Mu-opioid receptors in the ventral tegmental area are targeted to presynaptically and directly modulate mesocortical projection neurons.

Mesocorticolimbic projections originating from dopaminergic and GABAergic neurons in the ventral tegmental area (VTA) play a critical role in opiate addiction. Activation of mu-opioid receptors (MOR), which are located mainly within inhibitory neurons in the VTA, results in enhanced dopaminergic transmission in target regions, including the medial prefrontal cortex (mPFC). We combined retrograde tract-tracing and electron microscopic immunocytochemistry to determine if neurons in the VTA that project to the mPFC contain MOR or receive input from MOR-containing terminals. Rats received unilateral injections of the retrograde tracer Fluoro-Gold (FG) into the mPFC. Tissue sections throughout the VTA were then processed for electron microscopic examination of FG and MOR. Immunoperoxidase labeling for FG was present in VTA cell bodies that contained immunogold-silver particles for MOR that often were contacted by profiles exclusively immunoreactive for MOR, including somata and axon terminals. The majority of dually labeled profiles were dendrites that received convergent input from unlabeled axon terminals forming either symmetric or asymmetric type synapses. Within retrogradely labeled cell bodies and proximal dendrites, MOR immunoreactivity was mainly sequestered within the cytoplasm. In contrast, distal retrogradely labeled dendrites contained MOR gold particles located along the plasma membranes. These data suggest that opiates active at MOR in the VTA modulate cortical activity through 1) presynaptic actions on MOR in terminals contacting mesocortical cell bodies, and 2) direct activation of MOR in distal dendrites of projection neurons.