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Letters to the Editor   |    
Drs. Lieberman, Javitch, and Moore Reply
JEFFREY A. LIEBERMAN; JONATHAN A. JAVITCH; HOLLY MOORE,
Am J Psychiatry 2009;166:111-113. doi:10.1176/appi.ajp.2008.08091352r

To the Editor: Dr. Pomara raises a very important issue regarding the evaluation of the potential efficacy of xanomeline, or any candidate molecule, as an antipsychotic therapy in the treatment of schizophrenia, particularly pertaining to its effects on cognition. The standard preclinical screening strategies often do not include evaluation of the effects of chronic administration of a candidate drug. Although the reduced throughput and increased immediate costs would seem prohibitive, the actual cost of failing to assess a drug’s chronic effects on physiological and cognitive processes relevant to the disease is a reduction in predictive validity, particularly with regard to cognitive, behavioral, and/or physiological effects that may interfere with the drug’s therapeutic effects (1).

We were able to find very few studies examining the behavioral, neurochemical, or neurophysiological effects of the chronic administration of xanomeline or other M1 agonists. Reported effects of the chronic administration of xanomeline and other compounds with M4 agonism include a reduction in the proportion of spontaneously active dopamine neurons in the ventral tegmental area (2, 3)—an effect that would be predicted based on studies of other antipsychotic drugs—leading to decreased dopamine efflux in the striatum (4). In the case of M4 agonists, since medial dopamine neurons are more affected, the action of the drug in “clamping” dopamine release would be predicted to affect the medial striatum more than the lateral nigrostriatal pathway. This effect on mesostriatal dopamine release, which may be mediated via xanomeline’s actions on both midbrain dopamine neurons and in the striatum, must be considered as a potential mechanism underlying the ability of the drug to control psychosis.

Another issue to consider in assessing the mechanisms underlying the effects of xanomeline is the extent to which these effects result from M1/M4 agonism as opposed to effects of the compound on other molecular targets. For example, similar to clozapine, xanomeline is a relatively potent antagonist at serotonin 5-HT2A, 5-HT2C, and 5-HT7 receptors, with affinities for these receptors comparable with those for muscarinic receptors. Xanomeline also has moderate affinity for dopamine D3 receptors. The recent discovery of highly selective allosteric potentiators of M1 and M4 receptors (5–7) presently allows for a determination of the contribution of M1/M4 agonism to the beneficial effects of xanomeline.

An important “site of action” of xanomeline, as highlighted by Dr. Pomara, is the chronic regulation of acetylcholine release in the neocortex and hippocampus. In a number of studies, schizophrenia patients have exhibited decreased binding at M1 and M4 receptors, an effect consistent with chronically increased extracellular levels of acetylcholine (8). Many of these studies were conducted among medicated patients, and we have no way of knowing whether chronic “overstimulation” at M1 and M4 receptors is the mechanism by which receptor binding is reduced in schizophrenia. Nevertheless, this finding, as well as other findings, has led some investigators to postulate that chronic and/or intermittent hyperactivity of cortical cholinergic transmission plays a role in the attentional deficits and psychotic symptoms in schizophrenia (9). However, more recent studies have indicated that a higher resting “set point” for extracellular acetylcholine in the cortex may be beneficial as long as the system retains the capacity for phasic increases in cholinergic transmission (10). Increases in acetylcholine in response to (and contingent upon) cognitive demands are essential for normal attentional processing. Disruptions of attentional mechanisms produced by a loss of responsivity of cholinergic transmission in the cortex may contribute to inappropriate encoding of environmental contingencies.

