Background:Isolation-reared mice show social encounter-induced hyperactivity with activation of prefrontal serotonergic and dopaminergic systems, but it is not known whether this stress response is observed in other pathological conditions. Here we examined whether the social encounter stimulation induces abnormal behavior during withdrawal in chronic methamphetamine-treated mice.Methods:To induce methamphetamine-induced behavioral sensitization, male mice were injected with methamphetamine (1 mg/kg) once daily for 7 days.Results:The encounter with an intruder elicited hyperactivity 24 h after the last injection of methamphetamine in methamphetamine-sensitized mice. This response was observed even as long as 2 weeks after withdrawal of methamphetamine. The encounter increased c-Fos expression in the prefrontal cortex, dorsal raphe nucleus and ventral tegmental area in methamphetamine-sensitized mice, while it did not in control mice. Furthermore, the encounter increased extracellular serotonin (5-HT) and dopamine, but not noradrenaline, levels in the prefrontal cortex in methamphetamine-sensitized mice. Local injection of 5,7-dihydroxytryptamine and 6-hydroxydopamine into the prefrontal cortex attenuated encounter-induced hyperactivity in methamphetamine-sensitized mice and it markedly decreased prefrontal 5-HT and dopamine levels, respectively. Pharmacological analysis showed that the encounter-induced hyperactivity is mediated by dopamine D1 receptors and 5-HT2A receptors and attenuated by anxiolytics and antidepressants such as diazepam, osemozotan and selective 5-HT reuptake inhibitors. The effect of paroxetine was blocked by the 5-HT3 receptor antagonist azasetron.Conclusions:The present study shows that psychological stress elicits hyperactivity with activation of prefrontal 5-HT and dopamine systems in methamphetamine-dependent mice and suggests that the abnormal behavior is associated with anxiety and depression.

Male mice were treated with picrotoxin to decrease GABA A receptor function. Their anhedonic behaviour was measured using the female encounter test. The expression of c-Fos was determined immunohistochemically. KEY RESULTSPicrotoxin caused an anxiogenic effect on three behavioural tests, but it did not affect the immobility time in the forced swim test. Picrotoxin decreased female preference in the female encounter test and attenuated the female encounter-induced increase in c-Fos expression in the nucleus accumbens. Picrotoxin-induced anhedonia was ameliorated by fluvoxamine and S-(+)-fluoxetine, selective serotonin reuptake inhibitors with high affinity for the σ 1 receptor. The effect of fluvoxamine was blocked by a 5-HT 1A or a σ 1 receptor antagonist, and co-administration of the σ 1 receptor agonist (+)-SKF-10047 and the 5-HT 1A receptor agonist osemozotan mimicked the effect of fluvoxamine. By contrast, desipramine, duloxetine and paroxetine, which have little affinity for the σ 1 receptor, did not affect picrotoxin-induced anhedonia. The effect of fluvoxamine was blocked by a dopamine D 2/3 receptor antagonist. Methylphenidate, an activator of the prefrontal dopamine system, ameliorated picrotoxin-induced anhedonia. CONCLUSION AND IMPLICATIONSPicrotoxin-treated mice show anhedonic behaviour that is ameliorated by simultaneous activation of 5-HT 1A and σ 1 receptors. These findings suggest that the increased prefrontal dopamine release is associated with the anti-anhedonic effect observed in picrotoxin-treated mice.Abbreviations SSRI, selective serotonin reuptake inhibitor