Behavioral motor recovery in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned squirrel monkey (Saimiri sciureus): changes in striatal dopamine and expression of tyrosine hydroxylase and dopamine transporter proteins

Abstract

The neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) provides an excellent opportunity to study repair and response to injury in the basal ganglia. Administration to mammals leads to the destruction of nigrostriatal dopaminergic neurons and depletion of striatal dopamine. In the squirrel monkey (Saimiri sciureus), MPTP-lesioning results in parkinsonian motor symptoms including bradykinesia, postural instability, and rigidity. Over time animals display motor behavioral recovery. To better understand this mechanism we employed a lesioning regimen of two or six subcutaneous injections of MPTP (2.0 mg/kg, free-base) to generate mild or moderate parkinsonism. Brain tissue was harvested at 6 weeks or 9 months after the last injection and analyzed for dopamine and its metabolites by high performance liquid chromatography (HPLC), and by immunohistochemical staining and Western immunoblotting for the expression of tyrosine hydroxylase (TH), dopamine transporter (DAT), and dopamine- and cAMP-responsive protein phosphatase of 32 kDa (DARPP-32), an effector molecule enriched in striatal medium spiny neurons. Several months after MPTP-lesioning, when squirrel monkeys displayed full motor behavioral recovery, striatal dopamine levels remained low with a greater return in the ventral striatum. This finding is consistent with other reports using neurotoxicant-lesioning models of the basal ganglia in rodents and other species of nonhuman primates. Elevated dopamine turnover ratio and decreased DAT expression appeared in early behavioral recovery at the 6-week time point in both mild- and moderate-parkinsonian monkeys. Tyrosine hydroxylase and DAT expression was increased in late stage recovery even within dopamine-depleted regions and supports sprouting. Altered DARPP-32 expression suggests a role of medium spiny neurons in recovery.