Until the appropriate studies are conducted, we have no way of knowing the effects of chronic M1 receptor stimulation on cognitive modulation of acetylcholine release in the cortex. However, it is encouraging to note that chronic administration of the M1 agonist CI1017 resulted in improvement in the acquisition of a hippocampally dependent Pavlovian association, possibly through downregulation of an M1-mediated after-hyperpolarization of hippocampal neurons. Thus, selective downregulation of M1 receptor-mediated effects through chronic stimulation (and possible internalization [11]) of M1 receptors may serve to increase responsivity of neocortical and hippocampal neurons to acetylcholine through nicotinic and other muscarinic mechanisms and leave intact modulation by other monoaminergic systems, including dopamine. Consequently, we might be tempted to postulate that xanomeline may represent an improvement over dopamine D2 antagonists in that it controls striatal dopamine release without blocking D2 receptors but also maintains—perhaps even therapeutically adjusts—a set point for cortical cholinergic transmission that also permits dynamic cholinergic transmission. The latter mechanism may serve to help improve or preserve attentional abilities and, in turn, reduce the probability of inappropriate association formation that may contribute to psychosis and reduced functional outcome (12). We hope that those vested in this therapy are moved to test these hypotheses with chronic drug studies in animal models.

1.Miyamoto S, Duncan GE, Marx CE, Lieberman JA: Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol Psychiatry 2005; 10:79–104
 
2.Bymaster FP, Shannon HE, Rasmussen K, Delapp NW, Mitch CH, Ward JS, Calligaro DO, Ludvigsen TS, Sheardown MJ, Olesen PH, Swedberg MD, Sauerberg P, Fink-Jensen A: Unexpected antipsychotic-like activity with the muscarinic receptor ligand (5R, 6R)6-(3-propylthio-1, 2, 5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane. Eur J Pharmacol 1988; 356:109–119
 
3.Shannon HE, Rasmussen K, Bymaster FP, Hart JC, Peters SC, Swedberg MDB, Jeppesen L, Sheardown MJ, Sauerberg P, Fink-Jensen A: Xanomeline, an M1/M4 preferring muscarinic cholinergic receptor agonist, produces antipsychotic-like activity in rats and mice. Schizophr Res 2000; 42:249–259
 
4.Moore H, Todd CL, Grace AA: Striatal extracellular dopamine levels in rats with haloperidol-induced depolarization block of substantia nigra dopamine neurons. J Neurosci 1988; 18:5068–5077
 
5.Brady AE, Jones CK, Bridges TM, Kennedy JP, Thompson AD, Heiman JU, Breininger ML, Gentry PR, Yin H, Jadhav SB, Shirey JK, Conn PJ, Lindsley CW: Centrally active allosteric potentiators of the M4 muscarinic acetylcholine receptor reverse amphetamine-induced hyperlocomotor activity in rats. J Pharmacol Exper Ther 2008; Sept 4 [Epub ahead of print]
 
6.Chan WY, McKinzie DL, Bose S, Mitchell SN, Witkin JM, Thompson RC, Christopoulos A, Lazareno S, Dirdsall NJ, Bymaster FP, Fleder CC: Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia. Proc Natl Acad Sci U S A 2008; 105:10978–10983
 
7.Langmead CJ, Austin NE, Branch CL, Brown JT, Buchanan, KA, Davies CH, Forbes IT, Fry VA, Hagan JJ, Jones GA, Jeggo R, Kew JN, Mazzali A, Melarange R, Patel N, Pardoe J, Randall AD, Roberts C, Roopun A, Starr KR, Teriakidis A, Wood MD, Whittington M, Wu Z, Watson J: Characterization of a CNS penetrant, selective M1 muscarinic receptor agonist, 77-LH-28-1. Br J Pharmacol 2008; 154:1104–1105
 
8.Raedler TJ, Bymaster FP, Tandon R, Copolov D, Dean B: Towards a muscarinic hypothesis of schizophrenia. Mol Psychiatry 2007; 12:232–246
 
9.Sarter M: Neuronal mechanisms of the attentional dysfunctions in senile dementia and schizophrenia: two sides of the same coin? Psychopharmacology 1994; 114:539–550
 
10.Sarter M, Martinez V, Kozak R: A neurocognitive animal model dissociating between acute illness and remission periods of schizophrenia. Psychopharmacology 2008; July 10 [Epub ahead of print]
 
11.Volpicelli LA, Levey AI: Muscarinic acetylcholine receptor subtypes in cerebral cortex and hippocampus. Prog Brain Res 2004; 145:59–66
 
12.Robbins TW: Synthesizing schizophrenia: a bottom-up, symptomatic approach. Schizophr Bull 2005; 31:854–864
 
+

References

+The authors’ disclosures accompany the original editorial.

