Piribedil enhances frontocortical and hippocampal release of acetylcholine in freely moving rats by blockade of alpha 2A-adrenoceptors: a dialysis comparison to talipexole and quinelorane in the absence of acetylcholinesterase inhibitors.
In a dialysis procedure not requiring perfusate addition of acetylcholinesterase inhibitors to "boost" basal levels of acetylcholine (ACh), the influence of the antiparkinson agent piribedil upon levels of ACh in frontal cortex and dorsal hippocampus of freely moving rats was compared with those of other antiparkinson drugs and selective ligands at alpha(2)-adrenoceptors (ARs). Suggesting a tonic, inhibitory influence of alpha(2A)-ARs upon cholinergic transmission, the alpha(2)-AR agonist 5-bromo-6-[2-imidazolin-2-yl-amino]-quinoxaline tartrate (UK14,304), and the preferential alpha(2A)-AR agonist guanabenz reduced levels of ACh. They were elevated by the antagonists 2(2-methoxy-1,4 benzodioxan-2-yl)-2-imidazoline HCl (RX821002) and atipamezole and by the preferential alpha(2A)-AR antagonist 2-(2H-(1-methyl-1,3-dihydroisoindole)methyl)-4,5-dihydroimidazole (BRL44008). In contrast, trans-2,3,9,13b-tetrahydro-1,2-dimethyl-1H-dibenz[c,f]imidazo[1,5-a]azepine (BRL41992) and prazosin, preferential alpha(2B/2C)-AR antagonists, were inactive. The dopaminergic agonist and antiparkinson agent piribedil, which behaves as an antagonist at alpha(2)-ARs, dose dependently increased extracellular levels of ACh. This action was absent upon pretreatment with a maximally effective dose of RX821002. On the other hand, a further dopaminergic agonist and antiparkinson agent, talipexole, which possesses agonist properties at alpha(2)-ARs, dose dependently reduced levels of ACh. This action was also blocked by RX821002. In contrast to piribedil and talipexole, quinelorane, which interacts with dopaminergic receptors but not alpha(2)-ARs, failed to affect ACh levels. Finally, in analogy to the frontal cortex, piribedil likewise elicited a dose-dependent increase in extracellular levels of ACh in the dorsal hippocampus. In conclusion, in distinction to talipexole and quinelorane, and reflecting its antagonist properties at alpha(2A)-ARs, piribedil reinforces cholinergic transmission in the frontal cortex and dorsal hippocampus of freely moving rats. These actions may be related to its facilitatory influence upon cognitive function.
Gobert
A
A
Department of Psychopharmacology, Institut de Recherches Servier, Paris, France.
Di Cara
B
B
Cistarelli
L
L
Millan
M J
MJ
D000109:Acetylcholine / Q000378:metabolism*; D018674:Adrenergic Antagonists / Q000494:pharmacology*; D058669:Adrenergic alpha-2 Receptor Antagonists; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D000068438:Brimonidine Tartrate; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D003956:Dialysis; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D019329:Idazoxan / Q000031:analogs & derivatives / Q000494:pharmacology; D010891:Piribedil / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D018674:Adrenergic Antagonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D001381:Azepines; D002800:Cholinesterase Inhibitors; D018491:Dopamine Agonists; D011804:Quinolines; D011810:Quinoxalines; D000068438:Brimonidine Tartrate; C024763:talipexole; D010891:Piribedil; C058525:2-methoxyidazoxan; D000109:Acetylcholine; D004298:Dopamine; D019329:Idazoxan; C047726:quinelorane