Introduction: The GABAergic system of the brain plays a key role in morphine tolerance and sensitization. As isoniazid is a modulator of the GABAergic system, the present study aims to understand whether isoniazid can influence the induction of tolerance and sensitization to the rewarding effects of morphine. 
Methods: The rewarding effects of morphine and isoniazid were assessed using a Conditioned Place Preference (CPP) procedure in female mice. Tolerance to the rewarding effects of morphine was induced with high-dose morphine (25 mg/kg, SC), twice a day, for four days. Also, the sensitization was induced with an effective dose of morphine (5 mg/kg, SC), once a day, for three days. During the induction of tolerance or sensitization, the different groups of mice received saline or isoniazid (25, 50, and 75 mg/kg, IP) one hour before each morphine injection.
Results: Morphine (0.5-10 mg/kg, SC) produced a significant CPP, but isoniazid (25, 50, and 75 mg/kg, IP) did not induce place preference or place aversion in mice. Although an effective dose of morphine (5 mg/kg, SC) did not induce CPP in morphine tolerated mice, an ineffective dose (0.5 mg/kg, SC) could produce a significant CPP in morphine-sensitized animals. The administration of isoniazid before morphine (on the days of tolerance or sensitization induction) inhibited the development of tolerance or sensitization to the rewarding effect of morphine in the CPP paradigm.
Conclusion: Isoniazid can be a useful drug for the prevention of tolerance and sensitization to the rewarding effects of morphine.