Role of the dopaminergic system in the acquisition, expression and reinstatement of MDMA-induced conditioned place preference in adolescent mice

Abstract

Background: The rewarding effects of 3,4-methylenedioxy-metamphetamine (MDMA) have been demonstrated in conditioned place preference (CPP) procedures, but the involvement of the dopaminergic system in MDMA-induced CPP and reinstatement is poorly understood.

Methodology/principal findings: In this study, the effects of the DA D1 antagonist SCH 23390 (0.125 and 0.250 mg/kg), the DA D2 antagonist Haloperidol (0.1 and 0.2 mg/kg), the D2 antagonist Raclopride (0.3 and 0.6 mg/kg) and the dopamine release inhibitor CGS 10746B (3 and 10 mg/kg) on the acquisition, expression and reinstatement of a CPP induced by 10 mg/kg of MDMA were evaluated in adolescent mice. As expected, MDMA significantly increased the time spent in the drug-paired compartment during the post-conditioning (Post-C) test, and a priming dose of 5 mg/kg reinstated the extinguished preference. The higher doses of Haloperidol, Raclopride and CGS 10746B and both doses of SCH 23390 blocked acquisition of the MDMA-induced CPP. However, only Haloperidol blocked expression of the CPP. Reinstatement of the extinguished preference was not affected by any of the drugs studied. Analysis of brain monoamines revealed that the blockade of CPP acquisition was accompanied by an increase in DA concentration in the striatum, with a concomitant decrease in DOPAC and HVA levels. Administration of haloperidol during the Post-C test produced increases in striatal serotonin, DOPAC and HVA concentrations. In mice treated with the higher doses of haloperidol and CGS an increase in SERT concentration in the striatum was detected during acquisition of the CPP, but no changes in DAT were observed.

Conclusions/significance: These results demonstrate that, in adolescent mice, the dopaminergic system is involved in the acquisition and expression of MDMA-induced CPP, but not in its reinstatement.

Figure 1. Effects of DA antagonists on the acquisition of MDMA-induced CPP.

(1a for the DA release inhibitor CGS 10746B; 1b for the D2 DA antagonist Haloperidol; 1c for the D2 Da antagonist Raclopride; and 1d for the D1 DA antagonist SCH 23390). The bars represent the time in seconds spent in the drug-paired compartment before conditioning sessions during the pre-conditioning test (white bars) and after conditioning sessions during the post-conditioning test (black bars). *** p>0.001; ** p>0.05; significant difference in the time spent in the drug-paired compartment in pre-conditioning vs post-conditioning tests.

Figure 2. Effects of DA antagonists on the expression of an MDMA-induced CPP.

(2a for the DA release inhibitor CGS 10746B; 2b for the D2 DA antagonist Haloperidol; 2c for the D2 Da antagonist Raclopride; and 2d for the D1 DA antagonist SCH 23390). The bars represent the time in seconds spent in the drug-paired compartment before conditioning sessions during the pre-conditioning test (white bars) and after conditioning sessions during the post-conditioning test (black bars). *** p>0.001; ** p>0.01; * p>0.05; significant difference in the time spent in the drug-paired compartment in pre-conditioning vs post-conditioning tests.

Figure 3. Effects of DA antagonists on the reinstatement of MDMA-induced CPP.

(3a for the DA release inhibitor CGS 10746B; 3b for the D2 DA antagonist Haloperidol; 3c for the D2 Da antagonist Raclopride; and 3d for the D1 DA antagonist SCH 23390). The bars represent the time in seconds spent in the drug-paired compartment before conditioning sessions during the pre-conditioning test (white bars), the post-conditioning test (black bars), the extinction test (light gray) and the reinstatement test (dark gray). *** p>0.001; * p<0.05; significant difference in the time spent in the drug-paired compartment in pre-conditioning vs post-conditioning tests.

Figure 4. Concentration of the Actin DA transporter DAT and the serotonin transporter SERT.

Mice were treated during the acquisition or expression phase of the MDMA-induced CPP. In the acquisition phase (4a and 4b), mice were treated during the conditioning phase of the CPP with saline (Sal, n = 12), MDMA 10 mg/kg + saline (M10, n = 13), MDMA 10 mg/kg + Haloperidol 0.2 mg/kg (M10+HAL 0.2 Acq, n = 6), MDMA 10 mg/kg + SCH 23390 0.125 mg/kg (M10+SCH 0.125 Acq, n = 5), MDMA 10 mg/kg + SCH 23390 0.250 mg/kg (M10+SCH 0.250 Acq, n = 6), MDMA 10 mg/kg + Raclopride 0.6 mg/kg (M10+RACL 0.6 Acq, n = 7), and MDMA 10 mg/kg + CGS 10746B 10 mg/kg (M10+CGS 10 Acq, n = 7). In the expression phase (4c and 4d) mice were treated on the test day of the CPP with (Sal, n = 12), MDMA 10 mg/kg + saline (M10, n = 13), MDMA 10 mg/kg + Haloperidol 0.1 mg/kg (M10+HAL 0.1 Exp, n = 8), and MDMA 10 mg/kg + Haloperidol 0.2 mg/kg (M10+HAL 0.2 Exp, n = 8). Data are presented as means with ±S.E.M. The images which can be seen belong to the same gel. Differences with respect to the saline group *p<0.05, ** p<0.01.