This study investigates the role of serotonin (5-hydroxytryptamine; 5-HT) receptor 1A (5-HT1A) in mood control using mice lacking this receptor. The researchers generated 5-HT1A knockout mice through homologous recombination and found that these mice exhibit decreased exploratory activity and increased fear of aversive environments, such as open or elevated spaces. They also observed that 5-HT1A knockout mice showed reduced immobility in the forced swim test, a measure often associated with antidepressant treatment. Despite the absence of 5-HT1A receptors, the knockout mice maintained normal levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA), possibly due to up-regulation of 5-HT1B autoreceptors. Heterozygous 5-HT1A mutants displayed intermediate phenotypes in most behavioral tests, with receptor density approximately half that of wild-type mice. These findings suggest that 5-HT1A receptors play a crucial role in modulating exploratory and fear-related behaviors, and that reductions in 5-HT1A receptor density due to genetic defects or environmental stressors may lead to heightened anxiety. The study also highlights gender differences, with males showing more pronounced effects of 5-HT1A receptor absence than females. Overall, the 5-HT1A knockout mice provide a valuable model for studying anxiety-related disorders and the potential mechanisms of antidepressant actions.This study investigates the role of serotonin (5-hydroxytryptamine; 5-HT) receptor 1A (5-HT1A) in mood control using mice lacking this receptor. The researchers generated 5-HT1A knockout mice through homologous recombination and found that these mice exhibit decreased exploratory activity and increased fear of aversive environments, such as open or elevated spaces. They also observed that 5-HT1A knockout mice showed reduced immobility in the forced swim test, a measure often associated with antidepressant treatment. Despite the absence of 5-HT1A receptors, the knockout mice maintained normal levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA), possibly due to up-regulation of 5-HT1B autoreceptors. Heterozygous 5-HT1A mutants displayed intermediate phenotypes in most behavioral tests, with receptor density approximately half that of wild-type mice. These findings suggest that 5-HT1A receptors play a crucial role in modulating exploratory and fear-related behaviors, and that reductions in 5-HT1A receptor density due to genetic defects or environmental stressors may lead to heightened anxiety. The study also highlights gender differences, with males showing more pronounced effects of 5-HT1A receptor absence than females. Overall, the 5-HT1A knockout mice provide a valuable model for studying anxiety-related disorders and the potential mechanisms of antidepressant actions.