title: Dopamine bioavailability in the mPFC modulates operant learning performance in rats: an experimental study with a computational interpretation.
abstract: Dopamine encodes reward and its prediction in reinforcement learning. Catechol-O-methyltransferase (COMT) activity in the medial prefrontal cortex (mPFC) has been shown to influence cognitive abilities by modifying dopamine clearance. Nevertheless, it is unknown how COMT in the mPFC influences operant learning. Systemic entacapone (50mg/kg), as well as local entacapone (3 pg) and recombinant COMT (17 μg) in the mPFC were administered to male Long Evans rats prior to training in an operant conditioning task. We found that systemic and local administration of the COMT inhibitor entacapone significantly improves learning performance. Conversely, recombinant COMT administration totally impaired learning. These data have been interpreted through a computational model where the phasic firing of dopaminergic neurons was computed by means of a temporal difference algorithm and dopamine bioavailability in the mPFC was simulated with a gating window. The duration of this window was selected to simulate the effects of inhibited or enhanced COMT activity (by entacapone or recombinant COMT respectively). The model accounts for an improved performance reproducing the entacapone effects, and a detrimental impact on learning when the clearance is increased reproducing the recombinant COMT effects. The experimental and computational results show that learning performance can be deeply influenced by COMT manipulations in the mPFC.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06519, USA.
authors.forename: Maximiliano
authors.initials: M
authors.lastname: Rapanelli
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06519, USA.
authors.forename: Luciana Romina
authors.initials: LR
authors.lastname: Frick
authors.affiliation: Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (IByME - CONICET), Vuelta de Obligado 2490, C1428ADN Ciudad de Buenos Aires, Argentina.
authors.forename: Anabel M M
authors.initials: AM
authors.lastname: Miguelez Fernández
authors.affiliation: Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (IByME - CONICET), Vuelta de Obligado 2490, C1428ADN Ciudad de Buenos Aires, Argentina; Instituto de Ingeniería Biomédica, Facultad de Ingeniería, Universidad de Buenos Aires, Paseo Colon 850, Ciudad de Buenos Aires, Argentina. Electronic address: silvano@fi.uba.ar.
authors.forename: B Silvano
authors.initials: BS
authors.lastname: Zanutto
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000465:Algorithms; D000818:Animals; D002394:Catechol O-Methyltransferase / Q000378:metabolism; D065098:Catechol O-Methyltransferase Inhibitors / Q000494:pharmacology; D002396:Catechols / Q000494:pharmacology; D003198:Computer Simulation; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000502:physiology; D008297:Male; D008959:Models, Neurological; D016571:Neural Networks, Computer; D009570:Nitriles / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology*; D020318:Rats, Long-Evans; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D009570:Nitriles; D011994:Recombinant Proteins; D015102:3,4-Dihydroxyphenylacetic Acid; C071192:entacapone; D002394:Catechol O-Methyltransferase; D004298:Dopamine
keywords: COMT; Computational model; Dopamine; Entacapone; Neural network; Prefrontal cortex