Abstract
Background: The muscarinic agonist xanomeline has been shown to reduce antipsychotic-like
behaviors in patients with Alzheimer’s disease. Because atypical antipsychotic agents
increase dopamine release in prefrontal cortex and induce immediate early gene expression
in prefrontal cortex and nucleus accumbens, the effect of xanomeline was determined
on these indices.
Methods: The effect of xanomeline on extracellular levels of monoamines in brain regions
was determined using a microdialysis technique, and changes in expression of the immediate
early genes c-fos and zif/268 in brain regions were evaluated using in situ hybridization
histochemistry.
Results: Xanomeline increased extracellular levels of dopamine in prefrontal cortex
and nucleus accumbens but not in striatum. Xanomeline increased expression of c-fos
and zif/268 in prefrontal cortex and nucleus accumbens. There was no change in immediate
early gene expression in striatum.
Conclusions: Xanomeline increased extracellular levels of dopamine, which is similar
to the effects of the atypical antipsychotics clozapine and olanzapine. The regional
pattern of immediate early gene expression induced by xanomeline resembled that of
atypical antipsychotic agents. Based on the antipsychotic-like activity of xanomeline
in Alzheimer’s patients and the similarity to atypical antipsychotic agents, we suggest
that xanomeline may be a novel antipsychotic agent.
Keywords
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References
- Drug-induced changes of dopamine turnover in striatum and limbic system in rat.J Pharm Pharmacol. 1975; 27: 439-441
- The prefrontal cortex in schizophrenia and other neuropsychiatric diseases.Prog Brain Res. 1990; 85: 521-537
- The effects of xanomeline, an M1-selective muscarinic agonist, on cognitive and behavioral symptoms in Alzheimer’s disease.Arch Neurol. 1997; 54: 465-473
- Comparative behavioral and neurochemical activities of cholinergic antagonists in rats.J Pharmacol Exp Ther. 1993; 267: 16-24
- Antagonism by olanzapine of dopamine D1, serotonin2, muscarinic, histamine H1 and α1-adrenergic receptors in vitro.Schizophr Res. 1999; 37: 107-122
- In vitro and in vivo biochemistry of olanzapine.J Clin Psychiatry. 1997; 58: 28-36
- Unexpected antipsychotic-like activity with the muscarinic agonist receptor ligand (5R,6R)6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane.Eur J Pharmacol. 1998; 358: 109-119
- Potential role of muscarinic receptors in schizophrenia.Life Sci. 1999; 64: 527-534
- Xanomeline.Drug Dev Res. 1997; 40: 158-170
- Neurochemical effects of the M1 agonist xanomeline (LY246708/NNC11–0232).J Pharmacol Exp Ther. 1994; 269: 282-289
- Typical and atypical neuroleptics.J Neurosci. 1983; 3: 1607-1619
- Physostigmine ameliorates the delusions of Alzheimer’s disease.Biol Psychiatry. 1993; 33: 536-541
- Effect of M1- and M2-muscarinic drugs on striatal dopamine release and metabolism.Brain Res. 1993; 630: 57-64
- Regionally specific effects of atypical antipsychotic drugs on striatal fos expression.Mol Cell Neurosci. 1992; 3: 332-341
- Mechanisms of action of atypical antipsychotic drugs. Implications for novel therapeutic strategies for schizophrenia.Schizophr Res. 1991; 4: 121-156
- Modulatory functions of neurotransmitters in the striatum.Trends Neurosci. 1994; 17: 228-233
- Selectivity of muscarinic antagonists in radioligand and in vivo experiments for the putative M1, M2, and M3 receptors.J Pharmacol Exp Ther. 1987; 242: 257-262
- PET study of the M1 agonists [11C]Xanomeline and [11C]Butylthio-TZTP in monkey and man.Dementia. 1996; 7: 187-195
- Effect of typical and atypical neuroleptics on fos protein expression in the rat forebrain.Neurosci Lett. 1994; 182: 115-118
- The prefrontal landscape.Philos Trans R Soc Lond B Biol Sci. 1996; 351: 1445-1453
- Pronounced pharmacological deficits in M2 muscarinic acetylcholine receptor knockout mice.Proc Natl Acad Sci U S A. 1999; 96: 1692-1697
- Enhancement of D1 dopamine receptor-mediated locomotor stimulation in M4 muscarinic acetylcholine receptor mice.Proc Natl Acad Sci U S A. 1999; 96: 10483-10488
- Cholinergic therapy of behavioral disturbances in Alzheimer’s disease.Neuropsychiatr Neuropsychol Behav Neurol. 1993; 6: 229-234
- Activation of midbrain presumed dopaminergic neurones by muscarinic cholinergic.Br J Pharmacol. 1998; 124: 455-464
- M1 muscarinic antagonists interact with σ recognition sites.Life Sci. 1991; 49: 1229-1235
- Muscarinic receptor-mediated induction of Fos protein in rat brain.Neurosci Lett. 1993; 150: 122-126
- Activation of pirenzepine-sensitive muscarinic receptors induces a specific pattern of immediate-early gene expression in rat brain neurons.Mol Brain Res. 1994; 24: 166-178
