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 M₁ 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 M₁ 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 M₁-mediated transmission. There is also evidence that the relationship between cholinergic activity, including that associated with M₁ 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 M₁-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 M₁ and M₄ 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 M₁ receptors in brain regions implicated in cognition (especially memory), which are presently feasible, may provide an indirect measure.

1.Lieberman JA, Javitch JA, Moore H: Cholinergic agonists as novel treatments for schizophrenia: the promise of rational drug development for psychiatry. Am J Psychiatry 2008; 165:931—9362.Li Z, Bonhaus DW, Huang M, Prus AJ, Dai J, Meltzer HY: AC260584 (4-[3-(4-butylpiperidin-1-yl)-propyl]-7-fluoro-4H-benzo[1, 4] oxazin-3-one), a selective muscarinic M₁ receptor agonist, increases acetylcholine and dopamine release in rat medial prefrontal cortex and hippocampus. Eur J Pharmacol 2007; 572:129—1373.Shekhar A, Potter WZ, Lightfoot J, Lienemann J, Dubé S, Mallinckrodt C, Bymaster FP, McKinzie DL, Felder CC: Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia. Am J Psychiatry 2008; 165:1033—10394.Crook JM, Tomaskovic-Crook E, Copolov DL, Dean B: Low muscarinic receptor binding in prefrontal cortex from subjects with schizophrenia: a study of Brodmann’s areas 8, 9, 10, and 46 and the effects of neuroleptic drug treatment. Am J Psychiatry 2001; 158:918—925