Catechol-o-methyltransferase inhibition improves set-shifting performance and elevates stimulated dopamine release in the rat prefrontal cortex

Abstract

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.

Figure 1.

Effect of tolcapone on set-shifting trials to criterion. Vehicle (closed bars; n = 10) or 30 mg/kg tolcapone (open bars; n = 10) was administered 1 hr before the start of the task. Tolcapone-treated animals performed significantly better on the EDS stage of the task (^*p < 0.001). There was no significant effect of tolcapone on simple discrimination (SD), compound discrimination (CD), intradimensional shift (IDS), or any of the reversal stages (Rev1-3).

Figure 2.

Effect of tolcapone on stimulated levels of DA (A, C, E) and NE (B, D, F). Tolcapone (30 mg/kg) (open symbols) or vehicle (closed symbols) was administered 2 hr before drug challenge. Mean basal [DA]_EX and [NE]_EX levels were 15 and 80 fmol per sample, respectively. A, B, Clozapine (10 mg/kg) (at time 0; closed squares; n = 8) elevated [DA]_EX (A)(p < 0.01) and [NE]_EX (B) (p < 0.001) levels compared with vehicle (closed circles; n = 6). Tolcapone pretreatment (open squares; n = 7) significantly potentiated this rise in [DA]_EX (A) (p < 0.001) but not [NE]_EX (B) (p > 0.1). The effect of tolcapone (Tol) or vehicle (Veh) administration on both basal and clozapine (CLZ)-induced [DA]_EX (C) and [NE]_EX (D) for 2 hr after drug challenge is shown with the significant increase in [DA]_EX indicated with an asterisk. E, F, Tolcapone (open squares; n = 8) or vehicle (closed squares; n = 8) was administered 2 hr before potassium challenge. High potassium artificial CSF was perfused through the microdialysis probe for 20 min, starting at 0 min as indicated by the open bar. Tolcapone pretreatment significantly potentiated the potassium-induced rise in [DA]_EX (E) (p < 0.01) but not [NE]_EX (F) (p > 0.1).