Abstract

The development of serotonin receptor knockout mice has provided an opportunity to study antidepressant drug effects in animals with targeted genetic deletion of receptors involved in antidepressant responses. In the current study, the effects of two types of antidepressant drugs, the selective serotonin reuptake inhibitors fluoxetine and paroxetine and the selective norepinephrine reuptake inhibitor desipramine, were examined in 5-hydroxytryptamine (5-HT)_1A and 5-HT_1B receptor mutant mice using the tail suspension test (TST). Under baseline conditions, the immobility of 5-HT_1A receptor mutant mice, but not 5-HT_1B receptor mutant mice, was significantly lower than that of wild-type mice. The decreased baseline immobility in 5-HT_1A receptor mutant mice was reversed by pretreatment with α-methyl-para-tyrosine, but not bypara-chlorophenylalanine, suggesting mediation by enhanced catecholamine function. In wild-type mice, fluoxetine (10.0–20.0 mg/kg i.p.) and desipramine (5.0–20.0 mg/kg i.p.) both significantly decreased immobility in the TST. In 5-HT_1Areceptor mutant mice, desipramine (20.0 mg/kg i.p.) significantly decreased immobility, whereas fluoxetine (20.0 mg/kg i.p.) and paroxetine (20.0 mg/kg i.p.) had no effect. The immobility of 5-HT_1B receptor mutant mice was decreased similarly by desipramine (5.0–20.0 mg/kg i.p.). However, the effect of low doses of fluoxetine were significantly augmented in the 5-HT_1Breceptor mutant mice (2.5–20.0 mg/kg i.p.) compared with wild-type mice. Administration of selective 5-HT receptor antagonists in wild-type mice partially reproduced the phenotypes of the mutant mice. These results suggest that 5-HT_1A and 5-HT_1Breceptors have different roles in the modulation of the response to antidepressant drugs in the TST.