Therapeutic targeting of "DARPP-32": a key signaling molecule in the dopiminergic pathway for the treatment of opiate addiction.

Abstract

The 32-kDa dopamine- and adenosine 3',5'-monophosphate-regulated phosphoprotein (DARPP-32) is recognized to be critical to the pathogenesis of drug addiction. Opiates via the mu-receptor act on the dopaminergic system in the brain and modulates the expression of DARPP-32 phosphoprotein which is an important mediator of the activity of the extracellular signal-regulated kinase (ERK) signaling cascades, the activation of which represents an exciting nexus for drug-induced changes in neural long-term synaptic plasticity. Silencing of DARPP-32 using an siRNA against DARPP-32 may provide a novel gene therapy strategy to overcome drug addiction. In this study, we investigated the effect of the opiate (heroin) on D1 receptor (D1R) and DARPP-32 expression and additionally, evaluated the effects of DARPP-32-siRNA gene silencing on protein phosphatase-1 (PP-1), ERK, and cAMP response element-binding (CREB) gene expression in primary normal human astrocytes (NHA) cells in vitro. Our results indicate that heroin significantly upregulated both D1R and DARPP-32 gene expression, and that DARPP-32 silencing in the NHA cells resulted in the significant modulation of the activity of downstream effector molecules such as PP-1, ERK, and CREB which are known to play an important role in opiate abuse-induced changes in long-term neural plasticity. These findings have the potential to facilitate the development of DARPP32 siRNA-based therapeutics against drug addiction.

• Authors: Supriya D Mahajan, Ravikumar Aalinkeel, Jessica L Reynolds, Bindukumar B Nair, Donald E Sykes, Zihua Hu, Adela Bonoiu, Hong Ding, Paras N Prasad, Stanley A Schwartz
• Journal: International review of neurobiology (Int Rev Neurobiol) Vol. 88 Pg. 199-222 ( 2009) ISSN: 2162-5514 [Electronic] United States
• PMID: 19897079 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Dopamine and cAMP-Regulated Phosphoprotein 32
• Narcotics
• RNA, Small Interfering
• Receptors, Dopamine D1
• Heroin
• Extracellular Signal-Regulated MAP Kinases

Topics

• Cells, Cultured
• Dopamine and cAMP-Regulated Phosphoprotein 32 (drug effects, genetics, metabolism)
• Extracellular Signal-Regulated MAP Kinases (drug effects, metabolism)
• Gene Expression (drug effects)
• Heroin (pharmacology)
• Humans
• Image Processing, Computer-Assisted
• Narcotics (pharmacology)
• Oligonucleotide Array Sequence Analysis
• Opioid-Related Disorders (genetics, metabolism)
• RNA, Small Interfering
• Receptors, Dopamine D1 (biosynthesis, drug effects)
• Reverse Transcriptase Polymerase Chain Reaction
• Transfection