Antidepressant-like behavioral effects in 5-hydroxytryptamine(1A) and 5-hydroxytryptamine(1B) receptor mutant

The development of serotonin receptor knockout mice has provided an opportu nity 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 sero tonin reuptake inhibitors fluoxetine and paroxetine and the selective norep inephrine reuptake inhibitor desipramine, were examined in 5-hydroxytryptam ine (5-HT)(1A) and 5-HT1B receptor mutant mice using the tail suspension te st (TST). Under baseline conditions, the immobility of 5-HT1A receptor muta nt mice, but not 5-HT1B receptor mutant mice, was significantly lower than that of wild-type mice. The decreased baseline immobility in 5-HT1A recepto r mutant mice was reversed by pretreatment with a-methyl-para-tyrosine, but not by para-chlorophenylalanine, suggesting mediation by enhanced catechol amine function. In wild-type mice, fluoxetine (10.0-20.0 mg/kg i.p.) and de sipramine (5.0-20.0 mg/kg j.p.) both significantly decreased immobility in the TST. In 5-HT1A receptor mutant mice, desipramine (20.0 mg/kg i.p.) sign ificantly decreased immobility, whereas fluoxetine (20.0 mg/kg i.p.) and pa roxetine (20.0 mg/kg i.p.) had no effect. The immobility of 5-HT1B, recepto r 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 augmente d in the 5-HT1B receptor mutant mice (2.5-20.0 mg/kg i.p.) compared with wi ld-type mice. Administration of selective 5-HT receptor antagonists in wild -type mice partially reproduced the phenotypes of the mutant mice. These re sults suggest that 5-HT1A and 5-HT1B receptors have different roles in the modulation of the response to antidepressant drugs in the TST.