Ketamine induces immediate and delayed alterations of OCD-like behavior

Psychopharmacology (Berl). 2020 Mar;237(3):627-638. doi: 10.1007/s00213-019-05397-8. Epub 2020 Jan 11.

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: 5-HT1B; Compulsive; Ketamine; NMDA; OCD; Perseverative; Prepulse inhibition; RU24969.

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Antagonists / pharmacology
  • Excitatory Amino Acid Antagonists / therapeutic use*
  • Female
  • Ketamine / pharmacology
  • Ketamine / therapeutic use*
  • Mice
  • Mice, Inbred BALB C
  • Obsessive-Compulsive Disorder / chemically induced*
  • Obsessive-Compulsive Disorder / drug therapy*
  • Obsessive-Compulsive Disorder / psychology
  • Prepulse Inhibition / drug effects
  • Prepulse Inhibition / physiology
  • Random Allocation
  • Serotonin 5-HT1 Receptor Agonists / toxicity*
  • Serotonin Uptake Inhibitors / pharmacology
  • Serotonin Uptake Inhibitors / therapeutic use
  • Time Factors

Substances

  • Excitatory Amino Acid Antagonists
  • Serotonin 5-HT1 Receptor Agonists
  • Serotonin Uptake Inhibitors
  • Ketamine