[Anxiolytic effects of serotonin reuptake inhibitors and their mechanism of action]

Abstract

The purpose of this study was to examine the anxiolytic effects of serotonin (5-HT) reuptake inhibitors and to clarify their action mechanisms and roles in the brain serotonergic system in the psychopathology of anxiety. It has been proposed that conditioned fear stress (CFS)-induced freezing behavior in rats could be used as a model of anxiety. In the experiment using this model, acute treatment with the 5-HT reuptake inhibitors reduced CFS-induced freezing behavior, while acute treatment with the noradrenaline or dopamine reuptake inhibitors failed to alter CFS-induced freezing. CFS elevated extracellular 5-HT levels in the medial prefrontal cortex, and this elevations of 5-HT level was followed by a resolution of the freezing. A dose of 10 mg/kg of a selective 5-HT reuptake inhibitor (SSRI), citalopram, administered 60 min before exposure to CFS increased extracellular 5-HT concentrations immediately and potently, and reduced freezing. The 5-HT1A receptor antagonists, particularly at low doses, enhanced the antifreezing effect of citalopram. While the antifreezing effect of citalopram (10 mg/kg) disappeared by prolongation of the period between conditioning and exposure to CFS, acute challenge of citalopram (10 mg/kg) reduced freezing in the rats into which citalopram (10 mg/kg) had been injected twice daily for 7 days. From these findings, it is indicated that 1) 5-HT reuptake inhibitors decrease anxiety, 2) 5-HT release is increased at the nerve terminal under anxiety conditions, 3) the elevation of 5-HT levels in the terminal has an anxiolytic action which is closely related to the pharmacological effects of SSRI-class of anxiolytics, and 4) 5-HT1A receptor antagonist enhances the antifreezing effect of SSRI by blocking the autoreceptor-mediated negative feedback mechanisms of 5-HT neurons. By prolonging the period between conditioning and exposure to CFS, the author recognized the feasibility to establish an animal model which reflects the psychopathology of anxiety disorder more precisely. Presynaptic 5-HT1A receptor desensitization may account for the mechanism of action of repeated treatment with SSRI.