The M₁/M₄ preferring agonist xanomeline reverses amphetamine-, MK801- and scopolamine-induced abnormalities of latent inhibition: putative efficacy against positive, negative and cognitive symptoms in schizophrenia

Int J Neuropsychopharmacol. 2011 Oct;14(9):1233-46. doi: 10.1017/S1461145710001549. Epub 2011 Jan 7.


A major challenge in developing schizophrenia pharmacotherapy is treating the different symptoms of this disorder, typically divided into positive, negative and cognitive symptoms. M₁/M₄ muscarinic acetylcholine receptor (mAChR) agonists have emerged as a promising therapeutic target, particularly for positive and cognitive symptoms. Here, we examined the activity of the M₁/M₄ mAChR-preferring agonist xanomeline in four pharmacological latent inhibition (LI) models. LI is the poorer conditioning to a stimulus previously experienced as irrelevant during repeated non-reinforced pre-exposure to that stimulus. No-drug controls displayed LI if non-reinforced pre-exposure to a tone was followed by weak, but not strong, conditioning (2 vs. 5 tone-shock pairings). Amphetamine (1 mg/kg)- or scopolamine (0.15 mg/kg)-treated rats failed to show LI with weak conditioning, whereas MK801 (0.05 mg/kg)- or scopolamine (1.5 mg/kg)-treated rats persisted in displaying LI with strong conditioning. Xanomeline (5 mg/kg, 15 mg/kg) reversed amphetamine- and scopolamine-induced LI disruption, effects considered predictive of activity against positive symptoms of schizophrenia. In addition, xanomeline alleviated MK801-induced abnormally persistent LI. Activity of xanomeline on NMDA antagonist-induced behaviour was demonstrated here for the first time and suggests that the drug is effective against negative/cognitive symptoms. Finally, xanomeline alleviated abnormally persistent LI induced by scopolamine, which was suggested to model antipsychotic drug-resistant cognitive impairments, providing further evidence for the cognition-enhancing capacity of xanomeline. Although the use of xanomeline in schizophrenia was discontinued due to cholinergic-related side-effects, our findings suggest that M₁/M₄ mAChR agonism should be an important target in drug development in schizophrenia, potentially beneficial for treatment of positive, negative and cognitive symptoms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amphetamine / toxicity
  • Animals
  • Antimanic Agents / administration & dosage
  • Antimanic Agents / therapeutic use*
  • Behavior, Animal / drug effects
  • Cognition Disorders / etiology
  • Cognition Disorders / prevention & control
  • Dizocilpine Maleate / toxicity
  • Dose-Response Relationship, Drug
  • Kinetics
  • Male
  • Molecular Targeted Therapy
  • Muscarinic Agonists / administration & dosage
  • Muscarinic Agonists / therapeutic use*
  • Neural Inhibition / drug effects*
  • Neurotransmitter Agents / toxicity
  • Pyridines / administration & dosage
  • Pyridines / therapeutic use*
  • Rats
  • Rats, Wistar
  • Receptor, Muscarinic M1 / agonists*
  • Receptor, Muscarinic M4 / agonists*
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Schizophrenia / drug therapy*
  • Schizophrenia / physiopathology
  • Schizophrenia / prevention & control
  • Scopolamine / toxicity
  • Tachyphylaxis
  • Thiadiazoles / administration & dosage
  • Thiadiazoles / therapeutic use*


  • Antimanic Agents
  • Muscarinic Agonists
  • Neurotransmitter Agents
  • Pyridines
  • Receptor, Muscarinic M1
  • Receptor, Muscarinic M4
  • Receptors, N-Methyl-D-Aspartate
  • Thiadiazoles
  • Dizocilpine Maleate
  • xanomeline
  • Amphetamine
  • Scopolamine