D2-dopamine (DA) receptors enhance extracellular GABA levels in the rat prefrontal cortex (PFC). This is surprising because D2-like receptors activate inhibitory signal transduction pathways in most systems. The peptide transmitter neurotensin (NT) colocalizes exclusive with DA in a subpopulation of terminals in the PFC. I hypothesize that D2-elicited GABA release in the PFC may occur via stimulation of D2 autoreceptors and subsequent release of NT which in turn interacts with excitatory high affinity NT receptors on the GABAergic interneuron. In vivo microdialysis in freely moving rats will be used to determine if local administration of quinpirole enhances NT release and if NT administration increases extracellular GABA levels. Quinpirole-elicited GABA release will be measured in rats that have been treated with 6- hydroxydopamine to destroy PFC dopamine terminals, thereby eliminating D2 autoreceptors and NT. Finally, quinpirole-elicited GABA release will be measured in animals pretreated with SR 48692, the NT antagonist. GABA will be measured using HPLC while NT will be assayed using mass spectrometry. Immunohistochemistry will be used to localized high affinity NT receptors to GABA interneurons in the rat PFC. These studies should help clarify the consequences of PFC DA deafferentation in schizophrenia, and may point to the development of new therapeutic strategies.
