Dopamine (DA) axons in the prefrontal cortex (PFC) synapse with GABAergic interneurons as well as pyramidal cells. These investigators have reported that D2-like DA receptor agonists increase extracellular GABA levels in the PFC of the rat: in vitro data also suggest that D2 agonists increase GABA release in the PFC. This D2 receptor-mediated excitatory drive over GABAergic cells is surprising, since D2 receptors are typically inhibitory and couple to K+ channels that hyperpolarize neurons. Dopamine is co-localized with the peptide transmitter neurotensin (NT) in certain PFC axons. They hypothesize that the ability of D2 agonists to increase PFC GABA release is due to actions at D2 auto receptors and subsequent release of NT from cortical dopaminergic axons.
In Specific Aim I they will determine if systemic or local infusion of the D2 agonist quinpirole increases extracellular NT levels in the PFC, using in vivo microdialysis couple with GS-MS determination of NT in dialysis samples; GABA levels in the same samples will be assayed by HPLC. They will then assess if D2 agonists elicit NT release form DA axons by examining the effects of quinpirole (levels?) in rats with 6 hydroxydopamine lesions of the PFC DA innervation.
In Specific Aim II they will determine if administration of NT or the NT agonist PD149163 increase extracellular GABA levels in the PFC, and if such effects are blocked by pretreatment with NT receptor antagonists. Similarly, they will determine if the NT receptor antagonists block quinpirole-elicited increases in GABA levels. The investigators will also determine if PD149163 administration induces Fos in PFC GABAergic interneurons.
In specific aim III, the investigators will determine if D2 agonists elicit GABA release in PFC slices obtained from transgenic mice in which NT is not expressed, and determine if NT agonists induce Fos in PFC interneurons in wild-type and mutant mice. Recent data have suggested a dysfunction of GABAergic neurons in the PFC of schizophrenic subjects; it is not clear if this is a primary defect or one related to a decrease in the dopaminergic innervation of the cortex. Moreover, a large literature suggest that NT may have atypical antipsychotic drug like properties, the proposed studies address current hypotheses of schizophrenia and may increase our knowledge of the pathophysiology of schizophrenia.
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