This study investigates the role of serotonin (5-HT) receptor 1A (5-HT1A) in anxiety-related behaviors using a mouse model lacking this receptor. Mice without 5-HT1A receptors showed decreased exploratory activity and increased fear of aversive environments, such as open or elevated spaces. They also exhibited reduced immobility in the forced swim test, a behavior typically associated with antidepressant treatment. Despite the absence of 5-HT1A receptors, these mice had normal levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA), possibly due to up-regulation of 5-HT1B autoreceptors. Heterozygous mutants showed intermediate phenotypes in most behavioral tests. The 5-HT1A receptor is found on serotonergic neurons, where it acts as an autoreceptor, and on non-serotonergic neurons. 5-HT1A agonists are used in the treatment of anxiety disorders, and antagonists may enhance the efficacy of certain antidepressants. However, the clinical value and mechanism of these drugs remain unclear. The study used homologous recombination to generate mice lacking the 5-HT1A receptor. These mice had normal growth and viability and did not display obvious anatomical or behavioral abnormalities. Autoradiography studies confirmed the absence of 5-HT1A receptors in knockout mice. Superfusion experiments showed that 5-HT1A agonists inhibited 5-HT release, while 5-HT1B agonists had a larger inhibitory effect in knockout mice, suggesting up-regulation of 5-HT1B autoreceptors. Behavioral studies revealed that knockout mice displayed decreased exploratory activity and increased anxiety-like behaviors in the open field and elevated plus maze tests. In the forced swim test, knockout mice showed reduced immobility, which may reflect the absence of presynaptic 5-HT1A receptors, similar to the desensitization of 5-HT1A receptors from chronic antidepressant treatment. The study suggests that 5-HT1A receptors are involved in modulating exploratory and fear-related behaviors. Reductions in 5-HT1A receptor density due to genetic defects or environmental stressors may result in heightened anxiety. The findings indicate that 5-HT1A knockout mice could serve as a model for environmental or genetic conditions that down-regulate 5-HT1A receptor levels. The study also highlights gender differences in 5-HT1A receptor function and suggests that the absence of 5-HT1A receptors may lead to increased anxiety-like behaviors.This study investigates the role of serotonin (5-HT) receptor 1A (5-HT1A) in anxiety-related behaviors using a mouse model lacking this receptor. Mice without 5-HT1A receptors showed decreased exploratory activity and increased fear of aversive environments, such as open or elevated spaces. They also exhibited reduced immobility in the forced swim test, a behavior typically associated with antidepressant treatment. Despite the absence of 5-HT1A receptors, these mice had normal levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA), possibly due to up-regulation of 5-HT1B autoreceptors. Heterozygous mutants showed intermediate phenotypes in most behavioral tests. The 5-HT1A receptor is found on serotonergic neurons, where it acts as an autoreceptor, and on non-serotonergic neurons. 5-HT1A agonists are used in the treatment of anxiety disorders, and antagonists may enhance the efficacy of certain antidepressants. However, the clinical value and mechanism of these drugs remain unclear. The study used homologous recombination to generate mice lacking the 5-HT1A receptor. These mice had normal growth and viability and did not display obvious anatomical or behavioral abnormalities. Autoradiography studies confirmed the absence of 5-HT1A receptors in knockout mice. Superfusion experiments showed that 5-HT1A agonists inhibited 5-HT release, while 5-HT1B agonists had a larger inhibitory effect in knockout mice, suggesting up-regulation of 5-HT1B autoreceptors. Behavioral studies revealed that knockout mice displayed decreased exploratory activity and increased anxiety-like behaviors in the open field and elevated plus maze tests. In the forced swim test, knockout mice showed reduced immobility, which may reflect the absence of presynaptic 5-HT1A receptors, similar to the desensitization of 5-HT1A receptors from chronic antidepressant treatment. The study suggests that 5-HT1A receptors are involved in modulating exploratory and fear-related behaviors. Reductions in 5-HT1A receptor density due to genetic defects or environmental stressors may result in heightened anxiety. The findings indicate that 5-HT1A knockout mice could serve as a model for environmental or genetic conditions that down-regulate 5-HT1A receptor levels. The study also highlights gender differences in 5-HT1A receptor function and suggests that the absence of 5-HT1A receptors may lead to increased anxiety-like behaviors.