title: Combined Neuropeptide S and D-Cycloserine Augmentation Prevents the Return of Fear in Extinction-Impaired Rodents: Advantage of Dual versus Single Drug Approaches.
abstract: Despite its success in treating specific anxiety disorders, the effect of exposure therapy is limited by problems with tolerability, treatment resistance, and fear relapse after initial response. The identification of novel drug targets facilitating fear extinction in clinically relevant animal models may guide improved treatment strategies for these disorders in terms of efficacy, acceleration of fear extinction, and return of fear.
  
  
  
  The extinction-facilitating potential of neuropeptide S, D-cycloserine, and a benzodiazepine was investigated in extinction-impaired high anxiety HAB rats and 129S1/SvImJ mice using a classical cued fear conditioning paradigm followed by extinction training and several extinction test sessions to study fear relapse.
  
  
  
  Administration of D-cycloserine improved fear extinction in extinction-limited, but not in extinction-deficient, rodents compared with controls. Preextinction neuropeptide S caused attenuated fear responses in extinction-deficient 129S1/SvImJ mice at extinction training onset and further reduced freezing during this session. While the positive effects of either D-cycloserine or neuropeptide S were not persistent in 129S1/SvImJ mice after 10 days, the combination of preextinction neuropeptide S with postextinction D-cycloserine rendered the extinction memory persistent and context independent up to 5 weeks after extinction training. This dual pharmacological adjunct to extinction learning also protected against fear reinstatement in 129S1/SvImJ mice.
  
  
  
  By using the potentially nonsedative anxiolytic neuropeptide S and the cognitive enhancer D-cycloserine to facilitate deficient fear extinction, we provide here the first evidence of a purported efficacy of a dual over a single drug approach. This approach may render exposure sessions less aversive and more efficacious for patients, leading to enhanced protection from fear relapse in the long term.
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), Leopold-Franzens-University of Innsbruck, Innsbruck, Austria (Dr Sartori, Ms Maurer, Mr Murphy, and Drs Schmuckermair, Muigg, Whittle, and Singewald); Department of Behavioral and Molecular Neurobiology, University of Regensburg, Regensburg, Germany (Dr Neumann). simone.sartori@uibk.ac.at nicolas.singewald@uibk.ac.at.
authors.forename: Simone B
authors.initials: SB
authors.lastname: Sartori
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), Leopold-Franzens-University of Innsbruck, Innsbruck, Austria (Dr Sartori, Ms Maurer, Mr Murphy, and Drs Schmuckermair, Muigg, Whittle, and Singewald); Department of Behavioral and Molecular Neurobiology, University of Regensburg, Regensburg, Germany (Dr Neumann).
authors.forename: Verena
authors.initials: V
authors.lastname: Maurer
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), Leopold-Franzens-University of Innsbruck, Innsbruck, Austria (Dr Sartori, Ms Maurer, Mr Murphy, and Drs Schmuckermair, Muigg, Whittle, and Singewald); Department of Behavioral and Molecular Neurobiology, University of Regensburg, Regensburg, Germany (Dr Neumann).
authors.forename: Conor
authors.initials: C
authors.lastname: Murphy
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), Leopold-Franzens-University of Innsbruck, Innsbruck, Austria (Dr Sartori, Ms Maurer, Mr Murphy, and Drs Schmuckermair, Muigg, Whittle, and Singewald); Department of Behavioral and Molecular Neurobiology, University of Regensburg, Regensburg, Germany (Dr Neumann).
authors.forename: Claudia
authors.initials: C
authors.lastname: Schmuckermair
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), Leopold-Franzens-University of Innsbruck, Innsbruck, Austria (Dr Sartori, Ms Maurer, Mr Murphy, and Drs Schmuckermair, Muigg, Whittle, and Singewald); Department of Behavioral and Molecular Neurobiology, University of Regensburg, Regensburg, Germany (Dr Neumann).
authors.forename: Patrick
authors.initials: P
authors.lastname: Muigg
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), Leopold-Franzens-University of Innsbruck, Innsbruck, Austria (Dr Sartori, Ms Maurer, Mr Murphy, and Drs Schmuckermair, Muigg, Whittle, and Singewald); Department of Behavioral and Molecular Neurobiology, University of Regensburg, Regensburg, Germany (Dr Neumann).
authors.forename: Inga D
authors.initials: ID
authors.lastname: Neumann
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), Leopold-Franzens-University of Innsbruck, Innsbruck, Austria (Dr Sartori, Ms Maurer, Mr Murphy, and Drs Schmuckermair, Muigg, Whittle, and Singewald); Department of Behavioral and Molecular Neurobiology, University of Regensburg, Regensburg, Germany (Dr Neumann).
authors.forename: Nigel
authors.initials: N
authors.lastname: Whittle
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), Leopold-Franzens-University of Innsbruck, Innsbruck, Austria (Dr Sartori, Ms Maurer, Mr Murphy, and Drs Schmuckermair, Muigg, Whittle, and Singewald); Department of Behavioral and Molecular Neurobiology, University of Regensburg, Regensburg, Germany (Dr Neumann). simone.sartori@uibk.ac.at nicolas.singewald@uibk.ac.at.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Singewald
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001007:Anxiety / Q000235:genetics / Q000523:psychology / Q000628:therapy*; D001522:Behavior, Animal / Q000187:drug effects*; D003071:Cognition / Q000187:drug effects; D003214:Conditioning, Classical / Q000187:drug effects; D003523:Cycloserine / Q000494:pharmacology*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005108:Extinction, Psychological / Q000187:drug effects*; D005239:Fear / Q000187:drug effects*; D007171:Implosive Therapy / Q000379:methods*; D008297:Male; D057507:Mice, 129 Strain; D009479:Neuropeptides / Q000494:pharmacology*; D011919:Rats, Inbred Strains; D012008:Recurrence; D013997:Time Factors
chemical_list: D014151:Anti-Anxiety Agents; D009479:Neuropeptides; D003523:Cycloserine
keywords: D-cycloserine; Fear extinction; fear relapse; neuropeptide S; renewal