The purpose of the present investigation was to study the effects of simultaneous manipulations of central cholinergic, adrenergic and glutamatergic systems on locomotion in an animal model of Parkinson's disease. Mice were deprived of their monoamine stores by pretreatment with the monoamine depleter reserpine and the catecholamine synthesis inhibitor alpha-methyl-p-tyrosine, given 18 h and 60 min, respectively, before the acute experiment. Traditionally, only dopaminergic agonists have been shown to reverse the akinesia thus produced. However, in the present study it is demonstrated that if a muscarine receptor antagonist (atropine or biperiden) is combined with an alpha-adrenergic agonist/alpha-adrenergic agonist precursor (clonidine or L-alpha-methyl-dopa), a marked locomotor stimulation can be achieved, although either agent given alone is ineffective. Adding an NMDA antagonist (MK-801, ketamine or SDZ EAA 494) to the combination biperiden + clonidine resulted in further potentiation of the locomotor stimulatory effects.