Recovery from methamphetamine induced long-term nigrostriatal dopaminergic deficits without substantia nigra cell loss.
After administration of methamphetamine (METH) (2x2 mg/kg, 6 h apart) to vervet monkeys, long term but reversible dopaminergic deficits were observed in both in vivo and post-mortem studies. Longitudinal studies using positron emission tomography (PET) with the dopamine transporter (DAT)-binding ligand, [11C]WIN 35,428 (WIN), were used to show decreases in striatal WIN binding of 80% at 1 week and only 10% at 1.5 years. A post-mortem characterization of other METH subjects at 1 month showed extensive decreases in immunoreactivity (IR) profiles of tyrosine hydroxylase (TH), DAT and vesicular monoamine transporter-2 (VMAT) in the striatum, medial forebrain bundle and the ventral midbrain dopamine (VMD) cell region. These IR deficits were not associated with a loss of VMD cell number when assessed at 1.5 years by stereological methods. Further, at 1.5 years, IR profiles of METH subjects throughout the nigrostriatal dopamine system appeared similar to controls although some regional deficits persisted. Collectively, the magnitude and extent of the dopaminergic deficits, and the subsequent recovery were not suggestive of extensive axonal degeneration followed by regeneration. Alternatively, this apparent reversibility of the METH-induced neuroadaptations may be related primarily to long-term decreases in expression of VMD-related proteins that recover over time.
Harvey
D C
DC
Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, CA 90095-1735, USA.
Lacan
G
G
Tanious
S P
SP
Melega
W P
WP
D000818:Animals; D002250:Carbon Radioisotopes; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D002452:Cell Count; D002521:Cercopithecus; D050483:Dopamine Plasma Membrane Transport Proteins; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism; D026901:Membrane Transport Proteins; D008694:Methamphetamine / Q000009:adverse effects*; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D009419:Nerve Tissue Proteins; D009434:Neural Pathways / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009479:Neuropeptides; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014055:Tomography, Emission-Computed; D014446:Tyrosine 3-Monooxygenase / Q000187:drug effects / Q000378:metabolism; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins
D002250:Carbon Radioisotopes; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D008694:Methamphetamine; D014446:Tyrosine 3-Monooxygenase