Methylphenidate enhances extinction of contextual fear

Abstract

Methylphenidate (MPH, Ritalin) is a norepinephrine and dopamine transporter blocker that is widely used in humans for treatment of attention deficit disorder and narcolepsy. Although there is some evidence that targeted microinjections of MPH may enhance fear acquisition, little is known about the effect of MPH on fear extinction. Here, we show that MPH, administered before or immediately following extinction of contextual fear, will enhance extinction retention in C57BL/6 mice. Animals that received MPH (2.5-10 mg/kg) before an extinction session showed decreased freezing response during extinction, and the effect of the 10 mg/kg dose on freezing persisted to the next day. When MPH (2.5-40 mg/kg) was administered immediately following an extinction session, mice that received MPH showed dose-dependent decreases in freezing during subsequent tests. MPH administered immediately after a 3-min extinction session or 4 h following the first extinction session did not cause significant differences in freezing. Together, these findings demonstrate that MPH can enhance extinction of fear and that this effect is sensitive to dose, time of injection, and duration of the extinction session. Because MPH is widely used in clinical treatments, these experiments suggest that the drug could be used in combination with behavioral therapies for patients with fear disorders.

Figure 1.

Effects of MPH (black arrow) administered immediately before a 12-min extinction session. Mice that received methylphenidate showed differences in freezing response during the Extinction session (5 and 10 mg/kg) and during Test Day 1 (10 mg/kg). Error bars indicate SEM. (*) P < 0.05 significant difference compared with saline (Dunnett's test).

Figure 2.

Between-session effects of MPH (black arrow) administered immediately after a 12-min extinction session. Error bars indicate SEM. (*) P < 0.05 significant difference compared with saline.

Figure 3.

Within-session effects of MPH administered immediately after a 12-min extinction session. Comparisons of methylphenidate doses (2.5, 5, 10, 20, and 40 mg/kg, panels A–E, respectively) to saline during test sessions revealed differences during particular 3-min blocks for all doses higher than 2.5 mg/kg. Error bars indicate SEM. (*) P < 0.05 significant difference compared with saline. (Asterisk [*] above black line) Significant difference compared with saline over total test session.

Figure 4.

Effects of MPH (black arrow) administered 4 h after a 12-min extinction session. Mice that received methylphenidate (0, 20, and 40 mg/kg) 4 h following extinction did not show significant differences in freezing response during test days. Error bars indicate SEM.

Figure 5.

Effects of MPH (black arrow) administered immediately after a 3-min extinction session. Mice that received methylphenidate (0, 10, and 20 mg/kg) following brief (3-min) extinction did not show significant differences in freezing response during test days. Error bars indicate SEM.