Levo-tetrahydropalmatine inhibits the acquisition of ketamine-induced conditioned place preference by regulating the expression of ERK and CREB phosphorylation in rats

• The drug l-THP attenuated the acquisition of ketamine-induced CPP in rats.
• l-THP prevented the increase in ERK phosphorylation in the Hip and CPu of the rats exhibiting CPP.
• l-THP decreased the phosphorylation of CREB in the Hip and CPu of the rats exhibiting CPP.
• l-THP may be a potential medicine for the treatment of ketamine addiction.

Levo-tetrahydropalmatine (l-THP) is an alkaloid purified from the Chinese herbs Corydalis and Stephania and has been used in many traditional Chinese herbal preparations for its sedative, analgesic and hypnotic properties. Previous studies demonstrated that l-THP has antagonistic activity on dopamine receptors; thus, it may have potential therapeutic effects on drug abuse. However, whether l-THP affects ketamine-induced conditioned place preference (CPP) remains unclear. Therefore, the present study was designed to evaluate the effects of l-THP on the rewarding behavior of ketamine through CPP. Results revealed that ketamine (5, 10 and 15 mg/kg) induced CPP in rats. Furthermore, Ketamine (10 mg/kg) promoted the phosphorylation of extracellular-regulated kinase (ERK) and cAMP responsive element binding protein (CREB) in the hippocampus (Hip) and caudate putamen (CPu), but not in the prefrontal cortex (PFc). l-THP (20 mg/kg) co-administered with ketamine during conditioning inhibited the acquisition of ketamine-induced CPP in rats. Furthermore, l-THP (20 mg/kg) prevented the enhanced phosphorylation of ERK and CREB in CPu and Hip. These results suggest that l-THP has potential therapeutic effects on ketamine-induced CPP. The underlying molecular mechanism may be related to its inhibitory effect on ERK and CREB phosphorylation in Hip and CPu. The present data supports the potential use of l-THP for the treatment of ketamine addiction.