Levo-tetrahydropalmatine, a natural, mixed dopamine receptor antagonist, inhibits methamphetamine self-administration and methamphetamine-induced reinstatement

Abstract Despite the high prevalence of methamphetamine (METH) use, no FDA-approved pharmacological treatment is currently available for individuals with a METH addiction. Levo-tetrahydropalmatine ( l -THP) is an alkaloid substance derived from corydalis and stephania that has been used in traditional Asian medicine for its analgesic, sedative and hypnotic properties. Previous pharmacological studies of l -THP indicated that it not only binds to D1 and D2 receptors but also has a low affinity for D3 receptors and may function as an antagonist. The unique pharmacological profile of l -THP suggests that it may have potential therapeutic effects on drug addiction; however, the effects of l -THP in individuals with METH addictions are largely unknown. In this study, we investigated the effects of l -THP on METH self-administration and METH-induced reinstatement. In our experiments, l -THP (1.25, 2.50 and 5.00 mg/kg, i.p.) decreased METH self-administration under the fixed-ratio 1 schedule. l -THP (2.50 and 5.00 mg/kg, i.p) also prevented the METH-induced reinstatement of METH-seeking behaviors. Interestingly, l -THP (1.25 and 2.50 mg/kg, i.p) did not affect locomotor activity following METH injection (1 mg/kg) suggesting that the observed effects of l -THP (2.50 mg/kg) on METH-induced reinstatement were not due to motor impairments. Thus, l -THP (a natural, mixed dopamine (DA) receptor antagonist) attenuates METH self-administration and METH-induced reinstatement.