This FIRST Award tests the hypotheses that dopamine (DA) is the signal that regulates development of its D1 receptor subtype, and that serotonin (5-HT) regulates the development of striatal D2 receptors after forebrain DA depletion. It is important to understand the above relationships in mammalian brain to provide a framework for understanding attention deficit disorder with hyperactivity and the schizophrenias which, although multifactorial in etiology, may involve damage to developing dopaminergic pathways. This project will investigate the relationships between DA, 5-HT and D1 and D2 receptor development in the DA-depleted neonatal rat, using neuroanatomic, neuropharmacologic, and biochemical techniques. Neonatal DA-depleted rats grow, thrive, and become hyperactive in new environments, but adult DA-depleted rats stop drinking, stop eating, and become bradykinetic. In contrast to adult rats, neonatal DA-depleted rats develop striatal hyperinnervation with serotonergic fibers, and have increased levels of rostral striatal D2 receptors. Data from this laboratory demonstrate marked reductions of striatal D1 receptors in neonatal, but not adult, rats with greater than or equal to 98% DA depletion. Repeated administration of the selective D1 agonist SKF-38393 to neonatal DA-depleted rats restores D1 receptors to control levels. Based on these findings, this project will address whether decreases in DA and increases in serotonin (5-HT) modify levels of D1 and D2 receptors in developing DA-depleted rats with and without 5-HT depletions. This project will also test the hypothesis that levels of D1 but not D2 receptors in neonatal DA-depleted rats can be regulated by treatment with selective D1 agonists. The hypothesis that 5-HT regulates expression of rostral striatal D2 receptors in DA-depleted rats will be further investigated using selective 5-HT antagonists. The proposed studies will help to provide insight into how DA and/or 5-HT may regulate development of DA receptor subtypes during normal development and after selective neurochemical injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29NS031233-03
Application #
2269165
Study Section
Neurosciences Research Review Committee (BPN)
Project Start
1992-03-16
Project End
1997-02-28
Budget Start
1994-03-01
Budget End
1995-02-28
Support Year
3
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Rochester
Department
Neurology
Type
Schools of Dentistry
DUNS #
208469486
City
Rochester
State
NY
Country
United States
Zip Code
14627