title: The agranular and granular insula differentially contribute to gambling-like behavior on a rat slot machine task: effects of inactivation and local infusion of a dopamine D4 agonist on reward expectancy.
abstract: Rats, like humans, are susceptible to the reinforcing effects of reward-related stimuli presented within a compound stimulus array, putatively analogous to the so-called near-miss effect. We have previously demonstrated using a rodent slot machine task (rSMT) that the reward expectancy these stimuli elicit is critically mediated by the dopamine D4 receptor. D4 receptors are principally located in prefrontal regions activated during slot machine play in humans, such as the insular cortex. The insula has recently attracted considerable interest as it appears to play a crucial role in substance and behavioral addictions. However, the insula is a heterogeneous area, and the relative contributions of subregions to addictive behaviors are unclear.
  
  
  
  Male Long Evans rats were trained to perform the rSMT, and then bilateral cannula targeting either the granular or agranular insula were implanted. The effects of inactivation and local administration of a D4 agonist were investigated.
  
  
  
  Temporary inactivation of the agranular, but not the granular insula impaired performance on the rSMT. In contrast, local infusion of the D4 agonist PD168077 into the agranular insula had no effect on task performance, but when administered into the granular insula, it improved animals' ability to differentiate winning from non-winning trials. The agranular insula may therefore modulate decision making when conflicting stimuli are present, potentially due to its role in generating a cohesive emotional percept based on both externally and internally generated signals, whereas the granular insular is not critical for this process. Nevertheless, D4 receptors within the granular insula may amplify the incentive salience of aversive environmental stimuli.
  
  
  
  These data provide insight into the neurobiological mechanism underpinning maladaptive reward expectancy during gambling and provide further evidence that D4 receptors represent a potential target for developing pharmacotherapies for problem gambling.
authors.affiliation: Department of Psychology, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada. pcocker@psych.ubc.ca.
authors.forename: P J
authors.initials: PJ
authors.lastname: Cocker
authors.affiliation: Department of Psychology, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada.
authors.forename: M Y
authors.initials: MY
authors.lastname: Lin
authors.affiliation: Department of Psychology, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada.
authors.forename: M M
authors.initials: MM
authors.lastname: Barrus
authors.affiliation: Translational Addiction Research Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada.|Alcohol Research and Treatment Clinic, Addiction Medicine Services, Ambulatory Care and Structured Treatments, CAMH, Toronto, Ontario, Canada.|Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.|Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada.|Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada.|Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada.
authors.forename: B
authors.initials: B
authors.lastname: Le Foll
authors.affiliation: Department of Psychology, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada. cwinstanley@psych.ubc.ca.
authors.forename: C A
authors.initials: CA
authors.lastname: Winstanley
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000503:physiopathology; D003657:Decision Making / Q000187:drug effects*; D004298:Dopamine; D018491:Dopamine Agonists / Q000494:pharmacology*; D005715:Gambling / Q000503:physiopathology*; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans; D050638:Receptors, Dopamine D4 / Q000819:agonists*; D012054:Reinforcement, Psychology; D012201:Reward
chemical_list: D001549:Benzamides; D018491:Dopamine Agonists; C493601:Drd4 protein, rat; C477501:N-((4-(2-cyanophenyl)-1-piperazinyl)methyl)-3-methylbenzamide; D010879:Piperazines; D050638:Receptors, Dopamine D4; D004298:Dopamine
keywords: Agranular insula; D4; Dopamine; Gambling; Granular insula; Near miss