Psychopharmacology of combined activation of the serotonin1A and σ1 receptors

The selective serotonin (5-HT) reuptake inhibitors (SSRIs) are generally used for the treatment of major depressive disorders, and the 5-HT1A 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-HT1A 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 GABAA receptor function and neurosteroid-deficient models, respectively. These findings suggest that the functional interaction between the 5-HT1A and σ1 receptors activates prefrontal dopaminergic system under the conditions of decreased brain GABAA receptor function and the neurochemical effect is linked to the behavioral effect. This review summarizes the pharmacological role of the 5-HT1A and σ1 receptors, focusing on the functional interaction between these receptors, and the role of prefrontal dopaminergic system in depressive-like behaviors.