The Val158Met polymorphism of the human
catechol-O-methyltransferase (COMT) gene affects activity of the
enzyme and influences performance and efficiency of the prefrontal cortex (PFC); however, although catecholaminergic neurotransmission is implicated, the underlying mechanisms remain elusive because studies of the role of COMT in PFC function are sparse. This study investigated the effect of
tolcapone, a brain-penetrant COMT inhibitor, on a rat model of attentional set shifting, which is dependent on
catecholamines and the medial PFC (mPFC). Additionally, we investigated the effect of
tolcapone on extracellular
catecholamines in the mPFC using microdialysis in awake rats.
Tolcapone significantly and specifically improved extradimensional (ED) set shifting.
Tolcapone did not affect basal extracellular
catecholamines, but significantly potentiated the increase in extracellular
dopamine (DA) elicited by either local administration of the depolarizing agent
potassium chloride or systemic administration of the
antipsychotic agent clozapine. Although extracellular
norepinephrine (NE) was also elevated by local depolarization and
clozapine, the increase was not enhanced by
tolcapone. We conclude that COMT activity specifically affects ED set shifting and is a significant modulator of mPFC DA but not NE under conditions of increased catecholaminergic transmission. These data suggest that the links between COMT activity and PFC function can be modeled in rats and may be specifically mediated by DA. The interaction between
clozapine and
tolcapone may have implications for the treatment of
schizophrenia.