title: Perturbations in reward-related decision-making induced by reduced prefrontal cortical GABA transmission: Relevance for psychiatric disorders.
abstract: The prefrontal cortex (PFC) is critical for higher-order cognitive functions, including decision-making. In psychiatric conditions such as schizophrenia, prefrontal dysfunction co-occurs with pronounced alterations in decision-making ability. These alterations include a diminished ability to utilize probabilistic reinforcement in guiding future choice, and a reduced willingness to expend effort to receive reward. Among the neurochemical abnormalities observed in the PFC of individuals with schizophrenia are alterations in the production and function of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). To probe how PFC GABA hypofunction may contribute to alterations in cost/benefit decision-making, we assessed the effects GABAA-receptor antagonist bicuculline (BIC; 50 ng in 0.5 μl saline/hemisphere) infusion in the medial PFC of rats during performance on a series of well-validated cost/benefit decision-making tasks. Intra-PFC BIC reduced risky choice and reward sensitivity during probabilistic discounting and decreased the preference for larger rewards associated with a greater effort cost, similar to the behavioral sequelae observed in schizophrenia. Additional experiments revealed that these treatments did not alter instrumental responding on a progressive ratio schedule, nor did they impair the ability to discriminate between reward and no reward. However, BIC induced a subtle but consistent impairment in preference for larger vs. smaller rewards of equal cost. BIC infusion also increased decision latencies and impaired the ability to "stay on task" as indexed by reduced rates of instrumental responding. Collectively, these results implicate prefrontal GABAergic dysfunction as a key contributing factor to abnormal decision-making observed in schizophrenia and other neuropsychiatric conditions with similar neurobiological and behavioral alterations.
authors.affiliation: Department of Psychology and Brain Research Centre, University of British Columbia, Vancouver, B.C. V6T 1Z4, Canada.
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Piantadosi
authors.affiliation: Department of Psychology and Brain Research Centre, University of British Columbia, Vancouver, B.C. V6T 1Z4, Canada.
authors.forename: Shahin
authors.initials: S
authors.lastname: Khayambashi
authors.affiliation: Department of Psychology and Brain Research Centre, University of British Columbia, Vancouver, B.C. V6T 1Z4, Canada.
authors.forename: Magdalen G
authors.initials: MG
authors.lastname: Schluter
authors.affiliation: Department of Psychology and Brain Research Centre, University of British Columbia, Vancouver, B.C. V6T 1Z4, Canada.
authors.forename: Agnes
authors.initials: A
authors.lastname: Kutarna
authors.affiliation: Department of Psychology and Brain Research Centre, University of British Columbia, Vancouver, B.C. V6T 1Z4, Canada. Electronic address: floresco@psych.ubc.ca.
authors.forename: Stan B
authors.initials: SB
authors.lastname: Floresco
mesh_terms: D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D003657:Decision Making / Q000187:drug effects / Q000502:physiology*; D004192:Discrimination, Psychological / Q000187:drug effects; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D008297:Male; D009042:Motivation / Q000187:drug effects / Q000502:physiology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D020318:Rats, Long-Evans; D012055:Reinforcement Schedule; D012201:Reward; D012309:Risk-Taking; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D058787:GABA-A Receptor Antagonists; D005680:gamma-Aminobutyric Acid; D001640:Bicuculline
keywords: Depression; Effort; Gamma-aminobutyric acid; Prefrontal cortex; Reward; Risk; Schizophrenia