Advertisement

Cholinergic Blockade Frees Fear Extinction from Its Contextual Dependency

Published:September 14, 2012DOI:https://doi.org/10.1016/j.biopsych.2012.08.006

      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.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Bolles R.C.
        • Fanselow M.S.
        A perceptual-defensive-recuperative model of fear and pain.
        Behav Brain Sci. 1980; 3: 291-301
        • Bouton M.E.
        • Mineka S.
        • Barlow D.H.
        A modern learning theory perspective on the etiology of panic disorder.
        Psychol Rev. 2001; 108: 4-32
        • Craske M.G.
        • Kircanski K.
        • Zelikowsky M.
        • Mystkowski J.
        • Chowdhury N.
        • Baker A.
        Optimizing inhibitory learning during exposure therapy.
        Behav Res Ther. 2008; 46: 5-27
        • Pavlov I.P.
        Conditioned Reflexes.
        Oxford University Press, London1927
        • Bouton M.E.
        Context, ambiguity, and unlearning: Sources of relapse after behavioral extinction.
        Biol Psychiatry. 2002; 52: 976-986
        • Bouton M.E.
        Context and behavioral processes in extinction.
        Learn Mem. 2004; 11: 485-494
        • Bouton M.E.
        • Bolles R.C.
        Role of conditioned contextual stimuli in reinstatement of extinguished fear.
        J Exp Psychol Anim Behav Process. 1979; 5: 368-378
        • Bouton M.E.
        • King D.A.
        Contextual control of the extinction of conditioned fear: Tests for the associative value of the context.
        J Exp Psychol Anim Behav Process. 1983; 9: 248-265
        • Mystkowski J.L.
        • Craske M.G.
        • Echiverri A.M.
        • Labus J.S.
        Mental reinstatement of context and return of fear in spider-fearful participants.
        Behav Ther. 2006; 37: 49-60
        • Mystkowski J.L.
        • Mineka S.
        • Vernon L.L.
        • Zinbarg R.E.
        Changes in caffeine states enhance return of fear in spider phobia.
        J Consult Clin Psychol. 2003; 71: 243-250
        • Mineka S.
        • Mystkowski J.L.
        • Hladek D.
        • Rodriguez B.I.
        The effects of changing contexts on return of fear following exposure therapy for spider fear.
        J Consult Clin Psychol. 1999; 67: 599-604
        • Walker D.L.
        • Ressler K.J.
        • Lu K.T.
        • Davis M.
        Facilitation of conditioned fear extinction by systemic administration or intra-amygdala infusions of D-cycloserine as assessed with fear-potentiated startle in rats.
        J Neurosci. 2002; 22: 2343-2351
        • Davis M.
        • Ressler K.
        • Rothbaum B.O.
        • Richardson R.
        Effects of D-cycloserine on extinction: Translation from preclinical to clinical work.
        Biol Psychiatry. 2006; 60: 369-375
        • Ressler K.J.
        • Rothbaum B.O.
        • Tannenbaum L.
        • Anderson P.
        • Graap K.
        • Zimand E.
        • et al.
        Cognitive enhancers as adjuncts to psychotherapy: Use of D-cycloserine in phobic individuals to facilitate extinction of fear.
        Arch Gen Psychiatry. 2004; 61: 1136-1144
        • Woods A.M.
        • Bouton M.E.
        D-cycloserine facilitates extinction but does not eliminate renewal of the conditioned emotional response.
        Behav Neurosci. 2006; 120: 1159-1162
        • Bouton M.E.
        • Vurbic D.
        • Woods A.M.
        D-cycloserine facilitates context-specific fear extinction learning.
        Neurobiol Learn Mem. 2008; 90: 504-510
        • Myers K.M.
        • Ressler K.J.
        • Davis M.
        Different mechanisms of fear extinction dependent on length of time since fear acquisition.
        Learn Mem. 2006; 13: 216-223
        • Wang P.S.
        • Berglund P.
        • Olfson M.
        • Pincus H.A.
        • Wells K.B.
        • Kessler R.C.
        Failure and delay in initial treatment contact after first onset of mental disorders in the National Comorbidity Survey Replication.
        Arch Gen Psychiatry. 2005; 62: 603-613
        • Debiec J.
        • Ledoux J.E.
        Disruption of reconsolidation but not consolidation of auditory fear conditioning by noradrenergic blockade in the amygdala.
        Neuroscience. 2004; 129: 267-272
        • Kindt M.
        • Soeter M.
        • Vervliet B.
        Beyond extinction: Erasing human fear responses and preventing the return of fear.
        Nat Neurosci. 2009; 12: 256-258
        • Soeter M.
        • Kindt M.
        Dissociating response systems: Erasing fear from memory.
        Neurobiol Learn Mem. 2010; 94: 30-41
        • Brunet A.
        • Orr S.P.
        • Tremblay J.
        • Robertson K.
        • Nader K.
        • Pitman R.K.
        Effect of post-retrieval propranolol on psychophysiologic responding during subsequent script-driven traumatic imagery in post-traumatic stress disorder.
