Interactions between modafinil and cocaine during the induction of conditioned place preference and locomotor sensitization in mice: implications for addiction

Abstract

Modafinil is a wake-promoting drug effective at enhancing alertness and attention with a variety of approved and off-label applications. The mechanism of modafinil is not well understood but initial studies indicated a limited abuse potential. A number of recent publications, however, have shown that modafinil can be rewarding under certain conditions. The present study assessed the reinforcing properties of modafinil using conditioned place preference and locomotor sensitization in mice. Experiment 1 examined a high dose of modafinil (75 mg/kg) as well as its interactions with cocaine (15 mg/kg). Cocaine alone and modafinil co-administered with cocaine induced sensitization of locomotor activity; modafinil alone showed little or no locomotor sensitization. Animals given modafinil alone, cocaine alone, and modafinil plus cocaine exhibited a strong and roughly equivalent place preference. When tested for sensitization using a low challenge dose of modafinil, cross-sensitization was observed in all cocaine-pretreated mice. Experiment 2 examined a low dose of modafinil that is similar to the dose administered to humans and has been shown to produce cognitive enhancements in mice. Low dose modafinil (0.75 mg/kg) did not produce conditioned place preference or locomotor sensitization. Together, these results suggest that modafinil has the potential to produce reward, particularly in cocaine addicts, and should be used with caution. However, the typical low dose administered likely moderates these effects and may account for lack of addiction seen in humans.

Fig. 1

Schematic of procedure for Experiment 1. (A) On Days 1–7, mice first received an injection of saline and were placed into the Saline Side of the chamber for 15 min. Immediately after, mice receive a group-specific drug injection (modafinil, cocaine, modafinil + cocaine, or saline) and were placed in the Drug Side of the chamber for 15 min. This data is depicted in Fig. 2. (B) During conditioned place preference testing a small hole between the two sides of the chamber allowed free access to either side of the chamber. On Day 10, all mice received an injection of saline and were placed into the chamber for 15 min. This data is depicted in Fig. 3A. (C) In order to test the context and drug specificity of sensitization, all mice received modafinil and saline on each of the Saline and Drug Sides. On Day 13, mice first received an injection of saline and were placed into the Saline Side for 15 min. Immediately after, mice received an injection of modafinil (0.75 mg/kg) and were placed into the Drug Side. Conversely, on Day 14, mice first received an injection of saline and were placed into the Drug Side for 15 min. Immediately after, mice received an injection of modafinil (0.75 mg/kg) and were placed into the Saline Side. This data is depicted in Fig. 3B and C. For Experiment 2, animals were then trained identically to part A above with either low dose modafinil (LoMod) or saline.

Fig. 2

Induction of sensitization. (A) Time course of drug action on Day 1 of training. Cocaine and Mod + Coc groups showed increased locomotor activity over controls. Modafinil alone failed to induce substantial locomotion. (B) Time course of drug action on Day 7 of training. All three drug groups showed an increased response over the saline control group. (C) Time course of locomotor sensitization. The difference in response from Day 1 to 7 is shown. Cocaine and Mod + Coc mice showed a significant increase in locomotor activity from Day 1 to Day 7. Modafinil mice did not differ from control mice. (D) Locomotor activity after saline treatment, by day. No group differences were observed. (E) Average locomotor activity after drug treatment, by day. Cocaine and Mod + Coc groups were enhanced over control mice. (F) Difference in locomotor activity of drug training trials between Day 1 and Day 7. Cocaine and Mod + Coc mice were enhanced over control mice. Modafinil mice did not differ from control mice. Each point represents the mean ± S.E.M. (*p < 0.05).

Fig. 3

Place preference and cross-sensitization testing. (A) After a saline injection, all three drug groups spent significantly more time in the drug-paired side of the chamber. The difference in time spent in drug-paired side and saline-paired side is shown. (B) Locomotor activity in the drug-paired side minus the saline paired side after an injection of a challenge dose of modafinil (0.75 mg/kg). Both cocaine- and modafinil + cocaine-trained mice showed higher locomotor activity in the Drug Side of the chamber, when compared to Saline controls. Thus, the sensitization observed in these groups cross-sensitized to modafinil administration. (C) Locomotor activity in the drug-paired side minus the saline paired side after an injection of saline. No significant group effects were found. Each point represents the mean ± S.E.M. (* versus saline side, p < 0.01).

Fig. 4

Low dose modafinil does not induce sensitization or place preference. (A) Time course of drug action on Day 1 (left) and Day 7 (right) of training. Low-dose Modafinil (LoMod) and Saline groups did not differ. (B) Average locomotor activity after saline treatment (left) and drug treatment (right), by day. No group differences were found. (C) Difference in locomotor activity of drug training trials between Day 1 and Day 7 shown as minute-by-minute (left) or averages (right). Both groups showed equivalent decreases from Day 1 to Day 7. (D) Left, conditioned place preference test displayed as the difference in time spent in the Drug and Saline sides. Both groups of mice spent a roughly equal amount of time in each side of the chamber. Middle, locomotor activity in the drug-paired side minus the saline paired side after an injection of a challenge dose of modafinil (0.75 mg/kg). Neither the LoMod or Saline group showed higher locomotor activity in the drug paired side. Right, locomotor activity in the drug-paired side minus the saline paired side after an injection of saline. Neither the LoMod or Saline group showed higher locomotor activity in the drug paired side. Each point represents the mean ± S.E.M.