Psychostimulants and vesicle trafficking: a novel mechanism and therapeutic implications.
The monoamine vesicular transporter 2 (VMAT-2) has been associated with dopamine (DA) sequestration and protection against neurodegeneration caused by the intracellular oxidation of this monoamine. The data presented herein suggest that methylphenidate treatment enhances the amount of VMAT-2 protein and possibly its activity in the presynaptic cytosol, where it is able to increase the sequestration of DA and likely protect against its instability. In contrast, methamphetamine (METH) has an opposite effect on cytosolic VMAT-2 resulting in degradation of DA terminals. The fact that posttreatment of methylphenidate after a neurotoxic regimen of METH protects against resulting loss of DA parameters suggests that treatment with methylphenidate, or other DA transporter blockers, may be protective against degenerative disorders of DA pathways, such as Parkinson's disease.
Hanson
Glen R
GR
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah 84112, USA. glen.hanson@hsc.utah.edu
Sandoval
Veronica
V
Riddle
Evan
E
Fleckenstein
Annette E
AE
D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology / Q000627:therapeutic use; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008694:Methamphetamine / Q000494:pharmacology* / Q000627:therapeutic use*; D008774:Methylphenidate / Q000494:pharmacology* / Q000627:therapeutic use*; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D050492:Vesicular Biogenic Amine Transport Proteins
D000697:Central Nervous System Stimulants; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D050492:Vesicular Biogenic Amine Transport Proteins; D008774:Methylphenidate; D008694:Methamphetamine