Catechol-O-methyltransferase (COMT) is a key enzyme involved in the metabolic degradation of catecholamines, and its disruption in mice has been linked to psychiatric disorders. The study generated a strain of mice with a disrupted COMT gene and examined the effects on brain catecholamine levels and behavior. Key findings include: 1. **Neurochemical Changes**: COMT-deficient mice showed sexually dimorphic and region-specific changes in dopamine levels, particularly in the frontal cortex. The HVA/DOPAC ratio, a measure of COMT activity, was significantly decreased in all brain regions tested. 2. **Behavioral Phenotypes**: - **Anxiety-like Behaviors**: Homozygous female COMT-deficient mice displayed increased anxiety in a dark/light exploratory model, while no significant effects were observed in males. - **Aggressive Behavior**: Heterozygous male COMT-deficient mice exhibited increased aggression compared to wild-type and homozygous males. - **Sensorimotor Gating**: No significant effects of genotype on prepulse inhibition (PPI) were observed in either sex. 3. **Discussion**: - The results suggest that COMT plays a crucial role in maintaining steady-state levels of catecholamines in the brain and may influence emotional and social behaviors. - The sexually dimorphic effects observed in COMT-deficient mice could help understand sex-specific penetrances of mutations predisposing to psychiatric disorders. - The increased dopamine levels in the frontal cortex of male mice may provide insights into the association between low COMT activity and obsessive-compulsive disorder (OCD) in males. Overall, the study provides evidence for the importance of COMT in the regulation of catecholamine levels and behavior, with sexually dimorphic and region-specific effects.Catechol-O-methyltransferase (COMT) is a key enzyme involved in the metabolic degradation of catecholamines, and its disruption in mice has been linked to psychiatric disorders. The study generated a strain of mice with a disrupted COMT gene and examined the effects on brain catecholamine levels and behavior. Key findings include: 1. **Neurochemical Changes**: COMT-deficient mice showed sexually dimorphic and region-specific changes in dopamine levels, particularly in the frontal cortex. The HVA/DOPAC ratio, a measure of COMT activity, was significantly decreased in all brain regions tested. 2. **Behavioral Phenotypes**: - **Anxiety-like Behaviors**: Homozygous female COMT-deficient mice displayed increased anxiety in a dark/light exploratory model, while no significant effects were observed in males. - **Aggressive Behavior**: Heterozygous male COMT-deficient mice exhibited increased aggression compared to wild-type and homozygous males. - **Sensorimotor Gating**: No significant effects of genotype on prepulse inhibition (PPI) were observed in either sex. 3. **Discussion**: - The results suggest that COMT plays a crucial role in maintaining steady-state levels of catecholamines in the brain and may influence emotional and social behaviors. - The sexually dimorphic effects observed in COMT-deficient mice could help understand sex-specific penetrances of mutations predisposing to psychiatric disorders. - The increased dopamine levels in the frontal cortex of male mice may provide insights into the association between low COMT activity and obsessive-compulsive disorder (OCD) in males. Overall, the study provides evidence for the importance of COMT in the regulation of catecholamine levels and behavior, with sexually dimorphic and region-specific effects.