title: 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.affiliation: Department of Psychology, Tel-Aviv University, Tel-Aviv, Israel. sbarak@gallo.ucsf.edu
authors.forename: Segev
authors.initials: S
authors.lastname: Barak
authors.forename: Ina
authors.initials: I
authors.lastname: Weiner
mesh_terms: D000661:Amphetamine / Q000633:toxicity; D000818:Animals; D018692:Antimanic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D003072:Cognition Disorders / Q000209:etiology / Q000517:prevention & control; D016291:Dizocilpine Maleate / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D007700:Kinetics; D008297:Male; D058990:Molecular Targeted Therapy; D018721:Muscarinic Agonists / Q000008:administration & dosage / Q000627:therapeutic use*; D009433:Neural Inhibition / Q000187:drug effects*; D018377:Neurotransmitter Agents / Q000633:toxicity; D011725:Pyridines / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D043643:Receptor, Muscarinic M1 / Q000819:agonists*; D043588:Receptor, Muscarinic M4 / Q000819:agonists*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012559:Schizophrenia / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D012601:Scopolamine / Q000633:toxicity; D013618:Tachyphylaxis; D013830:Thiadiazoles / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D018692:Antimanic Agents; D018721:Muscarinic Agonists; D018377:Neurotransmitter Agents; D011725:Pyridines; D043643:Receptor, Muscarinic M1; D043588:Receptor, Muscarinic M4; D016194:Receptors, N-Methyl-D-Aspartate; D013830:Thiadiazoles; D016291:Dizocilpine Maleate; C075257:xanomeline; D000661:Amphetamine; D012601:Scopolamine