The present experiments investigated the effects of the specific alpha(2)-adrenoceptor antagonist
atipamezole, alone and in combination with a
dopamine agonist, on motor function in rats with a unilateral
6-hydroxydopamine lesion of the nigro-striatal pathway and on exploratory behaviour and cardiovascular function in rats equipped with telemetry transmitters.
Dexmedetomidine, an alpha(2)-adrenoceptor agonist and the alpha(2)-adrenoceptor antagonists
idazoxan and
yohimbine were used as reference compounds. In the unilaterally lesioned animals, direct
dopamine agonists, such as
apomorphine, induce contralateral turning behaviour. Indirect agonists, such as
amphetamine, induce ipsilateral circling in the animals.
Atipamezole (0.3 mg/kg s.c) potentiated and
dexmedetomidine (10 micro g/kg s.c.) decreased contralateral circling evoked by
apomorphine (50 micro g/kg s.c.) and by
l-3,4-dihydroxyphenylalanine (
L-DOPA, 5 mg/kg i.p.).
Atipamezole also prolonged the duration of action of
L-DOPA.
Atipamezole dose-dependently induced ipsilateral turning behaviour and potentiated turning induced by
amphetamine (1 mg/kg i.p.). The alpha(1)-adrenoceptor antagonist
prazosin (0.1 mg/kg i.p.) partially antagonised the effect of
amphetamine and had a strong inhibitory effect on the
atipamezole-induced potentiation of the
amphetamine response.
Prazosin did not have any major effect on either the
apomorphine response itself or on the potentiation of the
apomorphine response by
atipamezole. This suggests that
atipamezole can modulate motor function both indirectly, by stimulating the release of
noradrenaline and directly, by blocking postsynaptic alpha(2)-adrenoceptors in neurones other than noradrenergic nerves. The alpha(2)-adrenoceptor antagonists, when tested at comparably effective central alpha(2)-adrenoceptor antagonising doses in a rat
mydriasis model:
atipamezole 0.3 mg/kg s.c.,
idazoxan 1 mg/kg s.c. and
yohimbine 3 mg/kg s.c., all induced ipsilateral turning behaviour and potentiated
apomorphine-induced contralateral circling. The effects of the alpha(2)-adrenoceptor antagonists were in general similar in these experiments. In habituated non-lesioned rats equipped with telemetry transmitters,
apomorphine (50 micro g/kg s.c.) decreased blood pressure in the home cage and in an open-field test. It also decreased spontaneous motor activity in the open field. Neither
atipamezole (0.3 mg/kg s.c.) nor
idazoxan (1 mg/kg s.c.) had any effect on blood pressure when given alone, but reversed the
apomorphine-induced decrease in blood pressure.
Atipamezole also diminished
apomorphine-induced sedation in the open-field test. In conclusion,
atipamezole improved the efficacy of
L-DOPA and
apomorphine in an animal model of
Parkinson's disease and also reduced adverse
dopaminergic effects on vigilance and on cardiovascular function. These results suggest that an investigation of the effects of specific alpha(2)-adrenoceptor antagonists in
Parkinson's disease patients is warranted.