Anti-anhedonic effect of selective serotonin reuptake inhibitors with affinity for sigma-1 receptors in picrotoxin-treated mice

Background and purpose: Prefrontal dopamine release by the combined activation of 5-HT_1A and sigma-1 (σ₁ ) receptors is enhanced by the GABA_A receptor antagonist picrotoxin in mice. Here, we examined whether this neurochemical event was accompanied by behavioural changes.

Experimental approach: 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 results: Picrotoxin 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 σ₁ receptor. The effect of fluvoxamine was blocked by a 5-HT_1A or a σ₁ receptor antagonist, and co-administration of the σ₁ 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 σ₁ 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 implications: Picrotoxin-treated mice show anhedonic behaviour that is ameliorated by simultaneous activation of 5-HT_1A and σ₁ receptors. These findings suggest that the increased prefrontal dopamine release is associated with the anti-anhedonic effect observed in picrotoxin-treated mice.