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

• Published in: Synapse (New York, N.Y.) N.Y.), 2000-03, Vol.35 (4), p.243-249
• Main Authors: Melega, William P., Laćan, Goran, Desalles, Antonio A.F., Phelps, Michael E.
• Format: Article
• Language: English
• Subjects: Animals; Carbon Radioisotopes - pharmacokinetics; Carrier Proteins - metabolism; Caudate Nucleus - diagnostic imaging; Caudate Nucleus - drug effects; Caudate Nucleus - metabolism; Cercopithecus aethiops; Cocaine - analogs & derivatives; Cocaine - pharmacokinetics; Corpus Striatum - diagnostic imaging; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Dopamine - metabolism; Dopamine Plasma Membrane Transport Proteins; dopamine transporter; Dopamine Uptake Inhibitors - pharmacokinetics; Glial Cell Line-Derived Neurotrophic Factor; Magnetic Resonance Imaging; Male; Membrane Glycoproteins; Membrane Transport Proteins; Methamphetamine - toxicity; monkey; Nerve Growth Factors; Nerve Tissue Proteins - toxicity; neuroprotection; neurotoxicity; Neurotoxins - toxicity; positron emission tomography; Putamen - diagnostic imaging; Putamen - drug effects; Putamen - metabolism; Tomography, Emission-Computed
• ISSN: 0887-4476; 1098-2396
• DOI: 10.1002/(SICI)1098-2396(20000315)35:4<243::AID-SYN1>3.0.CO;2-N

The effects of glial cell line‐derived neurotrophic factor (GDNF) pretreatment on methamphetamine (METH)‐induced striatal dopamine system deficits in the vervet monkey were characterized with [11C]WIN 35,428 (WIN)‐positron emission tomography (PET). WIN, a cocaine analog that binds to the dopamine transporter (DAT), was used to provide an index of striatal dopamine terminal integrity. In two subjects, GDNF (200 μg/40 μl) was injected into the caudate and putamen unilaterally vs. saline contralaterally. After 1–2 weeks, + and –GDNF striatal WIN‐PET binding values were equivalent as calculated by multiple time graphic analysis, suggestive of an absence of unilateral DAT up‐regulation. Three other subjects (n = 3) received GDNF injections into the caudate and putamen unilaterally and one week later, were administered METH HCl (2 × 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 binding was decreased by 72% in the +GDNF and by 92% in the –GDNF striatum relative to pre‐drug assessment values. Thus, GDNF pretreatment reduced the extent of METH‐induced decreases in WIN binding. Subsequent WIN‐PET studies (1.5–9‐month range) showed a protracted recovery of WIN binding in each striatum, indicative of long‐term but partially reversible METH neurotoxicity. Further, at each time point, WIN binding remained relatively higher in the +GDNF vs. –GDNF striatum. These results provide further evidence that the adult non‐human primate brain remains responsive to exogenously administered GDNF and that this pharmacotherapy approach can counteract aspects of neurotoxic actions associated with methamphetamine. Synapse 35:243–249, 2000. © 2000 Wiley‐Liss, Inc.