Reduction in Muscarinic M ₁ -Mediated Hypercholinergic State and Beneficial Cognitive Effects of Muscarinic Agonists in Schizophrenia

To the Editor: In their excellent editorial, published in the August 2008 issue of the Journal , Jeffrey A. Lieberman, M.D., Jonathan A. Javitch, M.D., Ph.D., and Holly Moore, Ph.D. (1) stated that the “cognitive benefits of xanomeline are thought to result from its stimulation of M ₁ receptors in the neocortex and hippocampus, an action that facilitates acetylcholine and dopamine release in these regions” ( 1 , p. 934). However, the Li et al. study (2) , which the authors cited in support of this mechanism of action, examined the acute effects of xanomeline. Consequently, these neurotransmitter effects may not be pertinent to the recent 4-week treatment trial among schizophrenia patients conducted by Shekhar et al. (3) . Acute and chronic treatment with muscarinic M ₁ agonists, even with weak agonists such as choline, is also known to produce rapid downregulation and desensitization of these receptors that could actually result in a reduction in M ₁ -mediated transmission. There is also evidence that the relationship between cholinergic activity, including that associated with M ₁ stimulation, and cognition has an inverted U-shaped dose response, in a manner in which both low and high activity can impair cognition. Taken together, these observations raise the possibility that brain region-specific reductions in M ₁ -mediated transmission and a reduction in hypercholinergic state might have also contributed to the beneficial cognitive effects of chronic treatment with xanomeline in schizophrenia in the Li et al. study.

Although there is presently no evidence of a generalized hypercholinergic state in schizophrenia, it is interesting to note that Crook et al. (4) ascribed their findings of reduced M ₁ and M ₄ receptors in the prefrontal cortex of schizophrenia patients to increased activity of cholinergic input to this region, leading to downregulation of these receptors. Consistent with this hypothesis, indices of extrinsic presynatic cholinergic input, including the nucleus of Meynert, and choline acetyltransferase activity in the prefrontal cortex are preserved.

Results from sleep studies, some of which were cited by Shekhar et al., have also provided evidence of cholinergic hyperactivity in pathways modulating rapid-eye-movement sleep in schizophrenia patients.

There are currently no techniques to determine region-specific presynaptic cholinergic activity in vivo. However, studies of the functional status and sensitivity of M ₁ receptors in brain regions implicated in cognition (especially memory), which are presently feasible, may provide an indirect measure.