The muscarinic agonist xanomeline increases monoamine release and immediate early gene expression in the rat prefrontal cortex

Perry, Kenneth W.; Nisenbaum, Laura; George, Carolyn; Shannon, Harlan E.; Felder, Christian C.; Bymaster, Frank P.

doi:10.1016/s0006-3223(00)01017-9

Cited by 43 publications

(30 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…168 Like atypical antipsychotics, xanomeline has also been shown to increase extracellular concentrations of dopamine in the prefrontal cortex. 169 The data on xanomeline, along with the findings on NDMC, support the proposition that muscarinic receptor agonists may offer a new therapeutic approach in schizophrenia.…”

Section: Use Of Cholinesterase Inhibitors In Schizophreniamentioning

confidence: 65%

“…The stimulation of M 1 /M 4 muscarinic receptors leads to a strong dopamine release in the cortex, whereas the dopamine release is less pronounced in the nucleus accumbens. 169,183 So far only little is known about the effects of the different muscarinic receptor subtypes on the regulation of dopamine. Knockout mice are helpful to clarify the physiological role of muscarinic receptor subtypes on the release of dopamine.…”

Section: Use Of Cholinesterase Inhibitors In Schizophreniamentioning

confidence: 99%

See 1 more Smart Citation

Towards a muscarinic hypothesis of schizophrenia

Raedler

Bymaster

Tandon³

et al. 2006

Mol Psychiatry

247

211

View full text Add to dashboard Cite

Although the neurotransmitter dopamine plays a prominent role in the pathogenesis and treatment of schizophrenia, the dopamine hypothesis of schizophrenia fails to explain all aspects of this disorder. It is increasingly evident that the pathology of schizophrenia also involves other neurotransmitter systems. Data from many streams of research including preclinical and clinical pharmacology, treatment studies, post-mortem studies and neuroimaging suggest an important role for the muscarinic cholinergic system in the pathophysiology of schizophrenia. This review will focus on evidence that supports the hypothesis that the muscarinic system is involved in the pathogenesis of schizophrenia and that muscarinic receptors may represent promising novel targets for the treatment of this disorder.

show abstract

Section: Use Of Cholinesterase Inhibitors In Schizophreniamentioning

confidence: 65%

Section: Use Of Cholinesterase Inhibitors In Schizophreniamentioning

confidence: 99%

Towards a muscarinic hypothesis of schizophrenia

Raedler

Bymaster

Tandon³

et al. 2006

Mol Psychiatry

247

211

View full text Add to dashboard Cite

show abstract

“…Although encouraging, there have been only two clinical studies with xanomeline published to date indicating that these initial findings should be viewed with caution until further clinical validation is reported. Xanomeline also showed robust efficacy in animal models predictive of APDlike activity comparable to the effects observed with the atypical antipsychotic clozapine, including reversal of psychostimulant-induced hyperlocomotion and disruption of prepulse inhibition (PPI) of the acoustic startle reflex (Andersen et al, 2003;Jones et al, 2005;Perry et al, 2001;Shannon et al, 2000;Stanhope et al, 2001). Unfortunately, xanomeline like other muscarinic agonists ultimately failed in clinical development due to a lack of complete receptor subtype selectivity resulting in adverse side effects associated with non-selective activation of peripheral M 2 and M 3 mAChRs (Bodick et al, 1997;Shekhar et al, 2008).…”

Section: Introductionmentioning

confidence: 91%

“…After recovery for 4-7 days, microdialysis probes (2 mm membrane length) were inserted the night before the experiment using methods previously reported by Perry et al (2001). The following day, rats were placed into open field chambers as used for the amphetamineinduced hyperlocomotion studies.…”

Section: In Vivo Microdialysis and Locomotor Activitymentioning

confidence: 99%

Antipsychotic Drug-Like Effects of the Selective M4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator VU0152100

