Age-dependent differences in dopamine transporter and vesicular monoamine transporter-2 function and their implications for methamphetamine neurotoxicity.
The abuse of methamphetamine (METH) is a serious public health problem because METH can cause persistent dopaminergic deficits in the brains of both animal models and humans. Surprisingly, adolescent postnatal day (PND)40 rats are resistant to these METH-induced deficits, whereas young adult PND90 rats are not. Studies described in this report used rotating disk electrode voltammetry and western blotting techniques to investigate whether there are age-dependent differences in monoamine transporter function in PND38-42 and PND88-92 rats that could contribute to this phenomenon. The initial velocities of dopamine (DA) transport into, METH-induced DA efflux from, and DA transporter (DAT) immunoreactivity in striatal suspensions are greater in PND38-42 rats than in PND88-92 rats. DA transport velocities into vesicles that cofractionate with synaptosomal membranes after osmotic lysis are also greater in PND38-42 rats. However, there is no difference in vesicular monoamine transporter-2 (VMAT-2) immunoreactivity between the two age groups in this fraction. This suggests that younger rats have a greater capacity to sequester cytoplasmic DA into membrane-associated vesicles due to kinetically upregulated VMAT-2 and also have increased levels of functionally active DAT. In the presence of METH, these may provide additional routes of cellular efflux for DA that is released from vesicles into the cytoplasm and thereby prevent cytoplasmic DA concentrations in younger rats from rising to neurotoxic levels after drug administration. These findings provide novel insight into the age-dependent physiological regulation of neuronal DA sequestration and may advance the treatment of disorders involving abnormal DA disposition including substance abuse and Parkinson's disease.
Volz
Trent J
TJ
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah 84112, USA.
Farnsworth
Sarah J
SJ
Rowley
Shane D
SD
Hanson
Glen R
GR
Fleckenstein
Annette E
AE
D000367:Age Factors; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050493:Vesicular Monoamine Transport Proteins / Q000187:drug effects* / Q000378:metabolism
D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; C493454:Slc18a2 protein, rat; D050493:Vesicular Monoamine Transport Proteins; D008694:Methamphetamine; D004298:Dopamine