Interactions between stress and the mesocorticolimbic dopamine system have been suggested from behavioral and electrophysiological studies. As corticotropin releasing factor (CRF) plays a role in stress responses, we investigated possible interactions between neurons containing CRF and those producing dopamine (DA) in the ventral tegmental area (VTA). We first investigated subcellular distribution of CRF in VTA by immunolabeling VTA sections with anti-CRF antibodies and analyzing these sections by electron microscopy. We found CRF-immunoreactivity present mostly in axon terminals establishing either symmetric or asymmetric synapses with VTA dendrites. Of functional importance, we established that the CRF asymmetric synapses are glutamatergic, as the CRF-immunolabeled terminals in these synapses co-expressed the vesicular glutamate transporter 2, and that CRF symmetric synapses are GABAergic, as the CRF-immunolabeled terminals in these synapses co-expressed glutamic acid decarboxylase. We then looked for synaptic interactions between CRF- and DA-containing neurons, by using antibodies against CRF and tyrosine hydroxylase (TH, a marker for DA neurons). We found that the majority of synapses between CRF-immunoreactive terminals and TH neurons are asymmetric (glutamatergic), and suggest that glutamatergic neurons containing CRF may be part of the neuronal circuitry that mediates stress responses involving the mesocorticolimbic dopamine system. The presence of CRF synapses in the VTA offers a mechanism for interactions between the stress-associated neuropeptide CRF and the mesocorticolimbic dopamine system. Current studies are aim to determine the source of these CRF inputs.
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