British journal of pharmacology | 2021
Mesencephalic dopaminergic neurons are essential for modafinil-induced arousal.
Abstract
BACKGROUND AND PURPOSE\nModafinil is a potent wake-promoting agent that is prescribed to treat narcolepsy and has a low incidence of abuse. Although previous studies have shown that modafinil-induced arousal depends on the dopaminergic receptors and transporters, the specific dopaminergic population underlying this mechanism remained unclear. Here, we investigated the role of mesencephalic dopaminergic neurons in modafinil-promoted arousal.\n\n\nEXPERIMENTAL APPROACH\nA dopamine indicator (dLight1.1) was employed to detect dopamine changes in the nucleus accumbens (NAc) and dorsal striatum (dStr). We specifically lesioned mesencephalic dopaminergic neurons via diphtheria toxin (DTA) in the dopamine transporter (DAT)-Cre mice. Then, the sleep-wake states were recorded to evaluate the effect of modafinil on arousal. Finally, the extent of DTA-induced lesions was determined by immunohistochemistry.\n\n\nKEY RESULTS\nModafinil promptly increased dopamine levels in the NAc and dStr in a dose- dependent manner. Lesioning of dopaminergic neurons in the substantia nigra pars compacta (SNc) or ventral tegmental area (VTA) had no significant effects on physiological sleep-wake cycles. Modafinil at 90 mg kg-1 increased continuous wakefulness for 355.3 min in control mice, however, these effects were slightly decreased by 6.7% in the SNc-lesioned mice, and were prominently diminished by 32.8% in VTA-lesioned mice. Furthermore, the modafinil-induced arousal was completely blocked in the SNc-VTA-lesioned mice, whereas lesions of the dorsal raphe nucleus did not alter it.\n\n\nCONCLUSION AND IMPLICATIONS\nTaken together, our findings indicate that mesencephalic dopaminergic neurons are essential for modafinil-induced arousal.