Electrophysiological and molecular analysis of aminergic neurons controlling arousal

Modafinil is a well-tolerated medication for excessive sleepiness, attention-deficitdisorder, cocaine dependence and as an adjunct to antidepressants with low propensity forabuse. We investigated the modafinil action on identified dopaminergic and GABAergicneurons in the ventral tegmental area (VTA) and substantia nigra (SN) of rat brain slices.Modafinil (20 μM) inhibited the firing of dopaminergic, but not GABAergic neurons. Thisinhibition was maintained in the presence of tetrodotoxin and was accompanied byhyperpolarization. Sulpiride (10μM), a D2-receptor antagonist, but not prazosine (20μM, anά1-adrenoreceptor blocker) abolished the modafinil action. Inhibition of dopamine reuptakewith a low dose of nomifensine (1μM) reduced the firing of DA neurons in a sulpiride-dependent manner and blunted the effect of modafinil. On acutely isolated neurons, modafinilevoked D2-receptor-mediated outward currents in tyrosine-hydroxylase positive cells,identified by single-cell RT-PCR, which reversed polarity near the K equilibrium potentialand were unchanged in the presence of nomifensine. Thus modafinil directly inhibits DAneurons through D2 receptors.