Long-term methamphetamine-induced decreases of [C-11]WIN 35,428 binding instriatum are reduced by GDNF: PET studies in the vervet monkey

The effects of glial cell line-derived neurotrophic factor (GDNF) pretreatm ent on methamphetamine (METH)-induced striatal dopamine system deficits in the vervet monkey were characterized with [C-11]WIN 35,428 (WIN)-positron e mission tomography (PET). WIN, a cocaine analog that binds to the dopamine transporter (DAT), was used to provide an index of striatal dopamine termin al integrity. In two subjects, GDNF (200 mu g/40 mu l) was injected into th e caudate and putamen unilaterally vs, saline contralaterally. After 1-2 we eks, + and -GDNF striatal WIN-PET binding values were equivalent as calcula ted by multiple time graphic analysis, suggestive of an absence of unilater al DAT up-regulation. Three other subjects (n = 3) received GDNF injections into the caudate and putamen unilaterally and one week later, were adminis tered METH HCl (2 x 2 mg/kg; i.m., 24 hours apart; a neurotoxic dosage for this species). At 1 week post-METH, WIN-PET studies showed that mean WIN bi nding was decreased by 72% in the + GDNF and by 92% in the -GDNF striatum r elative to pre-drug assessment values. Thus, GDNF pretreatment reduced the extent of METE-induced decreases in WIN binding. Subsequent WIN-PET studies (1.5-9-month range) showed a protracted recovery of WIN binding in each st riatum, indicative of long-term but partially reversible METH neurotoxicity . Further, at each time point, WIN binding remained relatively higher in th e + GDNF vs. -GDNF striatum. These results provide further evidence that th e adult non-human primate brain remains responsive to exogenously administe red GDNF and that this pharmacotherapy approach can counteract aspects of n eurotoxic actions associated With methamphetamine. (C) 2000 Wiley-Liss. Inc .