Potential role of muscarinic receptors in schizophrenia.

Abstract

The role of muscarinic receptors in schizophrenia was investigated using the muscarinic agonist PTAC. PTAC was highly selective for muscarinic receptors, was a partial agonist at muscarinic M2/M4 receptors and an antagonist at M1, M3 and M5 receptors. PTAC was highly active in animal models predictive of antipsychotic behavior including inhibition of conditioned avoidance responding in rats and blockade of apomorphine-induced climbing behavior in mice. d-Amphetamine-induced Fos expression in rat nucleus accumbens was inhibited by PTAC, thus directly demonstrating the ability of PTAC to modulate DA activity. In electrophysiological studies in rats, PTAC acutely inhibited the firing of A10 DA cells and after chronic administration decreased the number of spontaneously firing DA cells in the A10 brain area. However, PTAC did not appreciably alter the firing of A9 DA cells. Thus, PTAC appears to have novel antipsychotic-like activity and these data suggest that muscarinic compounds such as PTAC may represent a new class of antipsychotic agents.

• Authors: F P Bymaster, H E Shannon, K Rasmussen, N W DeLapp, J S Ward, D O Calligaro, C H Mitch, C Whitesitt, T S Ludvigsen, M Sheardown, M Swedberg, T Rasmussen, P H Olesen, L Jeppesen, P Sauerberg, A Fink-Jensen
• Journal: Life sciences (Life Sci) Vol. 64 Issue 6-7 Pg. 527-34 ( 1999) ISSN: 0024-3205 [Print] Netherlands
• PMID: 10069519 (Publication Type: Journal Article)

Chemical References

• 6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo(3.2.1)octane
• Antipsychotic Agents
• Bridged Bicyclo Compounds
• Dopamine Agents
• Muscarinic Agonists
• Muscarinic Antagonists
• Proto-Oncogene Proteins c-fos
• Receptors, Muscarinic
• Thiadiazoles
• Dopamine

Topics

• Animals
• Antipsychotic Agents (administration & dosage, metabolism, pharmacology, therapeutic use)
• Behavior, Animal (drug effects)
• Binding, Competitive
• Bridged Bicyclo Compounds (administration & dosage, metabolism, pharmacology, therapeutic use)
• CHO Cells
• Catalepsy (chemically induced)
• Cricetinae
• Dopamine (metabolism)
• Dopamine Agents (pharmacology)
• Dose-Response Relationship, Drug
• Electrophysiology
• Muscarinic Agonists (pharmacology)
• Muscarinic Antagonists (pharmacology)
• Neurons (drug effects, physiology)
• Proto-Oncogene Proteins c-fos (metabolism)
• Rats
• Receptors, Muscarinic (metabolism, physiology)
• Schizophrenia (drug therapy, physiopathology)
• Second Messenger Systems (drug effects)
• Thiadiazoles (administration & dosage, metabolism, pharmacology, therapeutic use)