Effect of a stereospecific D2-dopamine agonist on acetylcholine concentration in corpus striatum of rat brain.

The enantiomers of LY141865, trans(+/-)-4,4a,5,6,7,8a,9-octahydro-5-propyl-2H-pyrazolo[3,4-g]qu inoline, were compared as dopamine D2 agonists by determining their abilities to elevate acetylcholine concentrations in rat corpus striatum. The levorotatory isomer, LY156258, increased striatal acetylcholine concentration at doses of 0.1-1 mg/kg i.p., whereas the dextrorotatory isomer had no effect even at doses as high as 30 mg/kg. The levorotatory isomer also decreased striatal concentrations of the dopamine metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, but did not significantly alter dopamine or 5-hydroxyindoleacetic acid concentration. The dextrorotatory isomer had no effect on any of these substances alone and did not alter the effects of the levorotatory isomer. The elevation of striatal acetylcholine levels by LY156258 was mimicked by pergolide, a dopamine agonist, and was totally prevented by pretreatment with haloperidol, a dopamine antagonist. The elevation of striatal acetylcholine concentration by LY157258 was maximal at 0.5 hour and declined thereafter, following a time course similar to that of pergolide. Neither LY141865 nor LY156258 shared with peroglide and dopamine the ability to activate striatal adenylate cyclase in vitro, an effect mediated by D1 receptors. LY141865 and LY156258 (but not the dextrorotatory isomer) inhibited the binding of tritiated apomorphine and spiperone to striatal membrane receptors, but were not as potent as pergolide, they also had less effect, or no effect, on the binding of other tritiated ligands (dopamine, WB4101, clonidine, dihydroalprenolol, pyrilamine or quinuclidinyl benzilate) to their membrane receptors. These results indicate that LY156258 stereospecifically activates dopamine D2 receptors and the studies are the first evidence of sterospecificity of dopamine receptors mediating an increase in striatal acetylcholine concentration.