Amphetamine and cocaine suppress social play behavior in rats through distinct mechanisms

Abstract

Rationale: Social play behavior is a characteristic form of social behavior displayed by juvenile and adolescent mammals. This social play behavior is highly rewarding and of major importance for social and cognitive development. Social play is known to be modulated by neurotransmitter systems involved in reward and motivation. Interestingly, psychostimulant drugs, such as amphetamine and cocaine, profoundly suppress social play, but the neural mechanisms underlying these effects remain to be elucidated.

Objective: In this study, we investigated the pharmacological underpinnings of amphetamine- and cocaine-induced suppression of social play behavior in rats.

Results: The play-suppressant effects of amphetamine were antagonized by the alpha-2 adrenoreceptor antagonist RX821002 but not by the dopamine receptor antagonist alpha-flupenthixol. Remarkably, the effects of cocaine on social play were not antagonized by alpha-2 noradrenergic, dopaminergic, or serotonergic receptor antagonists, administered either alone or in combination. The effects of a subeffective dose of cocaine were enhanced by a combination of subeffective doses of the serotonin reuptake inhibitor fluoxetine, the dopamine reuptake inhibitor GBR12909, and the noradrenaline reuptake inhibitor atomoxetine.

Conclusions: Amphetamine, like methylphenidate, exerts its play-suppressant effect through alpha-2 noradrenergic receptors. On the other hand, cocaine reduces social play by simultaneous increases in dopamine, noradrenaline, and serotonin neurotransmission. In conclusion, psychostimulant drugs with different pharmacological profiles suppress social play behavior through distinct mechanisms. These data contribute to our understanding of the neural mechanisms of social behavior during an important developmental period, and of the deleterious effects of psychostimulant exposure thereon.

Figure 1

Effect of noradrenergic and dopaminergic antagonists on amphetamine-induced suppression of social play behavior. Amphetamine (amph, s.c.) dose-dependently reduced pinning (a) and pouncing (b) without affecting social exploration (c). The effect of amphetamine (0.2 mg/kg) was blocked by the alpha-2 adrenoreceptor antagonist RX821002 (rx, 0.2 mg/kg, i.p.), pinning (d) pouncing (e) social exploration (f). The effect of amphetamine on pinning (g), pouncing (h) and social exploration (i) was not blocked by the dopamine antagonist alpha-flupenthixol (flup, 0.125 mg/kg, i.p.). Bars show the frequency (mean+SEM) of pinning and pouncing and the mean duration spent on social exploration (s) of the different treatment groups. + indicates couples of animals treated with the test compound, − indicates couples treated with the corresponding vehicle. N=6–8 couples per treatment group. One or two-way ANOVA with Tukey post hoc test, ***p<0.001.

Figure 2

Effects of noradrenergic and dopaminergic antagonists on cocaine-induced suppression of social play behavior. Cocaine (coc, s.c.) dose-dependently suppressed pinning (a) and pouncing (b) and increased social exploration (c). The alpha-2 adrenoreceptor antagonist RX821002 (rx, 0.2 mg/kg, i.p.) and the dopamine receptor antagonist alpha-flupenthixol (flup, 0.125 mg/kg, i.p.) did not counteract the effects of cocaine (COC, 5 mg/kg) on pinning (d,g) and pouncing (e,h). Social exploration was unaffected by the treatments (f,i). Bars show the frequency of pinning and pouncing and the mean duration spent on social exploration (s) of the different treatment groups (mean+SEM). + indicates couples of animals treated with the test compound, − indicates couples treated with the corresponding vehicle. N=4–8 couples per treatment group. One or two-way ANOVA with Tukey post hoc test, *p<0.05, ***p<0.001.

Figure 3

Effects of 5-HT receptor antagonists on cocaine-induced suppression of social play behavior. 5-HT antagonists (methysergide: mts, 5HT1/2 antagonist, 2 mg/kg, s.c.; amperozide: apz, 5HT2 antagonist, 0.5 mg/kg, i.p.; ondansetron: ond, 5HT3 antagonist, 1.0 mg/kg, i.p.; WAY100365: way, 5HT1a antagonist, 0.1 mg/kg, s.c.; M100907: m100, 5HT2a antagonist, 0.2 mg/kg, s.c.) did not counteract the suppression of social play behavior induced by cocaine (coc, 5 mg/kg, s.c.): pinning (a,c,e,g,i), pouncing (b,d,f,h,j). Bars show the frequency (mean+SEM) of pinning and pouncing and the mean duration spent on social exploration (s) of the different treatment groups. + indicates couples of animals treated with the test compound, − indicates couples treated with the corresponding vehicle. N=5–8 couples per treatment group. Two-way ANOVA with Tukey post hoc test, *p<0.05, ***p<0.001.

