Modafinil Activates Phasic Dopamine Signaling in Dorsal and Ventral Striata

Abstract

Modafinil (MOD) exhibits therapeutic efficacy for treating sleep and psychiatric disorders; however, its mechanism is not completely understood. Compared with other psychostimulants inhibiting dopamine (DA) uptake, MOD weakly interacts with the dopamine transporter (DAT) and modestly elevates striatal dialysate DA, suggesting additional targets besides DAT. However, the ability of MOD to induce wakefulness is abolished with DAT knockout, conversely suggesting that DAT is necessary for MOD action. Another psychostimulant target, but one not established for MOD, is activation of phasic DA signaling. This communication mode during which burst firing of DA neurons generates rapid changes in extracellular DA, the so-called DA transients, is critically implicated in reward learning. Here, we investigate MOD effects on phasic DA signaling in the striatum of urethane-anesthetized rats with fast-scan cyclic voltammetry. We found that MOD (30-300 mg/kg i.p.) robustly increases the amplitude of electrically evoked phasic-like DA signals in a time- and dose-dependent fashion, with greater effects in dorsal versus ventral striata. MOD-induced enhancement of these electrically evoked amplitudes was mediated preferentially by increased DA release compared with decreased DA uptake. Principal component regression of nonelectrically evoked recordings revealed negligible changes in basal DA with high-dose MOD (300 mg/kg i.p.). Finally, in the presence of the D2 DA antagonist, raclopride, low-dose MOD (30 mg/kg i.p.) robustly elicited DA transients in dorsal and ventral striata. Taken together, these results suggest that activation of phasic DA signaling is an important mechanism underlying the clinical efficacy of MOD.

Atypical dopamine transporter inhibitors R-modafinil and JHW 007 differentially affect D2 autoreceptor neurotransmission and the firing rate of midbrain dopamine neurons

“…Similarly, R-modafinil also produced a greater enhancement of current widths in the SNc versus the VTA (Figure 6B; Two-way ANOVA, main effect of brain region F 1,26 = 9.748, P = 0.0044; main effect of concentration F 1,26 = 10.15, P = 0.0037, Sidak’s multiple comparisons test for 100 μM R-modafinil P = 0.0041). This is consistent with a recent voltammetry study that described larger effects of (±)-modafinil in the dorsal versus ventral striatum (Bobak et al, 2016). By contrast, there was no indication of a region-specific effect of JHW 007 on the amplitude or width of iontophoretically-induced DA currents either during drug perfusion or during drug washout (data not shown).…”

Effect of acute modafinil ingestion on cognitive and physical performance following mental exertion

“…Modafinil alters activation of front‐parietal control and dorsal attentional networks (Cera, Tartaro, & Sensi, ; Esposito et al, ) implicated in the cognitive processes that coordinate the pursuit of a goal (e.g., Chong et al, ). Neurochemically, modafinil could act although dopaminergic pathways (Bobak et al, ) or even adenosine receptor modulation (China et al, ) as has been a postulated mechanism for time on task and mental fatigue effects (Martin et al, ). Although modafinil–adenosine receptor interactions have only been shown in rat osteoblasts to date, research is continually uncovering its action in the brain providing numerous potential pathways for athletic enhancement (Vodovar et al, ; Wadhwa et al, ).…”

“…Neurochemically, modafinil could act although dopaminergic pathways (Bobak et al, 2016) or even adenosine receptor modulation (China et al, 2018) as has been a postulated mechanism for time on task and mental fatigue effects (Martin et al, 2018). Although modafiniladenosine receptor interactions have only been shown in rat osteoblasts to date, research is continually uncovering its action in the brain providing numerous potential pathways for athletic enhancement (Vodovar et al, 2018;Wadhwa et al, 2018).…”

Dopamine Effects of Stimulant and Non-Stimulant drugs used in the Treatment of Attention Deficit Hyperactivity Disorder

“…. While preventing DA uptake by inhibition of DAT has been considered to be its primary mode of action, recently MOD has also been shown to activate phasic DA signaling, which is suggested to be an additional mechanism contributing to its clinical effects (Bobak et al, 2016).…”

“…evoked phasic DA signals(Bobak et al, 2016). The evoked signals are considered phasic-like because of their resemblance to the naturally occurring phasic DA transients associated with reinforcement learning and elicited by burst firing of DA neurons(Covey et al, 2014).…”