1. The treatment of
Parkinson's disease relies predominantly upon
dopamine replacement
therapy, usually with l-
dihydroxyphenylalanine (
L-DOPA). However, side-effects of long-term treatment, such as
L-DOPA-induced
dyskinesias can be more debilitating than the disease itself. Non-dopaminergic treatment strategies might therefore be advantageous. 2. The aim of this study was to investigate the potential anti-parkinsonian efficacy of the
kappa-opioid receptor agonist,
enadoline, and the alpha-adrenoreceptor agonist,
clonidine, both alone or in combination, in the
reserpine-treated rat model of
Parkinson's disease. 3. Rats were treated with
reserpine (3 mg kg-1), and experiments carried out 18 h later, at which time they exhibited profound akinesia (normal animals 1251+/-228 mobile counts h-1,
reserpine-treated animals 9+/-2 mobile counts h-1). Both
enadoline and
clonidine increased locomotion in
reserpine-treated rats in a dose-dependent manner. The maximum locomotor-stimulating effect of
enadoline alone was seen at a dose of 0.2 mg kg-1 (208+/-63 mobile counts h-1). The maximum effect of
clonidine was seen at a dose of 2 mg kg-1 (536+/-184 mobile counts h-1). 4. Co-administration of
enadoline (0.1 mg kg-1) and
clonidine (0.01 - 0.1 mg kg-1) at sub-threshold doses, synergistically increased locomotion. 5. The synergistic stimulation of locomotion in the
reserpine-treated rat involved activation of
kappa-opioid receptors and a combination of both alpha1 and alpha2-adrenoreceptors. 6. The results presented suggest a need for further studies on the potential of stimulating kappa-
opioid and/or alpha-adrenoreceptors as a
therapy for
Parkinson's disease. Furthermore, the studies may offer potential mechanistic explanations of the ability of alpha2-adrenergic receptor antagonist to reduce
L-DOPA-induced
dyskinesia in
Parkinson's disease.