Juvenile 5HT(1B) receptor knockout mice exhibit reduced pharmacological sensitivity to 5HT(1A) receptor activation

Serotonin is an important modulator of anxiety and thus drugs that act on this system have frequently been shown to be either anxiogenic or anxiolytic. In addition serotonin has important trophic functions during early development and disruption of serotonin homeostasis is likely to have long-lasting repercussions in the adult. In the present study we examined the contribution of two serotonin receptor subtypes (5HT(1A) and 5HT(1B)) to the pathophysiology of anxiety during development. For this, we have studied homozygous knockout mice lacking the 5HT(1B) receptor and examined the effect of pharmacological manipulations of 5HT(1A) and 5HT(1B) receptors on locomotor activity and emission of ultrasonic vocalization (USV) in 7-8 days old mice. As shown before, drug naïve 5HT(1B) knockout pups showed reduced USV and were hyperactive, in comparison to wild type controls. The administration of RU24969 (a 5HT(1A/1B) agonist) showed a dose-dependent decrease in USV in the wild type and a biphasic effect in the mutants and resulted in dose-dependent increase in activity in the wild type and, to a lesser extent, in the knockouts. The selective 5HT(1A) agonist, 8OH-DPAT, dose-dependently blocked vocalization in both genotypes and also increased locomotion. To differentially activate 5HT(1B) receptors we first blocked 5HT(1A) receptors with WAY100315 and then treated with RU24969. At a high testing temperature, pretreatment with WAY100315 resulted in an anxiogenic effect in wild type pups but not in the knockouts. In agreement with our findings that 5HT(1B) knockout mice were in general less sensitive to 5HT(1A) activation, 5HT(1A) receptor binding was reduced in the knockouts in comparison to controls. Finally, treatment with diazepam dose-dependently decreased USVs in both group with the knockouts showing enhanced sensitivity to this drug. Our results show that important adaptations to a disturbance of serotonin homeostasis occur during the first week of life within the serotonergic system. The observed decreased in sensitivity of 5HT(1B) knockout mice to 5HT(1A) and increased to GABA(A) manipulations are discussed within the context of serotonergic plasticity during development and the implication for clinical treatment of anxiety in genetically predisposed individuals.