We have recently observed that dopamine stimulates the production of phosphoinositide second messengers in rat brain. The dopaminergic effect was mimicked by the selective dopamine D1 receptor agonist, SKF38393, and blocked by the selective D1 receptor antagonist, SCH23390, but not by the selective D2 receptor antagonist, sulpiride. Furthermore, the stimulatory effect of SKF38393 was observed in the striatum, hippocampus, frontal cortex, and amygdala, brain regions which contain significant levels of D1 receptors, but not in the cerebellum. Interestingly, the amygdala which exhibited a marked sensitivity to SKF38393-induced phosphoinositide hydrolysis in our studies, has previously been shown to contain D1-like receptors which do not couple to stimulation of dopamine-linked adenylate cyclase. These findings suggest that some actions of dopamine in the brain are mediated by a subtype of the dopamine receptor that is selectively coupled to phosphoinositide metabolism. This newfound action of dopamine has potential implications for the understanding and treatment of various dopamine-associated neuropathologies, including schizophrenia, parkinsonism, Huntington's chorea, and tardive dyskinesia. To further characterize this dopaminergic effect, we have devised experiments to characterize the receptor involved and possibly identify its selective agonists and antagonists, identify any G proteins that may be involved in the transduction mechanism, determine the relationship between the stimulation of phosphoinositide metabolism and dopamine-stimulated adenylate cyclase, and determine the regional brain distribution of this dopamine-stimulated phosphoinositide response. The findings of this project will help to lay a solid foundation for understanding the role of dopamine in central nervous system function and dysfunction, and for evaluating and possibly redefining various models of dopamine-associated neuropsychiatric disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS029514-01A1
Application #
3416359
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1991-09-30
Project End
1995-09-29
Budget Start
1991-09-30
Budget End
1992-09-29
Support Year
1
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Allegheny University of Health Sciences
Department
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19129
Schmidt, Azriel; Vogel, Robert; Rutledge, Su Jane et al. (2005) Cross-talk between an activator of nuclear receptors-mediated transcription and the D1 dopamine receptor signaling pathway. Pharmacol Biochem Behav 80:379-85
Jin, Li-Qing; Goswami, Satindra; Cai, Guoping et al. (2003) SKF83959 selectively regulates phosphatidylinositol-linked D1 dopamine receptors in rat brain. J Neurochem 85:378-86
Cai, Guoping; Wang, Hoau-Yan; Friedman, Eitan (2002) Increased dopamine receptor signaling and dopamine receptor-G protein coupling in denervated striatum. J Pharmacol Exp Ther 302:1105-12
Zhen, X; Zhang, J; Johnson, G P et al. (2001) D(4) dopamine receptor differentially regulates Akt/nuclear factor-kappa b and extracellular signal-regulated kinase pathways in D(4)MN9D cells. Mol Pharmacol 60:857-64
Jin, L Q; Wang, H Y; Friedman, E (2001) Stimulated D(1) dopamine receptors couple to multiple Galpha proteins in different brain regions. J Neurochem 78:981-90
Cai, G; Zhen, X; Uryu, K et al. (2000) Activation of extracellular signal-regulated protein kinases is associated with a sensitized locomotor response to D(2) dopamine receptor stimulation in unilateral 6-hydroxydopamine-lesioned rats. J Neurosci 20:1849-57
Can, A; Sayar, K; Friedman, E et al. (2000) The effects of agonist stimulation and beta(2)-adrenergic receptor level on cellular distribution of gs(alpha) protein. Cell Signal 12:303-9
Cai, G; Gurdal, H; Smith, C et al. (1999) Inverse agonist properties of dopaminergic antagonists at the D(1A) dopamine receptor: uncoupling of the D(1A) dopamine receptor from G(s) protein. Mol Pharmacol 56:989-96
Jin, L Q; Cai, G; Wang, H Y et al. (1998) Characterization of the phosphoinositide-linked dopamine receptor in a mouse hippocampal-neuroblastoma hybrid cell line. J Neurochem 71:1935-43
Zhen, X; Uryu, K; Wang, H Y et al. (1998) D1 dopamine receptor agonists mediate activation of p38 mitogen-activated protein kinase and c-Jun amino-terminal kinase by a protein kinase A-dependent mechanism in SK-N-MC human neuroblastoma cells. Mol Pharmacol 54:453-8

Showing the most recent 10 out of 22 publications