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.

Abstract

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.

• Authors: Segev Barak, Ina Weiner
• Journal: The international journal of neuropsychopharmacology (Int J Neuropsychopharmacol) Vol. 14 Issue 9 Pg. 1233-46 (Oct 2011) ISSN: 1469-5111 [Electronic] England
• PMID: 21211109 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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