title: Deconstructing craving: dissociable cortical control of cue reactivity in nicotine addiction.
abstract: BACKGROUND
  Cue reactivity, the ability of cues associated with addictive substances to induce seeking and withdrawal, is a major contributor to addiction. Although human imaging studies show that cigarette-associated cues simultaneously activate the insula and the orbitofrontal cortex and evoke craving, how these activities functionally contribute to distinct elements of cue reactivity remains unclear. Moreover, it remains unclear whether the simultaneous activation of these cortical regions reflects coordinated functional connectivity or parallel processing.
  
  
  METHODS
  We selectively lesioned the insula or orbitofrontal cortex with the excitotoxin ibotenic acid in mice, and their approach to nicotine-associated cues (n = 6-13/group) and avoidance of withdrawal-associated cues (n = 5-12/group) were separately examined in place conditioning paradigms. We additionally tested the role of these two cortical structures in approach to food-associated cues (n = 6-7/group) and avoidance of lithium chloride-associated cues (n = 6-7/group).
  
  
  RESULTS
  Our data show a double dissociation in which excitotoxic lesions of the insula and orbitofrontal cortex selectively disrupted nicotine-induced cue approach and withdrawal-induced cue avoidance, respectively. These effects were not entirely generalized to approach to food-associated cues or avoidance of lithium chloride-associated cues.
  
  
  CONCLUSIONS
  Our data provide functional evidence that cue reactivity seen in addiction includes unique neuroanatomically dissociable elements and suggest that the simultaneous activation of these two cortical regions in response to smoking-related cues does not necessarily indicate functional connectivity.
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Scott
authors.forename: Noboru
authors.initials: N
authors.lastname: Hiroi
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001245:Association Learning / Q000502:physiology; D002540:Cerebral Cortex / Q000503:physiopathology*; D003216:Conditioning, Operant / Q000502:physiology; D003463:Cues; D005502:Food; D008297:Male; D051379:Mice; D009538:Nicotine / Q000008:administration & dosage*; D012646:Self Administration; D014029:Tobacco Use Disorder / Q000503:physiopathology*
chemical_list: D009538:Nicotine