Male and Female Macaque: Beyond the Classic VTA

Dopamine (DA) is involved in stress and stress-related illnesses, including many psychiatric disorders. Corticotropin-releasing factor (CRF) plays a role in stress responses and targets the ventral midbrain DA system. This system is comprised of DA and non-DA cells and is divided into specific subregions. Although CRF inputs to the midline A10 nuclei of the DA system are well studied in rodents, in monkeys, CRF-containing terminals are also highly enriched in the expanded A10 parabrachial pigmented nucleus (PBP) and in the A8 retrorubral field subregion. In primates, the central extended amygdala, a rich source of CRF afferents across species, preferentially targets the PBP and A8 fields. We thus sought to characterize CRF terminals on DA (tyrosine hydroxylase, TH+) and non-DA (TH-) cell types in the PBP and A8 regions at the ultrastructural level using immuno-reactive electron microscopy (EM) for TH and CRF in male and female macaques. CRF labeling was present mostly in axon terminals, which mainly contacted non-DA dendrites in both subregions. Most CRF-positive terminals had inhibitory (symmetric) profiles. In the A8, CRF symmetric (inhibitory) contacts onto non-DA neurons were significantly greater than asymmetric (excitatory) profiles; this pattern was also seen in the PBP, but did not reach statistical significance. No sex differences were found. Hormonal assays suggested that our animals were at similar developmental stages and experienced similar stress levels. Together our findings suggest that at baseline, CRF terminals in the primate PBP and A8 largely regulate DA indirectly through non-DA neurons.