Vol. 305, Issue 1, 338-346, April 2003

Piribedil Enhances Frontocortical and Hippocampal Release of Acetylcholine in Freely Moving Rats by Blockade of _2A-Adrenoceptors: A Dialysis Comparison to Talipexole and Quinelorane in the Absence of Acetylcholinesterase Inhibitors

A. Gobert, B. Di Cara, L. Cistarelli and M. J. Millan

Department of Psychopharmacology, Institut de Recherches Servier, Paris, France

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 ₂-adrenoceptors (ARs). Suggesting a tonic, inhibitory influence of _2A-ARs upon cholinergic transmission, the ₂-AR agonist 5-bromo-6-[2-imidazolin-2-yl-amino]-quinoxaline tartrate (UK14,304), and the preferential _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 _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 _2B/2C-AR antagonists, were inactive. The dopaminergic agonist and antiparkinson agent piribedil, which behaves as an antagonist at 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 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 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 _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.