PI3K signaling supports amphetamine-induced dopamine efflux

• Published in: Biochemical and biophysical research communications Vol. 372; no. 4; pp. 656 - 661
• Main Authors: Lute, Brandon J., Khoshbouei, Habibeh, Saunders, Christine, Sen, Namita, Lin, Richard Z., Javitch, Jonathan A., Galli, Aurelio
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.08.2008
• Subjects: Amphetamine (AMPH); Amphetamine - pharmacology; Animals; Central Nervous System Stimulants; Chromones - pharmacology; Dopamine (DA); Dopamine - secretion; Dopamine Plasma Membrane Transport Proteins - genetics; Dopamine transporter (DAT); Drug abuse; Insulin; Mice; Mice, Transgenic; Morpholines - pharmacology; Neurons - drug effects; Neurons - secretion; Phosphatidylinositol 3-kinase (PI3K); Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; Protein Kinase Inhibitors - pharmacology; Signal Transduction - drug effects; Transient current; Dopamine transporter (DAT); Drug abuse; Transient current; Dopamine (DA); Phosphatidylinositol 3-kinase (PI3K); Amphetamine (AMPH); Insulin
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2008.05.091

The dopamine (DA) transporter (DAT) is a major molecular target of the psychostimulant amphetamine (AMPH). AMPH, as a result of its ability to reverse DAT-mediated inward transport of DA, induces DA efflux thereby increasing extracellular DA levels. This increase is thought to underlie the behavioral effects of AMPH. We have demonstrated previously that insulin, through phosphatidylinositol 3-kinase (PI3K) signaling, regulates DA clearance by fine-tuning DAT plasma membrane expression. PI3K signaling may represent a novel mechanism for regulating DA efflux evoked by AMPH, since only active DAT at the plasma membrane can efflux DA. Here, we show in both a heterologous expression system and DA neurons that inhibition of PI3K decreases DAT cell surface expression and, as a consequence, AMPH-induced DA efflux.