RT Journal Article
SR Electronic
T1 Modafinil Activates Phasic Dopamine Signaling in Dorsal and Ventral Striata
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 460
OP 470
DO 10.1124/jpet.116.236000
VO 359
IS 3
A1 Martin J. Bobak
A1 Matthew W. Weber
A1 Melissa A. Doellman
A1 Douglas R. Schuweiler
A1 Jeana M. Athens
A1 Steven A. Juliano
A1 Paul A. Garris
YR 2016
UL http://jpet.aspetjournals.org/content/359/3/460.abstract
AB 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.