Byun

Grannan

Bubser

et al. 2014

Neuropsychopharmacol

100

105

View full text Add to dashboard Cite

Accumulating evidence suggests that selective M 4 muscarinic acetylcholine receptor (mAChR) activators may offer a novel strategy for the treatment of psychosis. However, previous efforts to develop selective M 4 activators were unsuccessful because of the lack of M 4 mAChR subtype specificity and off-target muscarinic adverse effects. We recently developed VU0152100, a highly selective M 4 positive allosteric modulator (PAM) that exerts central effects after systemic administration. We now report that VU0152100 dose-dependently reverses amphetamine-induced hyperlocomotion in rats and wild-type mice, but not in M4 KO mice. VU0152100 also blocks amphetamine-induced disruption of the acquisition of contextual fear conditioning and prepulse inhibition of the acoustic startle reflex. These effects were observed at doses that do not produce catalepsy or peripheral adverse effects associated with non-selective mAChR agonists. To further understand the effects of selective potentiation of M 4 on region-specific brain activation, VU0152100 alone and in combination with amphetamine were evaluated using pharmacologic magnetic resonance imaging (phMRI). Key neural substrates of M 4 -mediated modulation of the amphetamine response included the nucleus accumbens (NAS), caudate-putamen (CP), hippocampus, and medial thalamus. Functional connectivity analysis of phMRI data, specifically assessing correlations in activation between regions, revealed several brain networks involved in the M 4 modulation of amphetamine-induced brain activation, including the NAS and retrosplenial cortex with motor cortex, hippocampus, and medial thalamus. Using in vivo microdialysis, we found that VU0152100 reversed amphetamine-induced increases in extracellular dopamine levels in NAS and CP. The present data are consistent with an antipsychotic drug-like profile of activity for VU0152100. Taken together, these data support the development of selective M 4 PAMs as a new approach to the treatment of psychosis and cognitive impairments associated with psychiatric disorders such as schizophrenia.

show abstract

“…Xanomeline also inhibited conditioned avoidance responding (Shannon et al, 2000), a traditional preclinical test used to predict antipsychotic activity (Arnt, 1982;Arnt et al, 1982). Furthermore, similar to the effects of the antipsychotic compounds clozapine and olanzapine, xanomeline increased extracellular levels of dopamine and immediateearly gene expression, that is, Fos, in the rat prefrontal cortex (Perry et al, 2001). Finally, xanomeline has been shown to reverse apomorphine-induced reduction in prepulse inhibition in rats (Stanhope et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

The Muscarinic M1/M4 Receptor Agonist Xanomeline Exhibits Antipsychotic-Like Activity in Cebus apella Monkeys

Andersen

Fink-Jensen

Peacock

et al. 2003

Neuropsychopharmacol

View full text Add to dashboard Cite

Xanomeline is a muscarinic M 1 /M 4 preferring receptor agonist with little or no affinity for dopamine receptors. The compound reduces psychotic-like symptoms in patients with Alzheimer's disease and exhibits an antipsychotic-like profile in rodents without inducing extrapyramidal side effects (EPS) at therapeutically relevant doses. In the present study, we examined whether the xanomeline-induced functional dopamine antagonism found in rodent studies could also be observed in nonhuman primates. In addition, we studied whether the lack of EPS observed in rodents also applies to primates. To this end, we investigated the effects of xanomeline on the behavior induced by D-amphetamine and (À)-apomorphine in drug-naive Cebus apella monkeys. Antipsychotic compounds antagonize amphetamine-induced motor unrest and stereotypies in this species. Xanomeline inhibited D-amphetamine-induced motor unrest, stereotypies and arousal as well as apomorphine-induced stereotypies and arousal in drug-naive Cebus apella monkeys. Xanomeline did not induce EPS but vomiting occurred in some monkeys at high doses, in accordance with emetic events observed in Alzheimer patients following xanomeline administration. Even when xanomeline was tested in EPS-sensitized Cebus apella monkeys, EPS were not observed at the dose range of xanomeline used in the D-amphetamine-apomorphine combination study (0.5-3 mg/kg). However, when xanomeline was tested at 4 mg/kg, moderate dystonia was seen in two out of three monkeys. It is concluded that xanomeline inhibits Damphetamine-and (À)-apomorphine-induced behavior in Cebus apella monkeys at doses that do not cause EPS. These data further substantiate that muscarinic receptor agonists may be useful in the pharmacological treatment of psychosis.

show abstract

The muscarinic agonist xanomeline increases monoamine release and immediate early gene expression in the rat prefrontal cortex

Cited by 43 publications

References 46 publications

Towards a muscarinic hypothesis of schizophrenia

Towards a muscarinic hypothesis of schizophrenia

Antipsychotic Drug-Like Effects of the Selective M4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator VU0152100

The Muscarinic M1/M4 Receptor Agonist Xanomeline Exhibits Antipsychotic-Like Activity in Cebus apella Monkeys

Contact Info

Product

Resources

About