L-isocorypalmine reduces behavioral sensitization and rewarding effects of cocaine in mice by acting on dopamine receptors.
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 10mg/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.
Center for Substance Abuse Research and Department of Pharmacology, Temple University School of Medicine, 3500 North Broad Street, Philadelphia, PA 19140, USA.
Wei
W
Xu
Yujun
Y
Wang
Zhongze
Z
Ma
Yi-Ting
YT
Chiu
Peng
P
Huang
Khampaseuth
K
Rasakham
Ellen
E
Unterwald
David Y-W
DY
Lee
Lee-Yuan
LY
Liu-Chen
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001600:Berberine Alkaloids / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D003042:Cocaine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000523:psychology*; D003216:Conditioning, Operant / Q000187:drug effects; D031311:Corydalis / Q000737:chemistry; D000242:Cyclic AMP / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D011954:Receptors, Dopamine / Q000187:drug effects*; D017447:Receptors, Dopamine D1 / Q000008:administration & dosage; D050641:Receptors, Dopamine D5 / Q000819:agonists; D012201:Reward
D001600:Berberine Alkaloids; D018491:Dopamine Agonists; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; C000589018:isocorypalmine; D050641:Receptors, Dopamine D5; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C014215:tetrahydropalmatine; D000242:Cyclic AMP; D003042:Cocaine
Cocaine; Conditioned place preference; Dopamine receptor; Isocorypalmine; Sensitization; Tetrahydropalmatine