Dissociable roles of mGlu5 and dopamine receptors in the rewarding and sensitizing properties of morphine and cocaine

Abstract

Rationale: Drugs of abuse are initially used because of their rewarding properties. As a result of repeated drug exposure, sensitization to certain behavioral effects of drugs occurs, which may facilitate the development of addiction. Recent studies have implicated the metabotropic glutamate receptor 5 (mGlu5 receptor) in drug reward, but its role in sensitization is unclear. Stimulation of dopamine receptors plays an important role in drug reward, but not in the sensitizing properties of cocaine and morphine.

Objective: This study aims to evaluate the role of mGlu5 and dopamine receptors in the development of cocaine- and morphine-induced conditioned place preference (CPP) and psychomotor sensitization.

Materials and methods: Rats were treated with the mGlu5 receptor antagonist MTEP (0, 1, 3, and 10 mg/kg, i.p.) or the dopamine receptor antagonist α-flupenthixol (0, 0.125, 0.25, and 0.5 mg/kg, i.p.) during place conditioning with either morphine (3 mg/kg, s.c.) or cocaine (15 mg/kg, i.p.). Furthermore, MTEP (1 mg/kg, i.p.) or α-flupenthixol (0.5 mg/kg, i.p.) was co-administered during cocaine (30 mg/kg, i.p.) or morphine (3.0 mg/kg, s.c.) pretreatment and psychomotor sensitization was tested 3 weeks post-treatment.

Results: MTEP attenuated the development of morphine- but not cocaine-induced CPP. In contrast, MTEP suppressed the development of cocaine- but not morphine-induced psychomotor sensitization. α-Flupenthixol blocked the development of both cocaine- and morphine-induced CPP but did not affect the development of sensitization to either drug.

Conclusion: Dopamine receptor stimulation mediates cocaine and morphine reward but not sensitization. In contrast, the role of mGlu5 receptors in reward and sensitization is drug-specific.

Fig. 1

The effect of MTEP- and α-flupenthixol on place conditioning. a Rats were conditioned with saline in both compartments (n = 8) or with 10 mg/kg MTEP, i.p., in one compartment and saline in the other (n = 8). b Rats were conditioned with saline in both compartments (n = 8) or with 0.5 mg/kg α-flupenthixol, i.p., in one compartment and saline in the other (n = 8). Data are presented as mean ± S.E.M. time spent in drug-paired and saline compartment on test day

Fig. 2

The effect of MTEP and α-flupenthixol on the development of cocaine-induced CPP. a Rats were conditioned with cocaine (15 mg/kg, i.p.) together with saline (0; n = 7), 1 (n = 8), 3 (n = 7), or 10 (n = 7) mg/kg, i.p., MTEP. b Rats were conditioned with cocaine (15 mg/kg, i.p.) together with saline (0; n = 16), 0.125 (n = 14), 0.25 (n = 15), or 0.5 (n = 15) mg/kg, i.p., α-flupenthixol. Data are presented as mean ± S.E.M. time spent in drug- and saline-paired compartment on test day. *p < 0.05 for difference in time spent in drug- and saline-paired compartment (Student’s t-test)

Fig. 3

The effect of MTEP and α-flupenthixol on the development of morphine-induced CPP. a Rats were conditioned with morphine (3 mg/kg, s.c.) together with saline (0; n = 15), or 1 (n = 14), 3 (n = 15), or 10 (n = 15) mg/kg, i.p. MTEP. b Rats were conditioned with morphine (3 mg/kg, s.c.) together with saline (0; n = 16), or 0.125 (n = 16), 0.25 (n = 15), or 0.5 (n = 16) mg/kg, i.p., α-flupenthixol. Data are presented as mean ± S.E.M. time spent in drug- and saline-paired compartment on test day. *p < 0.05 for difference in time spent in drug-paired and saline-paired compartment (Student’s t-test)

