Abstract
There is substantial controversy about the addictive potential of modafinil, a wake-promoting drug used to treat narcolepsy, proposed as pharmacotherapy for cocaine abuse, and used indiscriminately by healthy individuals due to its positive effects on arousal and cognition. The rapid-onset type of behavioral sensitization (i.e., a type of sensitization that develops within a few hours from the drug priming administration) has been emerged as a valuable tool to study binge-like patterns of drug abuse and the neuroplastic changes that occur quickly after drug administration that ultimately lead to drug abuse. Our aim was to investigate the possible development of rapid-onset behavioral sensitization to modafinil and bidirectional rapid-onset cross-sensitization with cocaine in male Swiss mice. A priming injection of a high dose of modafinil (64 mg/kg) induced rapid-onset behavioral sensitization to challenge injections of modafinil at the doses of 16, 32, and 64 mg/kg, administered 4 h later. Furthermore, rapid-onset cross-sensitization was developed between modafinil and cocaine (64 mg/kg modafinil and 20 mg/kg cocaine), in a bidirectional way. These results were not due to residual levels of modafinil as the behavioral effects of the priming injection of modafinil were no longer present and modafinil plasma concentration was reduced at 4 h post-administration. Taken together, the present findings provide preclinical evidence that modafinil can be reinforcing per se and can enhance the reinforcing effects of stimulants like cocaine within hours after administration.
Highlights
Most common drugs of abuse stimulate the release of dopamine in the mesoaccumbens dopaminergic system, which modulates both their reinforcing and psychomotor arousal effects (Wise and Bozarth, 1987; Alcaro et al, 2007)
Tukey’s post hoc test revealed that with respect to animals acutely treated with modafinil for the first time, only the VehMod32 and vehicle solution (Veh-)Mod64 groups presented a significant increase in locomotion when compared with the vehicle solution (Veh)-Veh control group, indicating that only the highest doses of modafinil were effective in promoting locomotor stimulant effects
The statistical analysis revealed that animals treated with a priming injection of 64 mg/kg modafinil and challenged with different doses of modafinil (Mod64-Mod16, Mod64Mod32, and Mod64-Mod64 groups) presented significantly greater locomotor activity when compared to their respective control groups treated initially with vehicle and challenged with different doses of modafinil (Veh-Mod16, Veh-Mod32, and VehMod64 groups), characterizing the development of rapid-onset behavioral sensitization to modafinil for all doses
Summary
Most common drugs of abuse stimulate the release of dopamine in the mesoaccumbens dopaminergic system, which modulates both their reinforcing and psychomotor arousal effects (Wise and Bozarth, 1987; Alcaro et al, 2007) Within this context, it has been shown that the repeated administration of drugs of abuse promotes a progressive and long-lasting increase in Modafinil and Cocaine Abuse the activity of the mesoaccumbens dopaminergic system, leading to a corresponding increase in their locomotor stimulatory effect in rodents (Vezina, 2004; Costa et al, 2007; O’Tuathaigh et al, 2010). This single injection-induced locomotor sensitization protocol provides a useful model for investigating the long-lasting effects of drugs of abuse (Valjent et al, 2010)
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