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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH057995-04
Application #
6132669
Study Section
Special Emphasis Panel (ZRG1-MDCN-3 (03))
Program Officer
Brady, Linda S
Project Start
1997-04-05
Project End
2005-03-31
Budget Start
2000-05-01
Budget End
2001-03-31
Support Year
4
Fiscal Year
2000
Total Cost
$292,539
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Psychiatry
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Bubser, Michael; Fadel, Jim R; Jackson, Lela L et al. (2005) Dopaminergic regulation of orexin neurons. Eur J Neurosci 21:2993-3001
Wang, Hui-Dong; Dunnavant, Floyd D; Jarman, Tabitha et al. (2004) Effects of antipsychotic drugs on neurogenesis in the forebrain of the adult rat. Neuropsychopharmacology 29:1230-8
Petrie, Kimberly A; Bubser, Michael; Casey, Cheryl D et al. (2004) The neurotensin agonist PD149163 increases Fos expression in the prefrontal cortex of the rat. Neuropsychopharmacology 29:1878-88
Rieck, Richard W; Ansari, M S; Whetsell Jr, William O et al. (2004) Distribution of dopamine D2-like receptors in the human thalamus: autoradiographic and PET studies. Neuropsychopharmacology 29:362-72
Scruggs, Jennifer L; Schmidt, Dennis; Deutch, Ariel Y (2003) The hallucinogen 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) increases cortical extracellular glutamate levels in rats. Neurosci Lett 346:137-40
Fadel, J; Deutch, A Y (2002) Anatomical substrates of orexin-dopamine interactions: lateral hypothalamic projections to the ventral tegmental area. Neuroscience 111:379-87
Woo, Nam-Sik; Lu, Jianming; England, Roger et al. (2002) Hyperexcitability and epilepsy associated with disruption of the mouse neuronal-specific K-Cl cotransporter gene. Hippocampus 12:258-68
Fadel, Jim; Bubser, Michael; Deutch, Ariel Y (2002) Differential activation of orexin neurons by antipsychotic drugs associated with weight gain. J Neurosci 22:6742-6
Bubser, Michael; Deutch, Ariel Y (2002) Differential effects of typical and atypical antipsychotic drugs on striosome and matrix compartments of the striatum. Eur J Neurosci 15:713-20
Bubser, M; Backstrom, J R; Sanders-Bush, E et al. (2001) Distribution of serotonin 5-HT(2A) receptors in afferents of the rat striatum. Synapse 39:297-304

Showing the most recent 10 out of 17 publications