Methylphenidate and atomoxetine inhibit social play behavior through prefrontal and subcortical limbic mechanisms in rats

Abstract

Positive social interactions during the juvenile and adolescent phases of life, in the form of social play behavior, are important for social and cognitive development. However, the neural mechanisms of social play behavior remain incompletely understood. We have previously shown that methylphenidate and atomoxetine, drugs widely used for the treatment of attention-deficit hyperactivity disorder (ADHD), suppress social play in rats through a noradrenergic mechanism of action. Here, we aimed to identify the neural substrates of the play-suppressant effects of these drugs. Methylphenidate is thought to exert its effects on cognition and emotion through limbic corticostriatal systems. Therefore, methylphenidate was infused into prefrontal and orbitofrontal cortical regions as well as into several subcortical limbic areas implicated in social play. Infusion of methylphenidate into the anterior cingulate cortex, infralimbic cortex, basolateral amygdala, and habenula inhibited social play, but not social exploratory behavior or locomotor activity. Consistent with a noradrenergic mechanism of action of methylphenidate, infusion of the noradrenaline reuptake inhibitor atomoxetine into these same regions also reduced social play. Methylphenidate administration into the prelimbic, medial/ventral orbitofrontal, and ventrolateral orbitofrontal cortex, mediodorsal thalamus, or nucleus accumbens shell was ineffective. Our data show that the inhibitory effects of methylphenidate and atomoxetine on social play are mediated through a distributed network of prefrontal and limbic subcortical regions implicated in cognitive control and emotional processes. These findings increase our understanding of the neural underpinnings of this developmentally important social behavior, as well as the mechanism of action of two widely used treatments for ADHD.

Keywords: amygdala; habenula; methylphenidate; noradrenaline; prefrontal cortex; social play behavior.

Figure 1.

Schematic representation of brain sections with microinjection placements in the anterior cingulate cortex (ACC), prelimbic cortex (PrL), infralimbic cortex (IL), medial/ventral orbitofrontal cortex (MO/VO), and ventrolateral orbitofrontal cortex (VLO). (Adapted with permission from Paxinos and Watson, 2007).

Figure 2.

Schematic representation of brain sections with microinjection placements in the nucleus accumbens (NAc) shell, basolateral amygdala (BLA), habenula, and mediodorsal (MD) thalamus. (Adapted with permission from Paxinos and Watson, 2007).

Figure 3.

The effect of methylphenidate (mph; 5.0 μg/0.3 μl, gray bar; social play behavior, n = 7; locomotor activity, n = 8) or atomoxetine (ato; 10.0 μg/0.3 μl, black bar; social play behavior, n = 8; locomotor activity: vehicle, n = 8; atomoxetine, n = 11) administration into the anterior cingulate cortex. Data are presented as mean + SEM. Both methylphenidate and atomoxetine reduced pinning (A) and pouncing (B) after infusion into the anterior cingulate cortex. Methylphenidate tended to increase and atomoxetine increased social exploration (C), but neither drug affected locomotor activity (D,E). *p ≤ 0.05, **p ≤ 0.01, ***p < 0.001, #p = 0.07, paired t test.

Figure 4.

The effect of methylphenidate (mph; 5.0 μg/0.3 μl, gray bar; social play behavior, n = 12; locomotor activity: vehicle, n = 7; methylphenidate, n = 9) or atomoxetine (ato; 10.0 μg/0.3 μl, black bar; social play behavior, n = 10; locomotor activity: vehicle, n = 12; atomoxetine, n = 9) administration into the infralimbic cortex on social play behavior. Data are presented as mean + SEM. Both methylphenidate and atomoxetine infusion into the infralimbic cortex decreased pinning (A) and pouncing (B). Methylphenidate did not affect and atomoxetine increase social exploration (C). Neither methylphenidate nor atomoxetine infusion into the infralimbic cortex affected locomotor activity (D, E). *p ≤ 0.05, **p ≤ 0.01, paired t test.

Figure 5.

The effect of methylphenidate (mph; 5.0 μg/0.3 μl, gray bar; social play behavior, n = 6; locomotor activity: n = 6) or atomoxetine (ato; 10.0 μg/0.3 μl, black bar; social play behavior, n = 6; locomotor activity: vehicle, n = 9; atomoxetine, n = 7) administration into the BLA on social play behavior. Data are presented as mean + SEM. Both methylphenidate and atomoxetine reduced pinning (A) and pouncing (B), but did not affect social exploration (C) or locomotor activity (D,E). *p < 0.05, independent (mph) or paired (ato) t test.

Figure 6.

The effect of methylphenidate (mph; 5.0 μg/0.3 μl, gray bar; social play behavior, n = 9; locomotor activity: n = 9) or atomoxetine (ato; 10.0 μg/0.3 μl, black bar; social play behavior, n = 7; locomotor activity: n = 8) administration into the habenula on social play behavior. Data are presented as mean + SEM. Both methylphenidate and atomoxetine infusion into the habenula decreased pinning (A) and pouncing (B), but not social exploration (C) or locomotor activity (D, E). *p ≤ 0.05, ***p ≤ 0.001, paired t test.