Modafinil Induces Rapid-Onset Behavioral Sensitization and Cross-Sensitization with Cocaine in Mice: Implications for the Addictive Potential of Modafinil

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.

Participation of Dopamine D1 and D2 Receptors in the Rapid-Onset Behavioral Sensitization to Modafinil

“…We chose doses of dopaminergic antagonists that did not alter spontaneous locomotion in mice, yet had been shown to decrease behavioral sensitization induced by other psychostimulant drugs. The dose of modafinil (64 mg/kg) was chosen based on our previous study showing the development of rapid-onset sensitization in mice ( Wuo-Silva et al, 2016 ).…”

“…As previously described, locomotor activity was measured in the open field arena ( Chinen et al, 2006 ; Wuo-Silva et al, 2016 ). The open-field apparatus consisted of a circular wooden box (40 cm in diameter and 50 cm high) with an open top and a floor divided into 19 approximately similar regions delimited by three concentric circles of different radii (8, 14, and 20 cm) intersected by radial line segments.…”

“…Using hand-operated counters and stopwatches, the locomotor activity (total number of entrances into any floor unit, i.e., number of crossings) was measured by an observer who was blind to the treatment allocation during a 10-min session. This interval has been proven effective in detecting behavioral sensitization induced by repeated treatment or a single injection of modafinil in mice ( Wuo-Silva et al, 2011 , 2016 ).…”

“…Moreover, modafinil alone also seems to exert rewarding properties, as it produces conditioned place preference and induces robust behavioral sensitization after single- and repeated-injection treatments in mice ( Paterson et al, 2010 ; Wuo-Silva et al, 2011 ; Shuman et al, 2012 ). More recently, modafinil has been shown to induce rapid-onset behavioral sensitization in mice using a paradigm in which sensitization is developed when a challenge drug injection is administered only a few hours after a priming injection of a high dose of the same drug ( Wuo-Silva et al, 2016 ).…”

Prenatal exposure to modafinil alters behavioural response to methamphetamine in adult male mice

“…This is typically seen in methamphetamine and related substances such as MDMA (3,4‐methylenedioxymethamphetamine or ecstasy) (Kucerova et al, 2006; Landa et al, 2009). A cross‐sensitization to modafinil stimulatory effects on locomotor behaviour were also shown in mice after repeated treatment with methamphetamine (Merhautova et al, 2012) or cocaine (Wuo‐Silva et al, 2016). This might support a suggestion that responses to modafinil stimulatory effects can be higher in psychostimulant abusers.…”