Dopamine D1 and D2 receptor family contributions to modafinil-induced wakefulness.

Editor's Note: These short, critical reviews of recent papers in the Journal, written exclusively by graduate students or postdoctoral fellows, are intended to summarize the important findings of the paper and provide additional insight and commentary. For more information on the format and purpose of the Journal Club, please see Modafinil (2-[(diphenylmethyl) sulfinyl] acetamide; United States brand name Provigil) is a wake-promoting agent first prescribed in France to treat narcolepsy-associated somnolence in the 1990s. Modafinil is currently prescribed in the United States for narcolepsy-associated somnolence, shift-work sleep disorder, and obstructive sleep apnea syndrome (Minzenberg and Carter, 2008), and it is being investigated for treating cognitive dysfunction in schizophrenia, depression, and attention deficit hyperactivity disorder (Minzenberg and Carter, 2008). Modafinil is considered safe, because subjects taking modafinil do not experience amphetamine-like withdrawal symptoms during discontinuation. Side effects of modafinil have been observed, however, including anxiety (4%), depression (4%), dyskinesia (2%), and psychosis [1 case (Wu et al., 2008)]. Understanding the precise mechanism(s) of action for modafinil may enable the development of more selective compounds having fewer side effects. Studies performed in vivo and in vitro have suggested several possible mechanisms for the action of modafinil, including inhibiting dopamine and nor-epinephrine transporters and increasing dopamine, serotonin, glutamate, and his-tamine release (Minzenberg and Carter, 2008). While it was suggested that effective doses of modafinil are insufficient to inhibit the dopamine transporter (DAT) and hence do not act via this mechanism (Mignot et al., 1994), a recent positron emission tomography study in monkeys indicated 50% binding of modafinil to the DAT at lower plasma concentrations than are induced by therapeutic doses (Madras et al., 2006). Moreover, mice lacking the DAT do not exhibit modafinil-induced wakefulness (Wisor et al., 2001). DAT knockout (KO) mice exhibit altered do-pamine D 1 and D 2 receptors, however, as well as other compensatory mechanisms such as norepinephrine abnormalities. Thus, the mechanism of modafinil-induced wakefulness requires further investigation. Qu et al. (2008) combined pharmacological and genetic techniques to investigate the contribution of D 1 and D 2 receptors to modafinil-induced wakefulness. The authors used male D 2 receptor KO mice, as well as the D 1-and D 2-family antagonists SCH23390 and raclopride, respectively , to investigate possible dopami-nergic mechanisms for modafinil-induced wakefulness. Mice were equipped with EEG and electromyogram electrodes in the cortex and both trapezius muscles respectively for polysomnographic recordings. Sleep–wakefulness states were recorded for 48 h, comparing baseline …