The alpha 2-adrenoceptor antagonist atipamezole potentiates anti-Parkinsonian effects and can reduce the adverse cardiovascular effects of dopaminergic drugs in rats.
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.
Haapalinna
Antti
A
Orion Corporation, Orion Pharma, P.O. Box 425, 20101, Turku, Finland. antti.haapalinna@orionpharma.com
Leino
Tiina
T
Heinonen
Esa
E
D058668:Adrenergic alpha-1 Receptor Antagonists; D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D002319:Cardiovascular System / Q000187:drug effects*; D015259:Dopamine Agents / Q000009:adverse effects* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D007093:Imidazoles / Q000494:pharmacology*; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D009068:Movement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D058668:Adrenergic alpha-1 Receptor Antagonists; D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D000978:Antiparkinson Agents; D015259:Dopamine Agents; D007093:Imidazoles; C050701:atipamezole; D007980:Levodopa