CATECHOL-O-METHYLTRANSFERASE-DEFICIENT MICE EXHIBIT SEXUALLY DIMORPHIC CHANGES IN CATECHOLAMINE LEVELS AND BEHAVIOR

Catechol-O-methyltransferase (COMT) is one of the major mammalian enzy mes involved in the metabolic degradation of catecholamines and is con sidered a candidate for several psychiatric disorders and symptoms, in cluding the psychopathology associated with the 22q11 microdeletion sy ndrome. By means of homologous recombination in embryonic stem cells, a strain of mice in which the gene encoding the COMT enzyme has been d isrupted was produced. The basal concentrations of brain catecholamine s were measured in the striatum, frontal cortex, and hypothalamus of a dult male and female mutants. Locomotor activity, anxiety-like behavio rs, sensorimotor gating, and aggressive behavior also were analyzed. M utant mice demonstrated sexually dimorphic and region-specific changes of dopamine levels, notably in the frontal cortex. In addition, homoz ygous COMT-deficient female (but not male) mice displayed impairment i n emotional reactivity in the dark/light exploratory model of anxiety. Furthermore, heterozygous COMT-deficient male mice exhibited increase d aggressive behavior. Our results provide conclusive evidence for an important sex- and region-specific contribution of COMT in the mainten ance of steady-state levels of catecholamines in the brain and suggest a role for COMT in some aspects of emotional and social behavior in m ice.