Attenuation of methamphetamine-induced behavioral sensitization in mice by systemic administration of naltrexone

Abstract

Repeated intermittent exposure to psychostimulants was found to produce behavioral sensitization. The present study was designed to establish a mouse model and by which to investigate whether opioidergic system plays a role in methamphetamine-induced behavioral sensitization. Mice injected with 2.5 mg/kg of methamphetamine once a day for 7 consecutive days showed behavioral sensitization after challenge with 0.3125 mg/kg of the drug on day 11, whereas mice injected with a lower daily dose (1.25 mg/kg) did not. Mice received daily injections with either 1.25 or 2.5 mg/kg of methamphetamine showed behavioral sensitization after challenge with 1.25 mg/kg of the drug on days 11, 21, and 28. To investigate the role of opioidergic system in the induction and expression of behavioral sensitization, long-acting but non-selective opioid antagonist naltrexone was administrated prior to the daily injections of and challenge with methamphetamine, respectively. Our results show that the expressions of behavioral sensitization were attenuated by pretreatment with 10 or 20 mg/kg of naltrexone either during the induction period or before methamphetamine challenge when they were tested on days 11 and 21. These results indicate that repeated injection with methamphetamine dose-dependently induced behavioral sensitization in mice, and suggest the involvement of opioid receptors in the induction and expression of methamphetamine-induced behavioral sensitization.

Fig. 1

Experimental protocol. For induction of behavioral sensitization, mice were injected with saline or METH once a day for 7 consecutive days in their home cages. The expressions of behavioral sensitization after short-term and long-term abstinence from METH were tested in locomotor arena on days 11 and 21, respectively (A). To investigate the involvement of opioid receptors in the induction of behavioral sensitization, NAT was administered 60 min prior to the daily injections of saline or METH, and the expressions of behavioral sensitization were tested on days 11 and 21 in the absence of NAT (B). To investigate the involvement of opioid receptors in the expression of sensitization, NAT was administered 60 min prior to saline or METH challenge (C).

Fig. 2

Dose effects of acute injection of METH on locomotor activity in mice. Temporal profiles of locomotor activity in mice induced by 0 (saline), 0.3125, 0.625, 1.25, 2.5 mg/kg (A), 3.75, 5, and 7.5 mg/kg (B) of METH. Dose–response of METH for locomotor activities during the first 5 min and the entire 120 min period of testing after drug injection are summarized in (C) and (D), respectively. Data are expressed as mean ± S.E.M. (n = 5). *P < 0.05, **P < 0.01, compared with the response induced by saline; ⁺P < 0.05, ⁺⁺P < 0.01, compared with the response induced by the dose of 0.3125 mg/kg; ^#P < 0.05, ^##P < 0.01, compared with the response induced by the dose of 0.625 mg/kg; ^$$P < 0.01, compared with the response induced by the dose of 1.25 mg/kg, according to Student–Newman–Keuls multiple comparison test after a one-way ANOVA.

Fig. 3

Effects of repeated injection of METH on locomotor activity in mice. Locomotor activities induced by daily injections of saline or 1.25 mg/kg of METH during the entire 120 min period of testing (A). Temporal profiles of locomotor activity in mice induced by 1.25 mg/kg of METH on days 1, 2, and 7 (B). Data are expressed as mean ± S.E.M. (n = 8–11). **P < 0.01, compared with the response in the same group of mice on day 1, according to Dunnett's post-tests after a one-way repeated measures ANOVA.

Fig. 4

Effects of METH on the induction and expression of behavioral sensitization. Dose effects of METH on locomotor activity in mice tested on day 11, 4 days after pretreatments with saline, 1.25 or 2.5 mg/kg of METH (A). Locomotor activities in mice induced by 1.25 mg/kg of METH on days 21 and 28, 14 and 21 days after repeated drug pretreatment, respectively (B). Data are expressed as mean ± S.E.M. (n = 5–8). *P < 0.05, **P < 0.01, compared with the response of the corresponding saline-pretreated (saline × 7) group, according to Student–Newman–Keuls multiple comparison test after a one-way ANOVA.

Fig. 5

Dose effects of NAT on the induction of behavioral sensitization. During the induction period, mice were pretreated with 0 (control), 5, 10, or 20 mg/kg of NAT prior to daily injections of saline (saline × 7) or 2.5 mg/kg of METH (METH × 7). Effects of NAT on the induction of behavioral sensitization were tested on days 11 (A) and 21 (B), respectively, by determining the locomotor activities in mice induced by 1.25 mg/kg of METH challenge in the absence of the antagonist. Data are expressed as total distance traveled (mean ± S.E.M.) for the entire 120 min period of testing (n = 8–12). ⁺P < 0.05, ⁺⁺P < 0.01, compared with the response of the corresponding control group; *P < 0.05, **P < 0.01, compared with the response of the corresponding saline-pretreated (saline × 7) group, according to Bonferroni post-tests after a two-way ANOVA.

Fig. 6

Dose effects of NAT on the expression of behavioral sensitization. Effects of NAT on the expression of behavioral sensitization after short-term and long-term periods of abstinence were tested on days 11 (A) and 21 (B), respectively, by determining the locomotor response to 1.25 mg/kg of METH challenge following the pretreatment of 0 (control), 5, 10, or 20 mg/kg of NAT. Data are expressed as total distance traveled (mean ± S.E.M.) for the entire 120 min period of testing (n = 10–16). ⁺P < 0.05, ⁺⁺P < 0.01, compared with the response of the corresponding control group; **P < 0.01, compared with the response of the corresponding saline-pretreated (saline × 7) group, according to Bonferroni post-tests after a two-way ANOVA.