l -Isocorypalmine reduces behavioral sensitization and rewarding effects of cocaine in mice by acting on dopamine receptors

Abstract Background We previously reported isolation of l -isocorypalmine ( l -ICP), a mono-demethylated analog of l -tetrahydropalmatine ( l -THP), from the plant Corydalis yanhusuo . Here we characterized its in vitro pharmacological properties and examined its effects on cocaine-induced behaviors in mice. Methods Receptor binding, cAMP and [35 S]GTPγS assays were used to examine pharmacological actions of l -ICP in vitro. Effects of l -ICP on cocaine-induced locomotor hyperactivity and sensitization and conditioned place preference (CPP) in mice were investigated. HPLC was employed to analyze metabolites of l -ICP in mouse serum. Results Among more than 40 targets screened, l -ICP and l -THP bound only to dopamine (DA) receptors. l -ICP was a high-affinity partial agonist of D1 and D5 receptors and a moderate-affinity antagonist of D2, D3 and D4 receptors, whereas l -THP bound to only D1 and D5 receptors, with lower affinities than l -ICP. At 10 mg/kg (i.p.), l -ICP inhibited spontaneous locomotor activity for a shorter time than l -THP. Pretreatment with l -ICP reduced cocaine-induced locomotor hyperactivities. Administration of l -ICP before cocaine once a day for 5 days reduced cocaine-induced locomotor sensitization on days 5 and 13 after 7 days of withdrawal. Pretreatment with l -ICP before cocaine daily for 6 days blocked cocaine-induced CPP, while l -ICP itself did not cause preference or aversion. HPLC analysis showed that l -ICP was the main compound in mouse serum following i.p. injection of l -ICP. Conclusions l -ICP likely acts as a D1 partial agonist and a D2 antagonist to produce its in vivo effects and may be a promising agent for treatment of cocaine addiction.