Recovery from methamphetamine induced long-term nigrostriatal dopaminergicdeficits without substantia nigra cell loss

After administration of methamphetamine (METH) (2x2: mg/kg, 6 h apart) to v ervet monkeys, long term but reversible dopaminergic deficits were observed in both in vivo and post-mortem studies. Longitudinal studies using positr on emission tomography (PET) with the dopamine transporter (DAT)-binding li gand, [C-11]WIN 35,428 (WIN), were used to show decreases in striatal WIN b inding of 80% at 1 week and only 10% at 1.5 years. A post-mortem characteri zation of other METH subjects at 1 month showed extensive decreases in immu noreactivity (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 no t associated with a loss of VMD cell number when assessed at 1.5 years by s tereological methods. Further, at 1.5],ears, IR profiles of METH subjects t hroughout the nigrostriatal dopamine system appeared similar to controls al though some regional deficits persisted. Collectively, the magnitude and ex tent of the dopaminergic deficits, and the subsequent recovery were not sug gestive of extensive axonal degeneration followed by regeneration. Alternat ively, this apparent reversibility of the METH-induced neuroadaptations may be related primarily to long-term decreases in expression of VMD-related p roteins that recover over time. (C) 2000 Elsevier Science B.V. All rights r eserved.