Effects of Isoniazid on Tolerance and Sensitization to the Rewarding Properties of Morphine: A Conditioned Place Preference Procedure Investigation in Mice

Abstract

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.

Keywords: Conditioned place preference; Isoniazid; Morphine; Reward; Sensitization; Tolerance.

Figure 1.

The one-way ANOVA results A. Effects of Morphine; or B. Isoniazid on the Induction of CPP Animals received the different doses of morphine (0.5, 1, 2.5, 5, and 10 mg/kg, SC) or isoniazid (25, 50, and 75 mg/kg, IP) in the conditioning phase of the CPP paradigm. The change in preference was calculated for the mice of each group for 10 minutes. Each point shows the Mean±SEM of the change in preference for eight mice. *P<0.05; ***P<0.001 compared with the saline control group.

Figure 2.

Effects of the Different High Doses of Morphine on the Induction of Tolerance to the Rewarding Effects of Morphine Three groups of mice received high doses of morphine (12.5, 25, and 50 mg/kg, SC) twice a day for four days. The induction of CPP was commenced with the effective dose of morphine (5 mg/kg, SC) on the fifth day of the experiment. Each point shows the Mean±SEM of the change in preference for eight mice; ***P<0.001 compared with the saline control group.

Figure 3.

Effects of Isoniazid on Tolerance Induction With the High-Dose of Morphine Tolerance was induced in three groups of mice by the injection of the high dose of morphine (25 mg/kg) twice a day for four days. One hour before the administration of the high doses of morphine, these groups of mice received the different doses of isoniazid (25, 50, and 75 mg/kg, IP). On the fifth day of the experiment, the CPP was induced by an effective dose of morphine. Each point shows the Mean±SEM of the change in preference for eight mice; *** P<0.001 compared with the saline control group.

Figure 4.

Effects of Isoniazid on the Acquisition of Sensitization to Morphine or Saline One hour after the administration of isoniazid (25, 50, and 75 mg/kg, IP) to three groups of mice, the animals received an effective dose of morphine (5 mg/kg, SC). Three other groups of mice received saline (10 mL/kg), one hour after the administration of the same doses of isoniazid. After a 5-day interval, the induction of CPP carried out with the ineffective dose of morphine (0.5 mg/kg), for all the animals. Each point shows the Mean±SEM of the change in preference for eight mice; ** P<0.01 compared with the morphine control group; ^### P<0.001 compared with the saline control group.