Relationship between muscarinic M-1 receptor binding and cognition in medication-free subjects with psychosis

Background: It is still unclear which underlying mechanisms are involved in cognitive deficits of psychotic disorders. Pro-cognitive effects of muscarinic M-1 receptor agonists suggest alterations in M-1 receptor functioning may modulate these symptoms. Post mortem studies in patients with schizophrenia have shown significantly reduced M-1 receptor expression rates in the dorsolateral prefrontal cortex (DLPFC) compared to controls. To date no in-vivo examinations of M-1 receptor binding in relation to cognitive impairments have been done. As cognitive deficits have similar course and prognostic relevance across psychotic disorders, the current study assessed M-1 receptor binding in the DLPFC and hippocampus in relation to cognitive functioning. Methods: Muscarinic M-1 receptor binding potential (BPND) was measured using I-123-IDEX, single photon emission computed tomography (SPECT) in 30 medication-free subjects diagnosed with a psychotic disorder. A computerized neuropsychological test battery was used to assess cognition, and the positive and negative syndrome scale (PANSS) to assess severity of psychotic symptoms. Results: Assessment of cognitive domains showed that lower M-1 BPND in the DLPFC was related to overall lower performance in verbal learning and memory. In addition, lower M-1 BPND in the DLPFC was related to greater negative symptom severity. Lastly, lower M-1 BPND in the hippocampus was related to worse delayed recognition of verbal memory. Conclusion: This is the first study to show that variation in M-1 receptors in the DLPFC is related to cognitive and negative symptom outcome in psychotic disorders. The M-1 receptor may be an important biomarker in biological stratification of patients with psychotic disorders.