Effort-related decision making in humanized COMT mice: Effects ofVal158Met polymorphisms and possible implications for negative symptomsin humans

Abstract

Catechol-o-methyltransferase (COMT) is an enzyme that metabolizes catecholamines, and is crucial for clearanceof dopamine (DA) in prefrontal cortex. Val158Met polymorphism, which causes a valine (Val) to methionine(Met) substitution at codon 158, is reported to be associated with human psychopathologies in some studies. TheVal/Val variant of the enzyme results in higher dopamine metabolism, which results in reduced dopaminetransmission. Thus, it is important to investigate the relation between Val158Met polymorphisms using rodentmodels of psychiatric symptoms, including negative symptoms such as motivational dysfunction. In the presentstudy, humanized COMT transgenic mice with two genotype groups (Val/Val (Val) and Met/Met (Met) homo-zygotes) and wild-type (WT) mice from the S129 background were tested using a touchscreen effort-based choiceparadigm. Mice were trained to choose between delivery of a preferred liquid diet that reinforced panel pressingon variousfixed ratio (FR) schedules (high-effort alternative), vs. intake of pellets concurrently available in thechamber (low-effort alternative). Panel pressing requirements were controlled by varying the FR levels (FR1, 2,4, 8, 16) in ascending and descending sequences across weeks of testing. All mice were able to acquire the initialtouchscreen operant training, and there was an inverse relationship between the number of reinforcers deliveredby panel pressing and pellet intake across different FR levels. There was a significant group x FR level interactionin the ascending limb, with panel presses in the Val group being significantly lower than the WT group in FR1–8,and lower than Met in FR4. Thesefindings indicate that the humanized Val allele in mice modulates FR/pellet-choice performance, as marked by lower levels of panel pressing in the Val group when the ratio requirementwas moderately high. These studies may contribute to the understanding of the role of COMT polymorphisms innegative symptoms such as motivational dysfunctions in schizophrenic patients.