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Ketamine induces immediate and delayed alterations of OCD-like behavior

  • Summer L. Thompson
  • Amanda C. Welch
  • Julia Iourinets
  • Stephanie C. DulawaEmail author
Original Investigation

Abstract

Rationale

Obsessive-compulsive disorder (OCD) is a psychiatric disorder characterized by intrusive obsessive thoughts and/or compulsive behaviors. Currently, serotonin reuptake inhibitors (SRIs) provide the only pharmacological monotherapy for OCD, but response rates are insufficient. Ketamine, a noncompetitive NMDA receptor antagonist, was reported to have rapid, sustained therapeutic effects in OCD patients. However, the mechanisms remain unknown.

Objectives

Here, we aimed to provide a platform for investigating mechanisms underlying anti-OCD effects of ketamine treatment by assessing whether ketamine pretreatment could alleviate 5-HT1B receptor (5-HT1BR)-induced OCD-like behavior in mice.

Methods

We assessed whether acute ketamine (0, 3, 10, 30 mg/kg), administered at two pretreatment time points (30 min, 24 h), would modulate 5-HT1BR-induced OCD-like behavior in mice. Behavioral measures were perseverative hyperlocomotion in the open field and deficits in prepulse inhibition (PPI) induced by acute pharmacological 5-HT1BR challenge.

Results

Three milligrams per kilogram of ketamine reduced 5-HT1BR-induced perseverative hyperlocomotion, but not PPI deficits, 24 h postinjection. In contrast, higher doses of ketamine were either ineffective (10 mg/kg) or exacerbated (30 mg/kg) 5-HT1BR-induced perseverative hyperlocomotion 30 min postinjection. At 24 h postinjection, 30 mg/kg ketamine reduced perseverative hyperlocomotion across all groups.

Conclusions

Our results suggest that the 5-HT1BR-induced model of OCD-like behavior is sensitive to a low dose of ketamine, a potential fast-acting anti-OCD treatment, and may provide a tool for studying mechanisms underlying the rapid therapeutic effects of ketamine in OCD patients.

Keywords

Ketamine OCD Compulsive Perseverative Prepulse inhibition NMDA 5-HT1B RU24969 

Notes

Funding and disclosures

This work was supported by an IMHRO Rising Star Depression Research Award in Memory of George Largay, a NARSAD Independent Investigator Award , and R21MH115395 to SD, and training grants: T32 GM07839 and T32 DA07255 to SLT.

Compliance with ethical standards

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Supplementary material

213_2019_5397_MOESM1_ESM.pdf (138 kb)
ESM 1 (PDF 137 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2020

Authors and Affiliations

  • Summer L. Thompson
    • 1
    • 2
  • Amanda C. Welch
    • 2
  • Julia Iourinets
    • 3
  • Stephanie C. Dulawa
    • 2
    Email author
  1. 1.Committee on NeurobiologyUniversity of ChicagoChicagoUSA
  2. 2.Department of PsychiatryUniversity of California San DiegoLa JollaUSA
  3. 3.University of Rochester School of Medicine and DentistryRochesterUSA

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