To the Editor: Dr. Pomara suggests that the clinical efficacy of xanomeline treatment for improving cognitive deficits in schizophrenia patients in our study (1) may not have been a result of sustained M1 receptor agonist properties, as hypothesized by Dr. Lieberman et al. (2), but rather a result of chronic agonist-induced desensitization and downregulation of cortical M1 receptors. Although M1 receptor desensitization contributing to the clinical efficacy of xanomeline is certainly possible, which is supported by some of the evidence cited by Dr. Pomara, such a hypothesis is difficult to test directly. On the other hand, it is equally possible that direct agonist effects of xanomeline may contribute to cognitive benefits for the following reasons.
First, the postmortem studies by Crook et al. (3) measured 3H-pirenzapine binding, a ligand that is not a highly selective M1 receptor antagonist and does not distinguish high versus low affinity states of the M1 receptor. Second, muscarinic M1 receptors appear to have a high receptor reserve requiring only a 15% occupancy to attain full signal transduction, suggesting that a significant decline in receptor number can possibly occur without causing functional consequences (4). Thus, the conclusion by Crook et al. that reductions in M1 receptor density in limbic regions were a result of hypercholinergic state has not been directly tested and remains speculative.
Interestingly, preclinical testing of another M4 receptor agonist, BuTAC, demonstrated that it possesses antipsychotic-like properties similar to xanomeline. However, unlike xanomeline, BuTAC is an antagonist at the M1 receptor and does not exhibit efficacy in spatial learning in rats. This may support the hypothesis that the cognitive benefits of xanomeline may well be the result of its agonist properties at the M1 receptor. Unfortunately, utilizing direct orthosteric agonists of receptors, it is difficult to conclude whether the effects of chronic administration of the drug are a result of continued agonism or desensitization of its receptors. Recently published data using muscarinic receptor potentiators further support a role for M1 and/or M4 positive modulation, rather than antagonism, as the primary mechanism driving antipsychotic efficacy (5, 6). With positive modulators, M1 and M4 receptors would be less sensitive to downregulation as a result of the allosteric mechanism of action. Indeed, positive allosteric modulation would be less prone to desensitization and would preserve spatial and temporal regulation of M1 receptor activation (4). Therefore, based on the high receptor reserve for the M1 receptor, and most likely for M4 receptor, and evidence based on recent M1 and M4 selective positive allosteric modulators, it is unlikely that orthosteric agonist-mediated desensitization is the sole explanation for muscarinic-based mechanisms of antipsychotic therapeutics.
1.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; 165:1033–10392.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; 165:931–9363.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; 158:918–9254.May LT, Leach K, Sexton PM, Christopoulos A: Allosteric modulation of G protein-coupled receptors. Annu Rev Pharmacol Toxicol 2007; 47:1–515.Chan WY, McKinzie DL, Bose S, Mitchell SN, Witkin JM, Thompson RC, Christopoulos A, Lazareno S, Birdsall NJ, Bymaster FP, Felder CC: Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia. Proc Natl Acad Sci U S A 2008; 105:10978–109836.Jones CK, Brady AE, Davis AA, Xiang Z, Bubser M, Tantawy MN, Kane AS, Bridges TM, Kennedy JP, Bradley SR, Peterson TE, Ansari MS, Baldwin RM, Kessler RM, Deutch AY, Lah JJ, Levey AI, Lindsley CW, Conn PJ: Novel selective allosteric activator of the M1 muscarinic acetylcholine receptor regulates amyloid processing and produces antipsychotic-like activity in rats. J Neurosci 2008; 28:10422–10433
The authors’ disclosures accompany the original article.
This letter (doi: 10.1176/appi.ajp.2008.08091352r1) was accepted for publication in October 2008.