Olangirhcaser elcitra published: 19 November 2010 doi: 10.3389/fnins.2010.00191 Anti-malaria drug melfoquine induces motor learning deifcits in humans Thomas A. van Essen1*, Ruben S. van der Giessen1, Sebastiaan K. E. Koekkoek1, Frans VanderWerf 1, Chris I. De Zeeuw1, Perry J. J. van Genderen 2, David Overbosch 2 and MarcelT. G. de Jeu1* 1 Department of Neuroscience, Erasmus Medical Center, Rotterdam, Netherlands 2 Travel Clinic, Havenziekenhuis and Institute forTropical Diseases, Rotterdam, Netherlands Edited by: Ian M. Stanford, Aston University, UK Reviewed by: Carol Holland, Aston University, UK Stephen D. Hall, Aston University, UK *Correspondence: Thomas A. van Essen and MarcelT. G. de Jeu, Department of Neuroscience, Erasmus Medical Center, Dr. Molewaterplein 50, 3015 GE Rotterdam, Netherlands. e-mail: t.vanessen@erasmusmc.nl; m.dejeu@erasmusmc.nl Mefloquine (a marketed anti-malaria drug) prophylaxis has a high risk of causing adverse events. Interestingly, animal studies have shown that mefloquine imposes a major deficit in motor learning skills by affecting the connexin 36 gap junctions of the inferior olive.We were therefore interested in assessing whether mefloquine might induce similar effects in humans.The main aim of this study was to investigate the effect of mefloquine on olivary-related motor performance and motor learning tasks in humans. We subjected nine participants to voluntary motor timing (dart throwing task), perceptual timing (rhythm perceptual task) and reflex timing tasks (eye- blink task) before and 24 h after the intake of mefloquine.The influence of mefloquine on motor learning was assessed by subjecting participants with and without mefloquine intake (controls: n = 11 vs mefloquine: n = 8) to an eye-blink conditioning task. Voluntary motor performance, perceptual timing, and reflex blinking were not affected by mefloquine use. However, the influence of mefloquine on motor learning was substantial; both learning speed as well as learning capacity was impaired by mefloquine use. Our data suggest that mefloquine disturbs motor learning skills. This adverse effect can have clinical as well as social clinical implications for mefloquine users. Therefore, this side-effect of mefloquine should be further investigated and recognized by clinicians. Keywords: mefloquine, gap junctions, motor behavior, eye-blink conditioning, cerebellum IIcudortnno The quinolone derivative mefloquine is widely used in the treat- ment and prophylaxis of malaria in travelers to areas with chlo- roquine-resistant falciparum malaria (Palmer et al., 1993). In the Netherlands mefloquine is generally prescribed when traveling for longer than 6 weeks to a malaria endemic region. Mefloquine has gained popularity due to its weekly dosing regime and is used worldwide by all kinds of civil and military organizations. A negative effect of mefloquine is that it occasionally causes neuropsychiatric adverse events. A number of studies on meflo- quine tolerability in young and healthy populations have shown that mild neuropsychiatric adverse events, like headache, strange or vivid dreams, dizziness, anxiety, and sleeplessness, may occur in up to 32% of mefloquine users (Schlagenhauf et al., 1996, 2003; van Riemsdijk et al., 2002), while more severe neuropsychiatric adverse events, like psychosis and bipolar disorder, have also been described (Croft and World, 1996; Piening and Young, 1996; Even et al., 2001; Toovey, 2009). Although, it is known that mefloquine interacts with an array of protein targets and cellular signaling pathways no studies have been performed regarding the nature of the origin of these adverse events (Lim and Go, 1985; Gribble et al., 2000; Maertens et al., 2000; Kang et al., 2001; Dow et al., 2003; Weiss et al., 2003; Cruikshank et al., 2004). Mefloquine has been shown to block connexin 36 (Cx36) gap junction very potently (Cruikshank et al., 2004; Margineanu and Klitgaard, 2006). Cx36 is a plasma membrane protein responsible for the formation of gap junctions between neurons (Condorelli et al., 1998; Sohl et al., 2005) and has been found in many brain areas such as thalamus, hippocampus, basal ganglia, cerebral cortex, olfactory bulb, brainstem, and retina (Condorelli et al., 2000). Cx36 is highly expressed in the gap junctions of the inferior olive (IO) and these electrical synapses are the main source of intra-olivary electrical transmissions (De Zeeuw et al., 1995; Condorelli et al., 2000). The IO gives rise to the climbing fibers projecting to the Purkinje cells in the cerebellar cortex and functionally integrates sensory information and motor output resulting in well coordi- nated motor performance, motor learning, and cognitive processes (Simpson et al., 1996; Strick et al., 2009). In mice that were injected with mefloquine in their IO, timing deficits of newly learned motor responses were found in an associa- tive motor learning task (Van Der Giessen et al., 2008), indicating the importance of Cx36 gap junctions in the process of learning- dependent timing. Other studies revealed that the IO is involved in the cognitive property of perception of temporal complex rhythmic stimuli (Xu et al., 2006; Liu et al., 2008; Wu et al., 2010). The impact of mefloquine on the IO and on the olivocerebellar dependent behaviors has never been investigated in humans. Results from animal studies and the high prevalence of mefloquine associated neuropsychiatric adverse events led us to study the hypothesis that mefloquine alters olivocerebellar related behaviors in humans. Therefore, we have investigated the effect of mefloquine on dif- ferent aspects of motor performance, perceptual timing, and motor learning in humans. We examined the influence of mefloquine by studying voluntary motor timing (dart throwing task: Smeets et al., www.frontiersin.org November 2010 | Volume 4 | Article 191 | 1