mu-Opioid receptor knockout mice are insensitive to methamphetamine-induced behavioral sensitization

Abstract

Repeated administration of psychostimulants to rodents can lead to behavioral sensitization. Previous studies, using nonspecific opioid receptor (OR) antagonists, revealed that ORs were involved in modulation of behavioral sensitization to methamphetamine (METH). However, the contribution of OR subtypes remains unclear. In the present study, using mu-OR knockout mice, we examined the role of mu-OR in the development of METH sensitization. Mice received daily intraperitoneal injection of drug or saline for 7 consecutive days to initiate sensitization. To express sensitization, animals received one injection of drug (the same as for initiation) or saline on day 11. Animal locomotor activity and stereotypy were monitored during the periods of initiation and expression of sensitization. Also, the concentrations of METH and its active metabolite amphetamine in the blood were measured after single and repeated administrations of METH. METH promoted significant locomotor hyperactivity at low doses and stereotyped behaviors at relative high doses (2.5 mg/kg and above). Repeated administration of METH led to the initiation and expression of behavioral sensitization in wild-type mice. METH-induced behavioral responses were attenuated in the mu-OR knockout mice. Haloperidol (a dopamine receptor antagonist) showed a more potent effect in counteracting METH-induced stereotypy in the mu-OR knockout mice. Saline did not induce behavioral sensitization in either genotype. No significant difference was observed in disposition of METH and amphetamine between the two genotypes. Our study indicated that the mu-opioid system is involved in modulating the development of behavioral sensitization to METH. (c) 2010 Wiley-Liss, Inc.

Fig. 1

Dose–response relationship of METH and locomotor activity in wild-type and μ-OR knockout mice. A: Basal locomotor activity before saline or METH injection. B: Locomotor activity after saline or METH injection. ^a,b,c,d,eP < 0.05 compared with the corresponding dose group within the genotype. ^#P < 0.05 between the genotypes on the same dose.

Fig. 2

Effect of repeated administration of saline (A) or METH (0.62 mg/kg; B) on locomotor activity in wild-type and μ-OR knockout mice. ⋆P < 0.05 compared with the response detected on day 1 within the genotype. ^#P < 0.05 between the genotypes on the same experimental day.

Fig. 3

Effect of repeated administration of METH at doses of 2.5 mg/kg (A) or 10 mg/kg (B) on stereotyped behaviors in wild-type and μ-OR knockout mice. ⋆P < 0.05 compared with the response detected on day 1 within the genotype. ^#P < 0.05 between the genotypes on the same experimental day.

Fig. 4

Dose–response relationship of haloperidol in counteracting METH-evoked stereotypy in sensitized wild-type mice (A) and μ-OR knockout mice (B). Both genotypes of mice were i.p. injected with METH (10 mg/kg) for 7 consecutive days to initiate sensitization. On day 11, after 4 abstinent days, each group of mice was injected s.c. with saline or one dose of haloperidol and then, 30 min later, injected with METH (10 mg/kg, i.p. injection). Animal stereotyped behaviors were monitored and scored at 15-min intervals for 5 hr.

Fig. 5

The blood METH (A) and amphetamine (B) concentration–time profiles after single and repeated i.p. injection of METH (2.5 mg/kg).