Catechol-O-methyltransferase (COMT) is one of the major mammalian enzymes involved in the metabolic degradation of catecholamines and is considered a candidate for several psychiatric disorders and symptoms, including the psychopathology associated with the 22q11 microdeletion syndrome. By means of homologous recombination in embryonic stem cells, a strain of mice in which the gene encoding the COMT enzyme has been disrupted was produced. The basal concentrations of brain catecholamines were measured in the striatum, frontal cortex, and hypothalamus of adult male and female mutants. Locomotor activity, anxiety-like behaviors, sensorimotor gating, and aggressive behavior also were analyzed. Mutant mice demonstrated sexually dimorphic and region-specific changes of dopamine levels, notably in the frontal cortex. In addition, homozygous COMT-deficient female (but not male) mice displayed impairment in emotional reactivity in the dark͞light exploratory model of anxiety. Furthermore, heterozygous COMT-deficient male mice exhibited increased aggressive behavior. Our results provide conclusive evidence for an important sex-and region-specific contribution of COMT in the maintenance of steady-state levels of catecholamines in the brain and suggest a role for COMT in some aspects of emotional and social behavior in mice.Catechol-O-methyltransferase (COMT) along with monoamine oxidases (MAO-A and -B) are the major mammalian enzymes involved in the metabolic degradation of dopamine, norepinephrine, and epinephrine. COMT is a Mg 2ϩ -dependent enzyme that catalyzes the transfer of methyl groups from S-adenosyl methionine to a hydroxyl group of a catecholic substrate: dopamine is converted into 3-methoxytyramine, and norepinephrine is converted into normetanephrine (1). COMT is widely distributed in the mammalian brain, although results from pharmacological studies suggest that the relative importance of methylation (by COMT) versus deamination (by MAO) in the metabolic degradation of catecholamines varies among brain regions, with methylation accounting for about 15% of released dopamine in striatum and in nucleus accumbens and for more than 60% in frontal cortex (2). The enzyme is absent from the dopaminergic terminals and is thought to be involved in the catabolism of extraneuronal dopamine in glial cells and͞or postsynaptic neurons (1). COMT activity is probably under hormonal control. Comparisons of liver COMT activity and thermostability in humans indicated an epigenetically determined significantly lower COMT activity in females (3). A limited number of studies in other species suggest that COMT activity can be reduced epigenetically by estrogens (4) and can be affected by the process of sexual differentiation of the brain (5).

Hemizygous cryptic deletions of the q11 band of human chromosome 22 have been associated with a number of psychiatric and behavioural phenotypes, including schizophrenia. Here we report the isolation and characterization of PRODH, a human homologue of Drosophila melanogaster sluggish-A (slgA), which encodes proline dehydrogenase responsible for the behavioural phenotype of the slgA mutant. PRODH is localized at chromosome 22q11 in a region deleted in some psychiatric patients. We also isolated the mouse homologue of slgA (Prodh), identified a mutation in this gene in the Pro/Re hyperprolinaemic mouse strain and found that these mice have a deficit in sensorimotor gating accompanied by regional neurochemical alterations in the brain. Sensorimotor gating is a neural filtering process that allows attention to be focused on a given stimulus, and is affected in patients with neuropsychiatric disorders. Furthermore, several lines of evidence suggest that proline may serve as a modulator of synaptic transmission in the mammalian brain. Our observations, in conjunction with the chromosomal location of PRODH, suggest a potential involvement of this gene in the 22q11-associated psychiatric and behavioural phenotypes.

We conclude that hypercholesterolemia but not hypertriglyceridemia leads to increased formation of superoxide and peroxynitrite, and thereby results in cardiac dysfunction in hearts of human apoB100 transgenic mice.