        J Psychiatr Res. 2008; 42: 503-506
        • Monfils M.H.
        • Cowansage K.K.
        • Klann E.
        • LeDoux J.E.
        Extinction-reconsolidation boundaries: Key to persistent attenuation of fear memories.
        Science. 2009; 324: 951-955
        • Schiller D.
        • Monfils M.H.
        • Raio C.M.
        • Johnson D.C.
        • Ledoux J.E.
        • Phelps E.A.
        Preventing the return of fear in humans using reconsolidation update mechanisms.
        Nature. 2010; 463: 49-53
        • Chang C.H.
        • Berke J.D.
        • Maren S.
        Single-unit activity in the medial prefrontal cortex during immediate and delayed extinction of fear in rats.
        PLoS One. 2010; 5: e11971
        • Clem R.L.
        • Huganir R.L.
        Calcium-permeable AMPA receptor dynamics mediate fear memory erasure.
        Science. 2010; 330: 1108-1112
        • Inda M.C.
        • Muravieva E.V.
        • Alberini C.M.
        Memory retrieval and the passage of time: From reconsolidation and strengthening to extinction.
        J Neurosci. 2011; 31: 1635-1643
        • Milekic M.H.
        • Alberini C.M.
        Temporally graded requirement for protein synthesis following memory reactivation.
        Neuron. 2002; 36: 521-525
        • Vansteenwegen D.
        • Vervliet B.
        • Iberico C.
        • Baeyens F.
        • Van den Bergh O.
        • Hermans D.
        The repeated confrontation with videotapes of spiders in multiple contexts attenuates renewal of fear in spider-anxious students.
        Behav Res Ther. 2007; 45: 1169-1179
        • Neumann D.L.
        • Waters A.M.
        • Westbury H.R.
        The use of an unpleasant sound as the unconditional stimulus in aversive Pavlovian conditioning experiments that involve children and adolescent participants.
        Behav Res Methods. 2008; 40: 622-625
        • Bouton M.E.
        • Garcia-Gutierrez A.
        • Zilski J.
        • Moody E.W.
        Extinction in multiple contexts does not necessarily make extinction less vulnerable to relapse.
        Behav Res Ther. 2006; 44: 983-994
        • Brooks D.C.
        • Bouton M.E.
        A retrieval cue for extinction attenuates spontaneous recovery.
        J Exp Psychol Anim Behav Process. 1993; 19: 77-89
        • Vansteenwegen D.
        • Vervliet B.
        • Hermans D.
        • Beckers T.
        • Baeyens F.
        • Eelen P.
        Stronger renewal in human fear conditioning when tested with an acquisition retrieval cue than with an extinction retrieval cue.
        Behav Res Ther. 2006; 44: 1717-1725
        • Culver N.C.
        • Stoyanova M.
        • Craske M.G.
        Clinical relevance of retrieval cues for attenuating context renewal of fear.
        J Anxiety Disord. 2011; 25: 284-292
        • Zelikowsky M.
        • Pham D.L.
        • Fanselow M.S.
        Temporal factors control hippocampal contributions to fear renewal after extinction.
        Hippocampus. 2011; 22: 1096-1106
        • Ji J.
        • Maren S.
        Hippocampal involvement in contextual modulation of fear extinction.
        Hippocampus. 2007; 17: 749-758
        • Ji J.
        • Maren S.
        Electrolytic lesions of the dorsal hippocampus disrupt renewal of conditional fear after extinction.
        Learn Mem. 2005; 12: 270-276
        • Corcoran K.A.
        • Maren S.
        Hippocampal inactivation disrupts contextual retrieval of fear memory after extinction.
        J Neurosci. 2001; 21: 1720-1726
        • Corcoran K.A.
        • Maren S.
        Factors regulating the effects of hippocampal inactivation on renewal of conditional fear after extinction.
        Learn Mem. 2004; 11: 598-603
        • Corcoran K.A.
        • Desmond T.J.
        • Frey K.A.
        • Maren S.
        Hippocampal inactivation disrupts the acquisition and contextual encoding of fear extinction.
        J Neurosci. 2005; 25: 8978-8987
        • Fanselow M.S.
        Contextual fear, gestalt memories, and the hippocampus.
        Behav Brain Res. 2000; 110: 73-81
        • Fanselow M.S.
        From contextual fear to a dynamic view of memory systems.
        Trends Cogn Sci. 2010; 14: 7-15
        • Anagnostaras S.G.
        • Maren S.
        • Fanselow M.S.
        Scopolamine selectively disrupts the acquisition of contextual fear conditioning in rats.
        Neurobiol Learn Mem. 1995; 64: 191-194
        • Gale G.D.
        • Anagnostaras S.G.
        • Fanselow M.S.
        Cholinergic modulation of pavlovian fear conditioning: Effects of intrahippocampal scopolamine infusion.
        Hippocampus. 2001; 11: 371-376
        • Anagnostaras S.G.
        • Maren S.
        • Sage J.R.
        • Goodrich S.
        • Fanselow M.S.
        Scopolamine and Pavlovian fear conditioning in rats: Dose-effect analysis.
