Psychopharmacology of combined activation of the serotonin1A and σ1 receptors

Abstract

The selective serotonin (5-HT) reuptake inhibitors (SSRIs) are generally used for the treatment of major depressive disorders, and the 5-HT_1A and σ₁ receptors are considered to be targets for treatment of psychiatric disorders. Some SSRIs such as fluvoxamine have agonistic activity towards for the σ₁ receptor, but it is not known whether the effect on the receptor plays a key role in the pharmacological effects. We have recently demonstrated that fluvoxamine shows an anti-anhedonic effect in picrotoxin-induced model of anxiety/depression, while the SSRI paroxetine, which have little affinity for the σ₁ receptor, does not. We also suggest that the anti-anhedonic effect of fluvoxamine is mediated by combined activation of the 5-HT_1A and σ₁ receptors and it is associated with activation of prefrontal dopaminergic system. In these studies, picrotoxin-treated mice and adrenalectomized/castrated mice were used as decreased GABA_A receptor function and neurosteroid-deficient models, respectively. These findings suggest that the functional interaction between the 5-HT_1A and σ₁ receptors activates prefrontal dopaminergic system under the conditions of decreased brain GABA_A receptor function and the neurochemical effect is linked to the behavioral effect. This review summarizes the pharmacological role of the 5-HT_1A and σ₁ receptors, focusing on the functional interaction between these receptors, and the role of prefrontal dopaminergic system in depressive-like behaviors.

Keywords: 5-HT(1A) receptor; GABA(A) receptor; Motivation; Prefrontal dopamine release; σ(1) receptor.