Strain‐dependent serotonin neuron feedback control: role of serotonin_2C receptors

Abstract

We investigated the role of serotonin 2C receptor-mediated feedback mechanisms in the response to citalopram in C57BL/ 6 and DBA/2 mice, which are respectively responders and nonresponders to selective serotonin reuptake inhibitors in the forced swimming test. The microdialysis technique was used to assess changes in extracellular serotonin and GABA in the mouse dorsal raphé (DR). Citalopram (1.25-20 mg/kg) raised extracellular serotonin and GABA in the DR of both mouse strains. These effects were abolished by depleting brain serotonin with p-chlorophenylalanine (300 mg/kg · 3). Systemic and/or intra-DR infusion of the serotonin 2C receptor antagonist 6-chloro-5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl] carbamoyl]-indoline (1 mg/kg and 0.1 lM, respectively) enhanced citalopram's effect on extracellular serotonin in the DR and medial prefrontal cortex and abolished the rise of GABA in the DR of DBA/2 mice but had no effect in C57BL/6 mice. The serotonin 2C receptor agonist Ro60-0175 (0.03-3.0 mg/kg) reduced extracellular serotonin and raised GABA in the DR of DBA/2 mice but had much less effect in C57BL/6 mice. These findings show that the sensitivity of serotonin 2C receptors determines the efficacy of augmentation strategies aimed at enhancing the effect of serotonin reuptake inhibitors on extracellular serotonin through the suppression of serotonin 2C receptor-mediated feedback control of serotonin neurons.

Response of Htr3a knockout mice to antidepressant treatment and chronic stress

“…In our conditions, 5‐HT 1A receptor desensitization occurred in Htr3a KO mice, not WT mice, under the low‐dose citalopram regimen (5 mg·kg −1 ·day −1 ). The amplitude of this desensitization was similar to that observed in WT mice with the 20 mg·kg −1 ·day −1 citalopram regimen (Martin et al, ), commonly used in preclinical studies (Calcagno and Invernizzi, ). Actually, Ferrés‐Coy et al () demonstrated that short‐term partial reduction of 5‐HTT expression by small interference RNA led to decreased in both 5‐HT 1A autoreceptor expression and function.…”

Recent advances in the neuropsychopharmacology of serotonergic hallucinogens

“…It is not clear why the 5-HT 2C receptor attenuates the HTR in certain studies and augments the response in others, but Fantegrossi et al (2010) have argued these differences may be strain dependent. For example, there are strain differences in the editing of 5-HT 2C mRNA (Calcagno and Invernizzi, 2010; Hackler et al, 2006). Since 5-HT 2C editing can influence the downstream coupling of the receptor (Burns et al, 1997), the nature of the interactions between 5-HT 2A and 5-HT 2C could potentially vary by mouse strain.…”

Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens

“…It is not clear why those two groups obtained such discrepant results with DOI in animals pretreated with SB 242,084, but the fact that the studies used different strains of mice may have been a contributing factor. It has been reported that there are strain differences in 5-HT 2C receptor mRNA editing (Calcagno and Invernizzi, 2010; Hackler et al, 2006). Editing of 5-HT 2C receptor mRNA can dramatically alter G-protein coupling (Burns et al, 1997), and thus differences in 5-HT 2C editing could potentially alter how 5-HT 2A and 5-HT 2C receptors interact in different strains of mice.…”