Rhodiola rosea Impairs Acquisition and Expression of Conditioned Place Preference Induced by Cocaine

Abstract

A novel approach to the treatment of adverse effects of drugs of abuse is one which makes use of natural products. The present study investigated the effect of Rhodiola rosea L. hydroalcoholic extract (RHO) on cocaine-induced hyperactivity and conditioned place preference (CPP) in mice. In a first experiment, mice received RHO (15, 20 or 25 mg/kg, IG), cocaine (25 mg/kg, i.p.) (COC), or a combination of both drugs (COC + RHO15, COC + RHO20, and COC + RHO25), and their locomotor activity was evaluated. In a second experiment, the effects of RHO on the acquisition, expression, and reinstatement of cocaine CPP (induced by drug priming or social defeat stress) were evaluated. RHO alone did not increase activity but potentiated the hyperactivity induced by cocaine. Rhodiola did not induce motivational effects by itself but attenuated the acquisition and expression of cocaine-induced CPP. Moreover, it was found that RHO did not block reinstatement. The results indicate that RHO is effective in reducing the rewarding properties of cocaine but is ineffective in preventing priming or stress-induced cocaine reinstatement. In light of these findings, the benefits of Rhodiola rosea L. as a treatment of cocaine addiction would seem to be limited.

Figure 1

Effects of RHO on cocaine-induced hyperactivity. Mice (n = 8 per group) were placed in the actimeter for a 30-min adaptation period (0–30 min). Afterwards, two groups received IG vehicle (Veh-sal and Coc), two groups received IG RHO 15 mg/kg (RHO15 + Coc, RHO15), two groups RHO 20 mg/kg (RHO20 + Coc, RHO20), and two groups RHO 25 mg/kg (RHO25 + Coc, RHO25), and their motor activity was registered over another hour (31–60, 61–90 min). Finally, the first two groups received a IP injection of saline (Veh-Sal) or cocaine 25 mg/kg (Coc), and the groups treated with RHO received an IP injection of cocaine 25 mg/kg (RHO15 + Coc, RHO20 + Coc, and RHO25 + Coc) or saline (RHO 15, RHO 20, and RHO 25), and their motor activity was registered over a further hour (91–120, 121–150 min). (a) represents the motor activity of all groups over the complete time of testing (0–150 min) and shows the time of RHO and cocaine administration in the corresponding groups. (b) represents the data for the last hour of the test (after cocaine administration to the corresponding groups). Values are means ± SEM. *P < 0.05; **P < 0.01; significant difference with respect to the values of the control (Veh-sal) group at the same time test.

Figure 2

Effects of RHO on the acquisition of cocaine-induced CPP. Mice (n = 11–13 per group) were treated with a vehicle IG, RHO (15, 20 or 25 mg/kg, IG), cocaine (Coc 25 mg/kg, IP), or RHO 15, 20 or 25 plus Coc. RHO was administered 60 min before each saline or cocaine injection. Immediately after this second injection mice were confined to the drug-paired compartment for the conditioning phase. Bars represent the time in seconds spent in the drug-paired compartment during preconditioning (white) and postconditioning (black). Values are means ± SEM. *P < 0.05; **P < 0.01; significant difference in the time spent in preconditioning versus postconditioning sessions.

Figure 3

Effects of RHO on the expression of cocaine-induced CPP. Mice (n = 9-10 per group) were conditioned with Cocaine (Coc 25 mg/kg, IP) and received IG Veh or RHO (15, 20 or 25 mg/kg) 60 min before the post-conditioning test. Bars represent the time in seconds spent in the drug-paired compartment during preconditioning (white) and post-conditioning (black). Values are means ± SEM. **P < 0.01; significant difference in the time spent in preconditioning versus post-conditioning sessions.

Figure 4

Effects of RHO on the priming- and stress-induced reinstatement of cocaine-induced CPP. Six groups of mice (n = 10–13 for group) were conditioned with cocaine (Coc 25 mg/kg, IP), underwent daily extinction sessions until the CPP was extinguished, and received the following treatments before the reinstatement test: vehicle, RHO 15, or 20 mg/kg 45 min before 12.5 mg/kg IP cocaine priming (Coc, Coc + RHO15, Coc + RHO20); vehicle, RHO 15, or 20 mg/kg 45 min before social defeat exposure (SD, SD + RHO15, SD + RHO20). Bars represent the time in seconds spent in the drug-paired compartment before conditioning sessions in the pre-C test (white bars), after conditioning sessions in the post-C test (black bars), in the last extinction session (light gray bars), and in the reinstatement test (dark gray bars). **P < 0.001, significant difference in the time spent in the drug-paired compartment in preconditioning versus post-conditioning or reinstatement test.