Effects of D-cycloserine on MPTP-induced behavioral and neurological changes: potential for treatment of Parkinson's disease dementia

Abstract

Glutamatergic dysfunction has been implicated in the neurodegeneration seen in Parkinson's disease (PD). Sub-chronic intraperitoneal injection with D-cycloserine (DCS), a partial agonist at the glycine binding site of the N-methyl-D-aspartate (NMDA) receptor, at dosages of 30, 100, or 200 mg/kg/day, was used to evaluate the role of NMDA receptors in neuronal and behavioral changes in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat model. Starting one day after intra-nigral infusion of MPTP, transient disturbance of motor function in the rotarod test was observed. This impairment spontaneously recovered to control levels 6 days after MPTP lesioning and DCS treatment facilitated recovery. MPTP lesioning also caused deficits in working memory and anxiety-like behavior in the T-maze and elevated plus-maze tests, respectively. Further, object recognition was disrupted in MPTP-lesioned rats, and interleukin-2 levels in the striatum, amygdala, and non-prefrontal cortex were increased, both changes being restored by DCS treatment. Furthermore, MPTP lesion-induced dopaminergic degeneration, microglial activation, and cell loss in the hippocampal CA1 area were all improved by DCS treatment. These results suggest that NMDA receptors are involved in PD-related neuronal and behavioral dysfunctions and that DCS may have clinical potential in the treatment of dementia associated with PD.