Differential modulation of (+)-amphetamine-induced rotation in unilateral substantia nigra-lesioned rats by alpha 1 as compared to alpha 2 agonists and antagonists.
In rats sustaining unilateral 6-hydroxy-dopamine lesions of the substantia nigra (SN), the indirect dopaminergic agonist, (+)-amphetamine (AMPH), dose-dependently induced robust, ipsilateral rotation: this could be dose-dependently abolished by the dopamine (D2/D1) antagonist, haloperidol. The selective alpha 1 antagonist, prazosin, dose-dependently attenuated the action of AMPH though rotation was not completely abolished. In the presence of a constant dose of prazosin, the dose-response curve for induction of rotation by AMPH was shifted to the right. The action of prazosin was mimicked by a further alpha 1 antagonist, corynanthine. In contrast, the selective alpha 1 agonist, ST 587, potentiated the rotation evoked by AMPH. The selective alpha 2 antagonist, idazoxan, dose-dependently potentiated the action of AMPH and, in the presence of a constant dose of idazoxan, the dose-response curve for AMPH was shifted to the left. This effect of idazoxan was mimicked by a further alpha 2 antagonist, yohimbine. In distinction, the selective alpha 2 agonist, UK 14,304, dose-dependently attenuated the action of AMPH, an action mimicked by the alpha 2 partial agonist, clonidine. Upon administration alone, the above mentioned drugs did not induce rotation. The data indicate that activation and antagonism of alpha 1 receptors enhance and inhibit rotation, respectively, whereas activation and antagonism of alpha 2 receptors inhibit and enhance rotation, respectively. These findings demonstrate an opposite alpha 1 and alpha 2 receptor-mediated control of rotation in this model. They suggest that an increase and decrease in noradrenergic tone, respectively, facilitate and inhibit locomotor activity controlled via the nigro-striatal dopaminergic pathway. The possible relevance of these findings to Parkinson's disease is discussed.
FONDAX, Groupe de Recherche Servier, Paris, France.
M
M
Mavridis
F C
FC
Colpaert
M J
MJ
Millan
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D003913:Dextroamphetamine / Q000494:pharmacology*; D004298:Dopamine / Q000502:physiology*; D004347:Drug Interactions; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012399:Rotation; D013239:Stereotyped Behavior / Q000187:drug effects*; D013378:Substantia Nigra / Q000187:drug effects / Q000502:physiology*
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D006220:Haloperidol; D003913:Dextroamphetamine; D004298:Dopamine; D009638:Norepinephrine