Roles of Adrenergic α(1) and Dopamine D(1) and D(2) Receptors in the Mediation of the Desynchronization Effects of Modafinil in a Mouse EEG Synchronization Model

BACKGROUND: Synchronized electroencephalogram (EEG) activity is observed in pathological stages of cognitive impairment and epilepsy. Modafinil, known to increase the release of catecholamines, is a potent wake-promoting agent, and has shown some abilities to desynchronize EEG,but its receptor mechanisms by which modafinil induces desynchoronization remain to be elucidated. Here we used a pharmacological EEG synchronization model to investigate the involvement of adrenergic α(1) receptors (R, α(1)R) and dopamine (DA) D(1) and D(2) receptors (D(1)Rs and D(2)Rs) on modafinil-induced desynchronization in mice. METHODOLOGY/PRINCIPAL FINDINGS: Mice were treated with cholinergic receptor antagonist scopolamine and monoamine depletor reserpine to produce experimental EEG synchronization characterized by continuous large-amplitude synchronized activity, with prominent increased delta and decreased theta, alpha, and beta power density. The results showed that modafinil produced an EEG desynchronization in the model. This was characterized by a general decrease in amplitude of all the frequency bands between 0 and 20 Hz, a prominent reduction in delta power density, and an increase in theta power density. Adrenergic α(1)R antagonist terazosin (1 mg/kg, i.p.) completely antagonized the EEG desynchronization effects of modafinil at 90 mg/kg. However, DA D(1)R and D(2)R blockers partially attenuated the effects of modafinil. The modafinil-induced decrease in the amplitudes of the delta, theta, alpha, and beta waves and in delta power density were completely abolished by pretreatment with a combination of the D(1)R antagonist SCH 23390 (30 µg/kg) and the D(2)R antagonist raclopride (2 mg/kg, i.p.). CONCLUSIONS/SIGNIFICANCE: These results suggest that modafinil-mediated desynchronization may be attributed to the activation of adrenergic α(1)R, and dopaminergic D(1)R and D(2)R in a model of EEG synchronization.