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

Abstract

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 15mg/kg) induced CPP in rats. Furthermore, Ketamine (10mg/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 (20mg/kg) co-administered with ketamine during conditioning inhibited the acquisition of ketamine-induced CPP in rats. Furthermore, l-THP (20mg/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.

Pharmacokinetic Effects of l-Tetrahydropalmatine on Ketamine in Rat Plasma by Ultraperformance Liquid Chromatography Tandem Mass Spectrometry

“…As a DA receptor antagonist, l - THP has therapeutic potential in the treatment of addiction to many drugs, including cocaine [ 15 ], heroin [ 16 ], and methamphetamine [ 17 ]. In our previous study, l - THP showed a potential therapeutic effect on KET addiction [ 10 ]. However, the pharmacokinetic effects of l - THP on KET remained unclear.…”

“…As a nonselective DA antagonist, l - THP has recently emerged as a promising agent for treating addiction to many types of drugs, including cocaine [ 6 , 7 ], methamphetamine [ 8 ], and oxycodone [ 9 ]. In our previous study, l - THP showed a potential therapeutic effect on KET addiction [ 10 ]. Moreover, l - THP is safe and effective, with no obvious side effects.…”

Cocaine Effects on Dopaminergic Transmission Depend on a Balance between Sigma-1 and Sigma-2 Receptor Expression

“…It is known that ERKs are involved in the plastic changes induced by the consumption of drugs of abuse ( Radwanska et al, 2005 ). In addition, the inhibition of ERK phosphorylation alters learned place-preference in a paradigm of drug-of-abuse consumption, whereas activation of ERK1/2 is necessary to establish the association between place preference and drug consumption ( Valjent et al, 2006 ; Du et al, 2017 ). In this context, knocking down ERK1 has shown that enhanced ERK2 signaling and repeated exposure to the drug facilitate the plastic changes leading to drug addiction ( Ferguson et al, 2006 ).…”

The sigma-1 receptor as key common factor in cocaine and food-seeking behaviors

“…Furthermore, activation of the MAP kinase pathway contributes to the plastic changes induced by drugs of abuse (see; Valjent et al 2004 and references therein). Activation of the MAP kinase pathway is needed for establishing an association between drug consumption and CPP (Valjent et al 2006, Du et al 2017. Of the two predominant ERK isoforms, ERK2 seems more directly involved in remodeling produced by repeated exposure to cocaine.…”