Cholinergic manipulation of motor disability and l-DOPA-induced dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets

Anti-cholinergic drugs are used in the treatment of Parkinson’s disease (PD) and they can improve motor disability in some patients and may alter the expression of dyskinesia. We report the effects of anti-cholinergic and pro-cholinergic agents administered alone and combined with l-DOPA, on motor function in 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets. Administration of atropine to MPTP-treated marmosets, not previously exposed to l-DOPA, improved motor disability but this did not occur with other centrally acting anti-cholinergics. Motor disability was worsened by centrally acting pro-cholinergics. However, neither peripherally acting anti- nor pro-cholinergics produced any effect on motor disability or dyskinesia. In MPTP-treated marmosets previously primed with l-DOPA to exhibit dyskinesia, acute l-DOPA challenge induced both chorea and dystonia. In these animals, centrally acting anti-cholinergics including atropine and trihexyphenidyl reversed motor deficits, but induced chorea. Combined with l-DOPA, both centrally and peripherally acting anti-cholinergics reduced peak locomotor activity and produced more chorea than dystonia compared to l-DOPA alone. Centrally acting pro-cholinergics decreased locomotor activity, worsened motor disability and induced dystonia. Co-administered with l-DOPA, pro-cholinergics reduced locomotor activity and decreased chorea while increasing dystonia compared with l-DOPA alone. In conclusion, anti-cholinergics can increase chorea with and without l-DOPA but improve motor disability. Pro-cholinergics decrease the proportion of chorea when combined with l-DOPA, increase motor disability and antagonise l-DOPA’s effectiveness. These data suggest that there may be a case for revisiting the use of anti-cholinergic drugs in the treatment of PD.