ORIGINAL INVESTIGATION Tolcapone enhances food-evoked dopamine efflux and executive memory processes mediated by the rat prefrontal cortex C. C. Lapish & S. Ahn & L. M. Evangelista & K. So & J. K. Seamans & A. G. Phillips Received: 17 August 2008 / Accepted: 16 September 2008 / Published online: 15 October 2008 # Springer-Verlag 2008 Abstract Background and rationale Genetic variations in catechol- O-methyl transferase (COMT) or administration of COMT inhibitors have a robust impact on cognition and executive function in humans. The COMT enzyme breaks down extracellular dopamine (DA) and has a particularly impor- tant role in the prefrontal cortex (PFC) where DA trans- porters are sparse. As such, the beneficial cognitive effects of the COMT inhibitor tolcapone are postulated to be the result of increased bioavailability of DA in the PFC. Furthermore, it has been shown previously that COMT inhibitors increase pharmacologically evoked DA but do not affect basal levels in the PFC. Objectives The current study characterized the ability of tolcapone to increase DA release in response to behavior- ally salient stimuli and improve performance of the delayed spatial win-shift (DSWSh) task. Results and conclusions Tolcapone enhanced PFC DA efflux associated with the anticipation and consumption of food when compared to saline controls. Chronic and acute treatment with tolcapone also reduced the number of errors committed during acquisition of the DSWSh. However, no dissociable effects were observed in experiments designed to selectively assay encoding or recall in well-trained animals, as both experiments showed improvement with tolcapone treatment. Taken together, these data suggest a generalized positive influence on cognition. Furthermore, these data support the conclusion of Apud and Weinberger (CNS Drugs 21:535–557, 2007) that agents which selec- tively potentiate PFC DA release may confer cognitive enhancement without the unwanted side effects produced by drugs that increase basal DA levels in cortical and subcortical brain regions. Keywords Prefrontal cortex . Catechol-O-methyl transferase . COMT . Microdialysis . Radial arm maze . Tolcapone . Cognitive enhancer . Dopamine . Rat Introduction Drugs such as methylphenidate, modafinil, beta blockers, and acetylcholinesterase inhibitors are used routinely in clinical neuroscience but are now being used with increas- ing frequency by members of the general public to enhance cognitive function (Stip et al. 2005; Maher 2008). Many of these cognitive enhancers target catecholamine neurotrans- mission by serving as direct or indirect noradrenaline or dopamine (DA) agonists and/or transporter blockers. While these drugs act throughout the brain, many of the cognitive processes affected are modulated by changes in catechol- amine levels specifically in the prefrontal cortex (PFC; Mattay et al. 1996, 2003; Goldman-Rakic et al. 2004). In most terminal regions of the nigrostriatal and mesolimbic DA system, extracellular DA concentration is tightly regulated by the DA transporter (DAT). However, DAT expression levels are relatively low in the PFC (Lewis et al. 2001; Sesack et al. 1998; Hall et al. 1999) while the expression levels of the enzyme catechol-O-methyl trans- ferase (COMT) are relatively high (Lloyd et al. 1975; Matsumoto et al. 2003b). Accordingly, extracellular DA concentration in the PFC is regulated by both the norepinephrine transporter (Moron et al. 2002; Carboni et Psychopharmacology (2009) 202:521–530 DOI 10.1007/s00213-008-1342-1 C. C. Lapish (*) : S. Ahn : L. M. Evangelista : K. So : J. K. Seamans : A. G. Phillips Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, Canada, V6T 2A1 e-mail: clapish@interchange.ubc.ca