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

Abstract

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

Pharmacological Analysis of GABAA Receptor and Sigma1R Chaperone Interaction: Research Report I―Investigation of the Anxiolytic, Anticonvulsant and Hypnotic Effects of Allosteric GABAA Receptors’ Ligands

“…Pre-administration of Sigma1R antagonist BD-1047 prevented this effect of fluvoxamine. However, the anti-anhedonic effect of paroxetine interacting with Sigma1R in the micromolar concentration range was manifested in this experimental model only when administered together with the selective Sigma1R agonist (+)-SKF-10.047 [64]. In PTZ-induced seizures and kainic-acid-induced status epilepticus models, compounds with agonist activity to Sigma1R (SKF-10.047, dextromethorphan, and carbetapentane) and Sigma1R positive modulators (SKF83959, SOMCL-668, and E1R) showed anticonvulsant properties.…”

“…The data on the attenuation of seizures by Sigma1R ligands with agonist properties [60] are consistent with the results obtained in the anhedonia modeling with the proconvulsive GABA A R antagonist picrotoxin. Only fluvoxamine and S-(+)-fluoxetine, high-affinity Sigma1R ligands with agonist properties [61,62], were shown to attenuate picrotoxin-induced anhedonia [63], unlike antidepressants with lower affinity for Sigma1R [64]. Pre-administration of Sigma1R antagonist BD-1047 prevented this effect of fluvoxamine.…”

Actions of progesterone on depression-like behavior in a model of surgical menopause are mediated by GABAA receptors

“…Therefore, the possible activation of GABAA receptors could occur by allosteric modulation exerted by progesterone itself of its biotransformation to allopregnanolone (Carver & Reddy, 2013;Reddy, 2018). Nonetheless, other neurotransmitter systems, such as the serotonergic and dopaminergic systems, may also be involved in these actions, similar to other antidepressant drugs that interact with the GABAergic system (Ago et al, 2016;Hasebe et al, 2017).…”