Catechol-O-methyltransferase (COMT) deficiency in mice leads to sexually dimorphic changes in catecholamine levels and behavior. Researchers created COMT-deficient mice using homologous recombination in embryonic stem cells. These mice showed altered dopamine levels in the frontal cortex, with homozygous female mice displaying reduced emotional reactivity in the dark/light exploratory model. Heterozygous male mice exhibited increased aggressive behavior. COMT is a key enzyme in the metabolism of catecholamines, and its activity varies by brain region and sex. In the striatum and nucleus accumbens, COMT accounts for about 15% of dopamine metabolism, while in the frontal cortex, it accounts for over 60%. COMT activity is influenced by hormones, with females showing lower activity due to epigenetic factors. The COMT gene is located on human chromosome 22, which is associated with schizophrenia and other psychiatric disorders. Variants of the COMT gene are linked to susceptibility to OCD and other psychiatric conditions. The study suggests that COMT plays a role in emotional and social behaviors in mice, with sex-specific effects. The findings highlight the importance of COMT in maintaining steady-state levels of catecholamines in the brain and its potential role in psychiatric disorders. The mouse model provides insights into the genetic and neurochemical mechanisms underlying sex differences in behavior and disease susceptibility.Catechol-O-methyltransferase (COMT) deficiency in mice leads to sexually dimorphic changes in catecholamine levels and behavior. Researchers created COMT-deficient mice using homologous recombination in embryonic stem cells. These mice showed altered dopamine levels in the frontal cortex, with homozygous female mice displaying reduced emotional reactivity in the dark/light exploratory model. Heterozygous male mice exhibited increased aggressive behavior. COMT is a key enzyme in the metabolism of catecholamines, and its activity varies by brain region and sex. In the striatum and nucleus accumbens, COMT accounts for about 15% of dopamine metabolism, while in the frontal cortex, it accounts for over 60%. COMT activity is influenced by hormones, with females showing lower activity due to epigenetic factors. The COMT gene is located on human chromosome 22, which is associated with schizophrenia and other psychiatric disorders. Variants of the COMT gene are linked to susceptibility to OCD and other psychiatric conditions. The study suggests that COMT plays a role in emotional and social behaviors in mice, with sex-specific effects. The findings highlight the importance of COMT in maintaining steady-state levels of catecholamines in the brain and its potential role in psychiatric disorders. The mouse model provides insights into the genetic and neurochemical mechanisms underlying sex differences in behavior and disease susceptibility.