Loss of [3H]4-DAMP binding to muscarinic receptors in the orbitofrontal cortex of Alzheimer's disease patients with psychosis.

Abstract

RATIONALE:

Neuropsychiatric behaviours in Alzheimer's disease (AD) patients have been associated with neocortical alterations of presynaptic cholinergic and muscarinic M2 receptor markers. In contrast, it is unclear whether non-M2 muscarinic receptors have a role to play in AD behavioural symptoms.

OBJECTIVES:

To correlate the alterations of neocortical postsynaptic muscarinic receptors with clinical features of AD.

MATERIALS AND METHODS:

[(3)H]4-DAMP were used in binding assays with lysates of Chinese hamster ovary (CHO) cells stably transfected with M1-M5 receptors. [(3)H]4-DAMP was further used to measure muscarinic receptors in the postmortem orbitofrontal cortex of aged controls and AD patients longitudinally assessed for cognitive decline and behavioural symptoms.

RESULTS:

[(3)H]4-DAMP binds to human postmortem brain homogenates and M1-, M3-, M4- and M5-transfected CHO lysates with subnanomolar affinity. Compared to the controls, the [(3)H]4-DAMP binding density is reduced only in AD patients with significant psychotic symptoms. The association between reduced [(3)H]4-DAMP binding and psychosis is independent of the effects of dementia severity or neurofibrillary tangle burden.

CONCLUSIONS:

This study suggests that the loss of non-M2 muscarinic receptors in the orbitofrontal cortex may be a neurochemical substrate of psychosis in AD and provides a rationale for further development of muscarinic receptor ligands in AD pharmacotherapy.

• Authors: S W Y Tsang, P T Francis, M M Esiri, P T H Wong, C P L H Chen, M K P Lai
• Journal: Psychopharmacology (Psychopharmacology (Berl)) Vol. 198 Issue 2 Pg. 251-9 (Jun 2008) ISSN: 0033-3158 [Print] Germany
• PMID: 18373228 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Muscarinic Antagonists
• Piperidines
• Receptor, Muscarinic M2
• Receptors, Muscarinic
• 4-diphenylacetoxy-1,1-dimethylpiperidinium

Topics

• Aged
• Aged, 80 and over
• Alzheimer Disease (complications, metabolism, psychology)
• Animals
• CHO Cells
• Cohort Studies
• Cricetinae
• Cricetulus
• Female
• Humans
• Longitudinal Studies
• Male
• Muscarinic Antagonists (pharmacology)
• Neocortex (drug effects, metabolism, pathology)
• Neurofibrillary Tangles (metabolism, pathology)
• Neuropsychological Tests
• Piperidines (pharmacology)
• Psychotic Disorders (complications, metabolism, psychology)
• Radioligand Assay
• Receptor, Muscarinic M2 (genetics, metabolism)
• Receptors, Muscarinic (drug effects, genetics)
• Synapses (drug effects, metabolism)
• Transfection