- Effect of tacrine on behavior in Alzheimer’s disease.J Geriatr Psychiatry Neurol. 1996; 9: 1-6
- Effects of acute and repeated administration of antidepressant drugs on extracellular levels of 5-hydroxytryptamine measured in vivo.J Pharmacol Exp Ther. 1995; 274: 866-876
- R(+)-8-OH-DPAT, a 5-HT1A receptor agonist, inhibits amphetamine-induced serotonin and dopamine release in rat medial prefrontal cortex.Brain Res. 1996; 743: 357-361
- Effects of antipsychotic drugs on extracellular dopamine levels in rat medial prefrontal cortex and nucleus accumbens.J Pharmacol Exp Ther. 1999; 288: 774-781
- Immunological localization of m1–m5 muscarinic acetylcholine receptors in peripheral tissues and brain.Life Sci. 1993; 52: 441-448
- Olanzapine increases in vivo dopamine and norepinephrine release in rat prefrontal cortex, nucleus accumbens and striatum.Psychopharmacology. 1998; 136: 153-161
- Organization of the catecholamines neurons projecting to the frontal cortex in the rat.Brain Res. 1978; 142: 1-24
- Dopamine and norepinephrine-containing neuron systems.in: Emson P.C. Chemical Neuroanatomy. Raven, New York1983: 229-256
- On the presence in the cerebral cortex of muscarinic receptor subtypes which differ in neuronal localization, function and pharmacological properties.J Pharmacol Exp Ther. 1985; 235: 230-233
- Neurotransmitter actions in the thalamus and cerebral cortex and their role in neuromodulation of thalamocortical activity.Prog Neurobiol. 1992; 39: 337-388
- Acetylcholinesterase-rich neurons of the human cerebral cortex.J Comp Neurol. 1991; 306: 193-220
- Differential cholinergic innervation within functional subdivisions of the human cerebral cortex.J Comp Neurol. 1992; 318: 316-328
- Preferential activation of cortical dopamine neurotransmission by clozapine.J Clin Psychiatry. 1994; 55: 27-29
- Effect of oxotremorine on homovanillic acid concentration in the striatum of the rat.Eur J Pharmacol. 1974; 25: 51-55
- The rat brain in stereotaxic coordinates, 2nd ed. Academic Press, San Diego1986
- Acetylcholine and hallucinations.Brain Cogn. 1995; 28: 240-258
- The muscarinic agonist xanomeline has antipsychotic-like activity in animals and in man.Schizophr Res. 1999; 36: 117-118
- Effect of serotonin and dopamine concentrations in microdialysis fluid from rat striatum.Life Sci. 1992; 50: 1683-1690
- Effects of olanzapine on regional c-Fos expression in rat forebrain.Neuropsychopharmacology. 1996; 14: 105-110
- Induction patterns of fos-like immunoreactivity in the forebrain as predictors of atypical antipsychotic activity.J Pharmacol Exp Ther. 1994; 271: 1058-1066
- Muscarinic agonists with antipsychotic-like activity.J Med Chem. 1998; 41: 4378-4384
- The role of D1-dopamine receptors in working memory.J Neurophysiol. 1994; 71: 515-528
- Olanzapine-induced fos expression in the rat forebrain.Eur J Pharmacol. 1998; 353: 13-21
- Antipsychotic-like pharmacologic profile of the muscarinic agonist BuTAC.Schizophr Res. 1999; 36: 314-315
- Xanomeline.J Pharmacol Exp Ther. 1994; 269: 271-281
- Muscarinic receptor agonists, like dopamine receptor antagonist antipsychotics, inhibit conditioned avoidance response in rats.J Pharmacol Exp Ther. 1999; 290: 901-907
- Muscarinic modulation of striatal dopamine, glutamate, and GABA release as measured with in vivo microdialysis.J Neurochem. 1997; 68: 1942-1948
- Electrophysiological effects of olanzapine, a novel atypical antipsychotic, on A9 and A10 dopamine neurons.Neuropsychopharmacology. 1996; 14: 97-104
- Topography of serotonin neurons in the dorsal raphe nucleus that send axon collaterals to the rat prefrontal cortex and nucleus accumbens.Brain Res. 1993; 624: 188-198
- BIMG 80, a novel potential antipsychotic drug.J Neurochem. 1997; 69: 182-190
- Functional effects of the muscarinic receptor agonist, xanomeline, at 5-HT1 and 5-HT2 receptors.Br J Pharmacol. 1998; 125: 1413-1420
- Expression of muscarinic acetylcholine and dopamine receptor mRNAs in rat basal ganglia.Proc Natl Acad Sci U S A. 1990; 87: 7050-7054
- Sequence and significance of dopamine metabolism in the rat brain.Neurochem Int. 1985; 7: 221-227
- Do neurotransmitters sampled by brain microdialysis reflect functional release?.Anal Chim Acta. 1999; 379: 263-274
- Differential effects of classical and atypical antipsychotic drugs on A9 and A10 dopamine neurons.Science. 1983; 221: 1054-1057
- Differential effects of M1 and M2-muscarinic drugs on striatal dopamine release and metabolism in freely moving rats.Brain Res. 1989; 495: 232-242
Article info
Publication history
Accepted:
July 28,
2000
Received in revised form:
March 24,
2000
Received in revised form:
July 27,
2000
Received:
December 2,
1999
Identification
Copyright
© 2001 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
