Repeated stress in young and old 5-HT(2C) receptor knockout mice.

Serotonin (5-HT)(2C) receptor null mutant (knockout, KO) mice develop hyperphagia and midlife obesity. Based upon previous observations indicating altered responsiveness to stressful environmental conditions in these mice, we hypothesized that this KO mouse was hyperresponsive to repeated stress. To test this, we examined the effect of two intensities of repeated stress on food intake and body weight in 5-HT(2C) receptor KO and wild-type (WT) mice. The stressors involved daily cage change (including handling) for 3 days then daily restraint for 4 days. On the final day, mice were immediately decapitated after restraint to assess levels of plasma hormones. Two ages were used: young (12 weeks) and old (32-34 weeks). Basally, young KO were prehyperphagic and weighed the same as WT. In the old mice, KO were frankly hyperphagic and heavier than WT. In response to repeated cage change alone, the genotype-specific difference in food intake in the young group was enhanced, whereas in the old group it was diminished. This stressor did not significantly affect body weight change or caloric efficiency with respect to age or genotype. Repeated restraint had little effect on the young mice. However, in the old mice, KO had decreases in relative body weight and caloric efficiency compared with WT. In the old KO mice, adrenocorticotrophic hormone (ACTH), corticosterone and insulin were increased compared with WT mice. Together, these findings indicate that 5-HT(2C) receptor KO mice are hyperresponsive to repeated stress and this effect is influenced by stressor intensity and initial metabolic state of the mouse.