Levo-tetrahydropalmatine attenuates the development and expression of methamphetamine-induced locomotor sensitization and the accompanying activation of ERK in the nucleus accumbens and caudate putamen in mice

Abstract

Levo-tetrahydropalmatine (l-THP) is an alkaloid purified from corydalis and has been used in many traditional Chinese herbal preparations for its analgesic, sedative, and hypnotic properties. Previous studies indicated that l-THP has modest antagonist activity against dopamine receptors and thus it might have potential therapeutic effects on drug addiction. However, whether and how l-THP contributes to methamphetamine (METH)-induced locomotor sensitization remains unclear. Therefore, the current study aims to examine the roles of l-THP in the development and expression of METH-induced locomotor sensitization as well as the accompanying extracellular-regulated kinase (ERK) activation in the nucleus accumbens (NAc), caudate putamen (CPu) and prefrontal cortex (PFc) in mice. We found that moderate doses of METH (0.5 and 2mg/kg) induced hyper-locomotor activity in mice on all METH injection days whereas high dose of METH (5mg/kg)-treated mice displayed only acute locomotor response to METH and severe stereotyped behaviors on the first day after drug injection. Interestingly, only 2mg/kg dose of METH-induced locomotor sensitization which was accompanied by the activation of ERK1/2 in the NAc and CPu in mice. Although l-THP (5 and 10mg/kg) per se did not induce obvious changes in locomotor activities in mice, its co-administration with METH could significantly attenuate acute METH-induced hyper-locomotor activity, the development and expression of METH-induced locomotor sensitization, and the accompanying ERK1/2 activation in the NAc and CPu. These results suggest that l-THP has potential therapeutic effect on METH-induced locomotor sensitization, and the underlying molecular mechanism might be related to its inhibitory effect on ERK1/2 phosphorylation in the NAc and CPu.