Introduction: Repeated administration of Morphine as an opioid may cause tolerance to its different actions, including locomotor stimulating effect. The purpose of the current study was to evaluate the effects of isoniazid, as a GABAergic drug, on tolerance to morphine locomotor stimulating effect in mice. Methods: Fourteen groups of male mice (22-30 g) were used. Acute locomotor effects of morphine (0,1,5,10,20,and 30 mg/kg, s.c.) or isoniazid (0, 25, 50, and75 mg/kg, i.p.) was evaluated using an infrared activity meter for 20 minutes. Tolerance to the locomotor effect of morphine was induced by injection of morphine (30 mg/kg, s.c., twice a day for 3 days). On the test day (day 4), One h. before administration of morphine (30 mg/kg, s.c.), one group (as control) received saline and the other three groups received isoniazid (25, 50, and 75 mg/kg, i.p.).Then, the locomotor activity of the animals was evaluated for 20 minutes. Results: Morphine showed biphasic effects on the locomotor activity of mice. While morphine decreased the locomotor activity in low dose (5 mg/kg), it increased the behavior in high dose (30 mg/kg). On the other hand, isoniazid showed no significant effect on locomotor activity. Moreover, chronic administration of a high dose of morphine could induce tolerance to its locomotor activating effects, Tolerance was shown in control animals that received a challenging dose of morphine (30 mg/kg) on the test day. The animals showed reduced locomotor activity even with the high dose of morphine (30 mg/kg). Administration of isoniazid before morphine inhibited the expression of locomotor tolerance induced by morphine. The animals that received isoniazid before morphine had higher locomotor activity compared with the saline-treated group. Conclusion: Isoniazid may inhibit the expression of tolerance to the locomotor-enhancing effect of morphine.
