Modafinil disrupts prepulse inhibition in mice: Strain differences and involvement of dopaminergic and serotonergic activation

Abstract

Modafinil is a wakefulness-promoting agent with possible beneficial effects for the management of addiction and in psychiatric conditions, but also with abuse potential of its own. The mechanism of action of modafinil remains unclear. We studied pharmacological mechanisms in the effect of modafinil on prepulse inhibition (PPI), a model of sensorimotor gating. Mice were tested in automated startle boxes after administration of modafinil and antagonist drugs. Oral administration of 100 mg/kg of modafinil, but not lower doses, caused a significant reduction of PPI in C57Bl/6 mice, but not Balb/c mice. This effect of modafinil could be blocked by co-treatment with the dopamine D₂ receptor antagonist, haloperidol, and the serotonin (5-HT) 2A receptor antagonist, ketanserin, but not the 5-HT_1A receptor antagonist, WAY100,635. At 30 mg/kg, which did not influence PPI, modafinil inhibited PPI disruption caused by the dopamine transporter inhibitor, GBR12909. There was no interaction between modafinil and the serotonin transporter inhibitor, fluoxetine. There were no consistent effects of modafinil on startle amplitude. These results show that oral modafinil treatment may cause disruption of PPI in mice. This effect was strain-dependent, involving dopamine D₂ and 5-HT_2A receptor activation, and was likely mediated by an interaction with the dopamine transporter. These results extend our insight into the behavioral effects of modafinil and could be of importance for the clinical use of this agent as they may indicate an increased risk of side-effects in conditions where PPI is already reduced, such as in schizophrenia and bipolar disorder.

Introduction

Modafinil is an anti-narcolepsy drug widely used off-label and as a mild stimulant (Kumar, 2008, Minzenberg and Carter, 2008). Modafinil has been trialed in the management of drug abuse and dependence (Martinez-Raga et al., 2008, Heinzerling et al., 2010) and its cognitive and stimulant effects could be useful in the treatment of schizophrenia and bipolar disorder (Morein-Zamir et al., 2007). In addition, modafinil is becoming widely used in social settings, as a doping agent and to combat jet-lag (Kumar, 2008, Minzenberg and Carter, 2008).

The pharmacological mechanism of action of modafinil may be by interacting with the dopamine transporter increasing dopamine release in the basal forebrain (Volkow et al., 2009, Zolkowska et al., 2009, Young and Geyer, 2010) resulting in stimulation of dopamine D₁ and D₂ receptors (Qu et al., 2008). Thus, modafinil may have effects similar to drugs of abuse such as cocaine and amphetamines (Volkow et al., 2009). In addition to dopaminergic effects, modafinil also increases serotonin release in the cortex (de Saint Hilaire et al., 2001), increases histamine release in the brain which interacts with its behavioural effects (Ishizuka et al., 2008) and may have antidepressant effects (de Saint Hilaire et al., 2001, Ferraro et al., 2005, Regenthal et al., 2009). Therefore the exact pharmacological action of modafinil on behavior remains unclear.

Prepulse inhibition (PPI) is a widely used model of sensorimotor gating, which is the ability to filter extraneous information and focus on relevant input (Swerdlow et al., 2008). Prepulse inhibition is disrupted in schizophrenia and other psychiatric illnesses (Swerdlow et al., 2008) and after treatment with dopamine receptor agonists, dopamine releasing agents and several serotonergic drugs (Geyer et al., 2001). Assessing the effect of modafinil on PPI may therefore inform on its mechanism of action and potential positive and side-effects in schizophrenia. However, in healthy humans and in rats, modafinil had no effect on baseline PPI (Samuels et al., 2007, Regenthal et al., 2009, McFadden et al., 2010). In contrast, after tail pinch stress or REM sleep deprivation in rats, modafinil caused disruption of PPI (Liu et al., 2011) and subchronic modafinil reversed restraint stress-induced deficits in PPI, as well as depression-like behaviors in rats (Regenthal et al., 2009).

The effects of modafinil on PPI have not been investigated in mice, even though this is the most widely used experimental species in psychiatric and psychopharmacological neuroscience because of the wide availability of genetic modifications. Therefore, and to further elucidate the neuropsychopharmacological mechanism of action of modafinil, we examined its effects on PPI and startle in mice. We administered modafinil orally, similarly to its common use in humans, and used two mouse strains, the C57Bl/6 and the Balb/c which differ in the regulation of PPI. We used a number of dopamine and serotonin (5-HT) receptor and uptake blockers to delineate the involvement of these neurotransmitter mechanisms in the action of modafinil on PPI.