+This letter (doi: 10.1176/appi.ajp.2008.08091352r) was accepted for publication in October 2008.

+

References

1.Miyamoto S, Duncan GE, Marx CE, Lieberman JA: Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol Psychiatry 2005; 10:79–104
 
2.Bymaster FP, Shannon HE, Rasmussen K, Delapp NW, Mitch CH, Ward JS, Calligaro DO, Ludvigsen TS, Sheardown MJ, Olesen PH, Swedberg MD, Sauerberg P, Fink-Jensen A: Unexpected antipsychotic-like activity with the muscarinic receptor ligand (5R, 6R)6-(3-propylthio-1, 2, 5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane. Eur J Pharmacol 1988; 356:109–119
 
3.Shannon HE, Rasmussen K, Bymaster FP, Hart JC, Peters SC, Swedberg MDB, Jeppesen L, Sheardown MJ, Sauerberg P, Fink-Jensen A: Xanomeline, an M1/M4 preferring muscarinic cholinergic receptor agonist, produces antipsychotic-like activity in rats and mice. Schizophr Res 2000; 42:249–259
 
4.Moore H, Todd CL, Grace AA: Striatal extracellular dopamine levels in rats with haloperidol-induced depolarization block of substantia nigra dopamine neurons. J Neurosci 1988; 18:5068–5077
 
5.Brady AE, Jones CK, Bridges TM, Kennedy JP, Thompson AD, Heiman JU, Breininger ML, Gentry PR, Yin H, Jadhav SB, Shirey JK, Conn PJ, Lindsley CW: Centrally active allosteric potentiators of the M4 muscarinic acetylcholine receptor reverse amphetamine-induced hyperlocomotor activity in rats. J Pharmacol Exper Ther 2008; Sept 4 [Epub ahead of print]
 
6.Chan WY, McKinzie DL, Bose S, Mitchell SN, Witkin JM, Thompson RC, Christopoulos A, Lazareno S, Dirdsall NJ, Bymaster FP, Fleder CC: Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia. Proc Natl Acad Sci U S A 2008; 105:10978–10983
 
7.Langmead CJ, Austin NE, Branch CL, Brown JT, Buchanan, KA, Davies CH, Forbes IT, Fry VA, Hagan JJ, Jones GA, Jeggo R, Kew JN, Mazzali A, Melarange R, Patel N, Pardoe J, Randall AD, Roberts C, Roopun A, Starr KR, Teriakidis A, Wood MD, Whittington M, Wu Z, Watson J: Characterization of a CNS penetrant, selective M1 muscarinic receptor agonist, 77-LH-28-1. Br J Pharmacol 2008; 154:1104–1105
 
8.Raedler TJ, Bymaster FP, Tandon R, Copolov D, Dean B: Towards a muscarinic hypothesis of schizophrenia. Mol Psychiatry 2007; 12:232–246
 
9.Sarter M: Neuronal mechanisms of the attentional dysfunctions in senile dementia and schizophrenia: two sides of the same coin? Psychopharmacology 1994; 114:539–550
 
10.Sarter M, Martinez V, Kozak R: A neurocognitive animal model dissociating between acute illness and remission periods of schizophrenia. Psychopharmacology 2008; July 10 [Epub ahead of print]
 
11.Volpicelli LA, Levey AI: Muscarinic acetylcholine receptor subtypes in cerebral cortex and hippocampus. Prog Brain Res 2004; 145:59–66
 
12.Robbins TW: Synthesizing schizophrenia: a bottom-up, symptomatic approach. Schizophr Bull 2005; 31:854–864
 
+
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