Potentiating effect of tramadol on methamphetamine-induced behavioral sensitization in mice

Rationale: Polydrug abuse is a common phenomenon in human drug addicts. Previous studies have shown that both tramadol (TRAM) and methamphetamine (METH) share the ability to modulate brain monoaminergic (dopamine, 5-hydroxytryptamine, and noradrenaline) systems that may be involved in behavioral sensitization to METH. Therefore, we hypothesized that there would be an interaction between TRAM and METH on behavioral sensitization induced by METH. Objectives: To investigate whether TRAM affects METH-induced behavioral sensitization. Methods: Male Kunming mice were subjected to two regimens of drugs: (1) Mice were injected with TRAM (1-16 mg/kg, i.p.) alone or a combination of TRAM and METH (1 mg/kg, i.p.) once daily for 7 days. After 7 drug-free days (on day 15), animals were challenged with the corresponding TRAM dose or METH (1 mg/kg, i.p.). On days 1, 7, and 15, locomotion was monitored in the open field test after the last injection. (2) Mice received METH (1 mg/kg, i.p.) once daily for 7 days, followed by 7 drug-free days. On day 15, a challenge of TRAM (1-16 mg/ kg, i.p.) or TRAM plus METH (1 mg/ kg, i.p.) was given and then locomotor activity was quantified. Results: TRAM or METH challenge did not induce hyperlocomotion in mice chronically treated with TRAM, and TRAM challenge was insufficient to induce subsequent hyperlocomotion in METH-sensitized mice. However, TRAM significantly increased METH-induced hyperlocomotion. TRAM plus METH-sensitized mice showed a significantly greater hyperlocomotor response to METH challenge than METH-sensitized mice. Furthermore, TRAM (16 mg/ kg, i.p.) plus METH (1 mg/ kg, i.p.) challenge enhanced the sensitized locomotor response compared to METH-alone (1 mg/ kg, i.p.) challenge in METH-sensitized mice. Conclusions: TRAM fails to produce behavioral sensitization, and there is no apparent cross-sensitization between TRAM and METH. However, TRAM can increase METH-induced hyperlocomotion and potentiate the development and expression of behavioral sensitization to METH.