Fig. 4

The effects of MTEP and α-flupenthixol on the locomotor response to cocaine during pretreatment. a Locomotor responses to cocaine (coc; 30 mg/kg, i.p.) or saline (sal) in rats treated 20 min before with MTEP (1.0 mg/kg, i.p.) or saline (sal) (n = 8 per group). b Locomotor responses to cocaine (coc; 30 mg/kg, i.p.) or saline (sal) in rats treated 30 min before with α-flupenthixol (flu; 0.5 mg/kg, i.p.) or saline (sal) (n = 9 per group). Locomotor responses were measured on days 1 and 5 of pretreatment. Data are presented as total distance traveled (cm) in 1 h after cocaine or saline, expressed in mean ± S.E.M.

Fig. 5

The effects of MTEP and α-flupenthixol on the locomotor response to morphine during pretreatment. a Locomotor responses to morphine (morp; 3.0 mg/kg , s.c.) or saline (sal) in rats treated 30 min before with MTEP (1.0 mg/kg, i.p.) or saline (sal) (n = 8 per group). b Locomotor responses to morphine (morp; 3.0 mg/kg, s.c.) or saline (sal) in rats treated 30 min before with α-flupenthixol (flu; 0.5 mg/kg,  i.p.) or saline (sal) (n = 9 per group). Locomotor responses were measured on days 1 and 10 of pretreatment. Data are presented as total distance traveled (cm) in 1 h after morphine or saline, expressed in mean ± S.E.M.

Fig. 6

a Locomotor responses to cocaine (10 mg/kg, i.p.), in animals pretreated for 5 days with: saline plus saline (sal-sal; n = 8), saline plus 30 mg/kg cocaine, i.p. (sal-coc; n = 8), 1.0 mg/kg MTEP, i.p., plus saline (mtep-sal; n = 8) or 1.0 mg/kg MTEP, i.p., plus 30 mg/kg cocaine, i.p. (mtep-coc; n = 8) 3 weeks post-treatment. b Locomotor responses to cocaine (10 mg/kg, i.p.) in animals pretreated for 5 days with: saline plus saline (sal-sal; n = 9), saline plus 30 mg/kg cocaine, i.p. (sal-coc; n = 9), 0.5 mg/kg α-flupenthixol, i.p., plus saline (flu-sal; n = 9), or 0.5 mg/kg α-flupenthixol, i.p., plus 30 mg/kg cocaine, i.p. (flu-coc; n = 9), 3 weeks post-treatment. Data are presented as mean ± S.E.M. distance traveled (in cm) per 10 min during habituation to the test cages (10–30 min), after a saline injection (40–60 min), and after the cocaine challenge (10 mg/kg, i.p., 70–120 min)

Fig. 7

a Locomotor responses to morphine (1.0 mg/kg, s.c.) in animals pretreated for 5 days with: saline plus saline (sal-sal; n = 6), saline plus 3.0 mg/kg morphine, s.c., (sal-morp; n = 5), 1.0 mg/kg MTEP, i.p., plus saline (mtep-sal; n = 6) or 1.0 mg/kg MTEP, i.p., plus 3.0 mg/kg morphine, s.c. (mtep-morp; n = 6), 3 weeks post-treatment. b Locomotor responses to morphine (1.0 mg/kg, s.c.) in animals pretreated for 5 days with: saline plus saline (sal-sal; n = 5), saline plus 3.0 mg/kg morphine, s.c. (sal-morp; n = 5), 0.5 mg/kg α-flupenthixol, i.p., plus saline (flu-sal; n = 5) or 0.5 mg/kg α-flupenthixol, i.p., plus 3.0 mg/kg morphine, s.c. (flu-morp; n = 6), 3 weeks post-treatment. Data are presented as mean ± S.E.M. distance traveled (in cm) per 10 min during habituation to the test cages (10–30 min), after a saline injection (40–60 min), and after the morphine challenge (1.0 mg/kg, s.c., 70–150 min)