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 n eurons in the ventral tegmental area (VTA) play a critical role in opiate a ddiction. Activation of mu -opioid receptors (MOR), which are located mainl y within inhibitory neurons in the VTA, results in enhanced dopaminergic tr ansmission in target regions, including the medial prefrontal cortex (mPFC) . We combined retrograde tract-tracing and electron microscopic immunocytoc hemistry to determine if neurons in the VTA that project to the mPFC contai n MOR or receive input from MOR-containing terminals. Rats received unilate ral injections of the retrograde tracer Fluoro-Gold (FG) into the mPFC. Tis sue sections throughout the VTA were then processed for electron microscopi c examination of FG and MOR. Immunoperoxidase labeling for FG was present i n VTA cell bodies that contained immunogold-silver particles for MOR that o ften were contacted by profiles exclusively immunoreactive for MOR, includi ng somata and axon terminals. The majority of dually labeled profiles were dendrites that received convergent input from unlabeled axon terminals form ing either symmetric or asymmetric type synapses. Within retrogradely label ed cell bodies and proximal dendrites, MOR immunoreactivity was mainly sequ estered within the cytoplasm. In contrast, distal retrogradely labeled dend rites contained MOR gold particles located along the plasma membranes. Thes e data suggest that opiates active at MOR in the VTA modulate cortical acti vity through 1) presynaptic actions on MOR in terminals contacting mesocort ical cell bodies, and 2) direct activation of MOR in distal dendrites of pr ojection neurons. Synapse 41:221-229, 2001. (C) 2001 Wiley-Liss, Inc.