Figure 3

Effects of 5-HT receptor antagonists on cocaine-induced suppression of social play behavior. 5-HT antagonists (methysergide: mts, 5HT1/2 antagonist, 2 mg/kg, s.c.; amperozide: apz, 5HT2 antagonist, 0.5 mg/kg, i.p.; ondansetron: ond, 5HT3 antagonist, 1.0 mg/kg, i.p.; WAY100365: way, 5HT1a antagonist, 0.1 mg/kg, s.c.; M100907: m100, 5HT2a antagonist, 0.2 mg/kg, s.c.) did not counteract the suppression of social play behavior induced by cocaine (coc, 5 mg/kg, s.c.): pinning (a,c,e,g,i), pouncing (b,d,f,h,j). Bars show the frequency (mean+SEM) of pinning and pouncing and the mean duration spent on social exploration (s) of the different treatment groups. + indicates couples of animals treated with the test compound, − indicates couples treated with the corresponding vehicle. N=5–8 couples per treatment group. Two-way ANOVA with Tukey post hoc test, *p<0.05, ***p<0.001.

Figure 4

Effects of combinations of monoaminergic antagonists on the play suppressant effects of cocaine (coc, 5 mg/kg, s.c.). A combination of RX821002 (rx, α2-adrenoreceptor antagonist, 0.2 mg/kg, i.p.) + methysergide (mts, 5-HT1/2 receptor antagonist, 2 mg/kg, s.c.), a combination of α-flupenthixol (flup, dopamine receptor antagonist, 0.125 mg/kg, i.p.) + methysergide (mts, 5-HT1/2 receptor antagonist, 2 mg/kg, s.c.) and a combination of RX821002 (rx, α2-adrenoreceptor antagonist, 0.2 mg/kg, i.p.) + α-flupenthixol (flup, dopamine receptor antagonist, 0.125 mg/kg, i.p.) + methysergide (mts, 5-HT1/2 receptor antagonist, 2 mg/kg, s.c.) did not antagonize the reduction in pinning (a,c,e) and pouncing (b,d,f) induced by cocaine. Bars show the frequency (mean+SEM) of pinning and pouncing and the mean duration spent on social exploration (s) of the different treatment groups. + indicates couples of animals treated with the test compounds, − indicates couples treated with the corresponding vehicles, N=7–8 couples per treatment group.

Figure 5

Effect of (combinations of) subeffective doses of monoamine reuptake inhibitors and a subeffective dose of cocaine on social play. Combined administration of a subeffective dose of fluoxetine (f3, serotonin reuptake inhibitor, 3 mg/kg, s.c.) and a subeffective dose of cocaine (coc, 0.5 mg/kg, s.c.) or combined administration of a subeffective dose of fluoxetine (f3, serotonin reuptake inhibitor, 3 mg/kg, s.c.) and GBR12909 (g3, dopamine reuptake inhibitor, 3 mg/kg, s.c.) together with a subeffective dose of cocaine (coc, 0.5 mg/kg, s.c.) had no effects on pinning (a,c) and pouncing (b,d). Combined administration of a subeffective dose of fluoxetine (f3, serotonin reuptake inhibitor, 3 mg/kg, s.c.) + GBR12909 (g3, dopamine reuptake inhibitor, 3 mg/kg) + atomoxetine (a0.1, noradrenaline reuptake inhibitor, 0.1 mg/kg, i.p.) together with a subeffective dose of cocaine (COC, 0.5 mg/kg, s.c.) significantly reduced pinning (e) but not pouncing (f). Bars show the frequency (mean±SEM) of pinning and pouncing and the mean duration spent on social exploration (s) of the different treatment groups. + indicates couples of animals treated with the test compounds, − indicates couples treated with the corresponding vehicles. N=6–8 couples per treatment group. Two-way ANOVA with Tukey post hoc test, *p<0.05, ***p<0.001.