title: Cholinergic blockade frees fear extinction from its contextual dependency.
abstract: BACKGROUND
  Fears that are maladaptive or inappropriate can be reduced through extinction training. However, extinction is highly context-sensitive, resulting in the renewal of fear after shifts in context and limiting the clinical efficacy of extinction training. Lesion and inactivation studies have shown that the contextualization of extinction depends on the hippocampus. Parallel studies have found that intrahippocampal scopolamine (Scop) blocks contextual fear conditioning. Importantly, this effect was replicated with a noninvasive technique in which a low dose of Scop was administered systemically. We aimed to transfer the effects of this noninvasive approach to block the contextualization of fear extinction.
  
  
  METHODS
  Rats were tone fear conditioned and extinguished under various systemic doses of Scop or the saline vehicle. They were subsequently tested (off drug) for tone fear in a context that was the same (control subjects) or shifted (renewal group) with respect to the extinction context.
  
  
  RESULTS
  The lowest dose of Scop produced a significant attenuation of fear renewal when renewal was tested either in the original training context or a novel context. The drug also slowed the rate of long-term extinction memory formation, which was readily overcome by extending extinction training. Scopolamine only gave this effect when it was administered during but not after extinction training. Higher doses of Scop severely disrupted extinction learning.
  
  
  CONCLUSIONS
  We discovered that disrupting contextual processing during extinction with the cholinergic antagonist Scop blocked subsequent fear renewal. Low doses of Scop might be a clinically promising adjunct to exposure therapy by making extinction more relapse-resistant.
authors.affiliation: Departments of Psychology and Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Moriel
authors.initials: M
authors.lastname: Zelikowsky
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Hast
authors.forename: Rebecca Z
authors.initials: RZ
authors.lastname: Bennett
authors.forename: Michael
authors.initials: M
authors.lastname: Merjanian
authors.forename: Nathaniel A
authors.initials: NA
authors.lastname: Nocera
authors.forename: Ravikumar
authors.initials: R
authors.lastname: Ponnusamy
authors.forename: Michael S
authors.initials: MS
authors.lastname: Fanselow
mesh_terms: D000161:Acoustic Stimulation; D000818:Animals; D018680:Cholinergic Antagonists / Q000494:pharmacology*; D003214:Conditioning, Classical / Q000187:drug effects* / Q000502:physiology; D004597:Electroshock; D005108:Extinction, Psychological / Q000187:drug effects* / Q000502:physiology; D005239:Fear / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology; D051381:Rats; D020318:Rats, Long-Evans; D012601:Scopolamine / Q000494:pharmacology*
chemical_list: D018680:Cholinergic Antagonists; D012601:Scopolamine