        Neuropsychopharmacology. 1999; 21: 731-744
        • Bar R.
        • Gil A.
        • Tal D.
        Safety of double-dose transdermal scopolamine.
        Pharmacotherapy. 2009; 29: 1082-1088
        • Perez L.M.
        • Farriols C.
        • Puente V.
        • Planas J.
        • Ruiz I.
        The use of subcutaneous scopolamine as a palliative treatment in Parkinson's disease.
        Palliat Med. 2011; 25: 92-93
        • Furey M.L.
        • Drevets W.C.
        Antidepressant efficacy of the antimuscarinic drug scopolamine: A randomized, placebo-controlled clinical trial.
        Arch Gen Psychiatry. 2006; 63: 1121-1129
        • Furey M.L.
        • Khanna A.
        • Hoffman E.M.
        • Drevets W.C.
        Scopolamine produces larger antidepressant and antianxiety effects in women than in men.
        Neuropsychopharmacology. 2010; 35: 2479-2488
        • Janowsky D.S.
        Serendipity strikes again: Scopolamine as an antidepressant agent in bipolar depressed patients.
        Curr Psychiatry Rep. 2011; 13: 443-445
        • Jacobs N.S.
        • Cushman J.D.
        • Fanselow M.S.
        The accurate measurement of fear memory in Pavlovian conditioning: Resolving the baseline issue.
        J Neurosci Methods. 2010; 190: 235-239
        • Santini E.
        • Sepulveda-Orengo M.
        • Porter J.T.
        Muscarinic receptors modulate the intrinsic excitability of infralimbic neurons and consolidation of fear extinction.
        Neuropsychopharmacology. 2012; 37: 2047-2056
        • Pitman R.K.
        • Orr S.P.
        • Altman B.
        • Longpre R.E.
        • Poire R.E.
        • Macklin M.L.
        Emotional processing during eye movement desensitization and reprocessing therapy of Vietnam veterans with chronic posttraumatic stress disorder.
        Compr Psychiatry. 1996; 37: 419-429
        • Pitman R.K.
        • Orr S.P.
        • Altman B.
        • Longpre R.E.
        • Poire R.E.
        • Macklin M.L.
        • et al.
        Emotional processing and outcome of imaginal flooding therapy in Vietnam veterans with chronic posttraumatic stress disorder.
        Compr Psychiatry. 1996; 37: 409-418
        • Plendl W.
        • Wotjak C.T.
        Dissociation of within- and between-session extinction of conditioned fear.
        J Neurosci. 2010; 30: 4990-4998
        • Craske M.G.
        • Kircanski K.
        • Zelikowsky M.
        • Mystkowski J.
        • Chowdhury N.
        • Baker A.
        Optimizing inhibitory learning during exposure therapy.
        Behav Res Ther. 2008; 46: 5-27
        • Bouton M.E.
        • Westbrook R.F.
        • Corcoran K.A.
        • Maren S.
        Contextual and temporal modulation of extinction: Behavioral and biological mechanisms.
        Biol Psychiatry. 2006; 60: 352-360
        • Ji J.
        • Maren S.
        Lesions of the entorhinal cortex or fornix disrupt the context-dependence of fear extinction in rats.
        Behav Brain Res. 2008; 194: 201-206
        • Ji J.
        • Maren S.
        Differential roles for hippocampal areas CA1 and CA3 in the contextual encoding and retrieval of extinguished fear.
        Learn Mem. 2008; 15: 244-251
        • Pang M.H.
        • Kim N.S.
        • Kim I.H.
        • Kim H.
        • Kim H.T.
        • Choi J.S.
        Cholinergic transmission in the dorsal hippocampus modulates trace but not delay fear conditioning.
        Neurobiol Learn Mem. 2010; 94: 206-213
        • Hunt P.S.
        • Richardson R.
        Pharmacological dissociation of trace and long-delay fear conditioning in young rats.
        Neurobiol Learn Mem. 2007; 87: 86-92
        • Feiro O.
        • Gould T.J.
        The interactive effects of nicotinic and muscarinic cholinergic receptor inhibition on fear conditioning in young and aged C57BL/6 mice.
        Pharmacol Biochem Behav. 2005; 80: 251-262
        • Bang S.J.
        • Brown T.H.
        Muscarinic receptors in perirhinal cortex control trace conditioning.
        J Neurosci. 2009; 29: 4346-4350
        • Rogers J.L.
        • Kesner R.P.
        Cholinergic modulation of the hippocampus during encoding and retrieval of tone/shock-induced fear conditioning.
        Learn Mem. 2004; 11: 102-107
        • Esclassan F.
        • Coutureau E.
        • Di Scala G.
        • Marchand A.R.
        A cholinergic-dependent role for the entorhinal cortex in trace fear conditioning.
        J Neurosci. 2009; 29: 8087-8093
        • Prado-Alcala R.A.
        • Haiek M.
        • Rivas S.
        • Roldan-Roldan G.
        • Quirarte G.L.
        Reversal of extinction by scopolamine.
        Physiol Behav. 1994; 56: 27-30