PPARγ receptors are involved in the effects of cannabidiol on orofacial dyskinesia and cognitive dysfunction induced by typical antipsychotic in mice

Prog Neuropsychopharmacol Biol Psychiatry. 2021 Dec 20:111:110367. doi: 10.1016/j.pnpbp.2021.110367. Epub 2021 May 25.


Tardive dyskinesia (TD) is a movement disorder that appears after chronic use of drugs that block dopaminergic receptors such as antipsychotics. Besides the motor symptoms, patients with TD also present cognitive deficits. Neuroinflammatory mechanisms could be involved in the development of these symptoms. A previous study showed that cannabidiol (CBD), the major non-psychotomimetic compound of Cannabis sativa plant, prevents orofacial dyskinesia induced by typical antipsychotics by activating peroxisome proliferator-activated receptors gamma (PPARγ). Here, we investigated if CBD would also reverse haloperidol-induced orofacial dyskinesia and associated cognitive deficits. We also verified if these effects depend on PPARγ receptor activation. Daily treatment with haloperidol (3 mg/kg, 21 days) increased the frequency of vacuous chewing movements (VCM) and decreased the discrimination index in the novel object recognition test in male Swiss mice. CBD (60 mg/kg/daily) administered in the last 7 days of haloperidol treatment attenuated both behavioral effects. Furthermore, haloperidol increased IL-1β and TNF-α levels in the striatum and hippocampus while CBD reverted these effects. The striatal and hippocampal levels of proinflammatory cytokines correlated with VCM frequency and discrimination index, respectively. Pretreatment with the PPARγ antagonist GW9662 (2 mg/kg/daily) blocked the behavioral effects of CBD. In conclusion, these results indicated that CBD could attenuate haloperidol-induced orofacial dyskinesia and improve non-motor symptoms associated with TD by activating PPARγ receptors.

Keywords: Cannabidiol; Cognitive deficit; Orofacial dyskinesia; PPARγ receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Dyskinesia Agents / adverse effects
  • Anti-Dyskinesia Agents / pharmacology
  • Antipsychotic Agents / adverse effects*
  • Behavior, Animal / drug effects
  • Cannabidiol / administration & dosage
  • Cannabidiol / pharmacology*
  • Cognitive Dysfunction* / drug therapy
  • Cognitive Dysfunction* / prevention & control
  • Corpus Striatum / drug effects
  • Dyskinesias / drug therapy*
  • Haloperidol / adverse effects
  • Haloperidol / pharmacology
  • Male
  • Mastication / drug effects
  • Mice
  • Neostriatum / drug effects
  • PPAR gamma / therapeutic use*
  • Rats
  • Rats, Wistar
  • Tardive Dyskinesia / chemically induced*


  • Anti-Dyskinesia Agents
  • Antipsychotic Agents
  • PPAR gamma
  • Cannabidiol
  • Haloperidol