Effects of Xanomeline, a Selective Muscarinic Receptor Agonist, on Cognitive Function and Behavioral Symptoms in Alzheimer Disease

Bodick, N.; Offen, Walter W.; Levey, Aĺlan I.; Cutler, Neal R.; Gauthier, Serge; Satlin, Andrew; Shannon, Harlan E.; Tollefson, Gary D.; Rasmussen, Kurt; Bymaster, Frank P.; Hurley, Daniel J.; Potter, William Z.; Paul, Steven M.

doi:10.1001/archneur.1997.00550160091022

Cited by 574 publications

(491 citation statements)

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“…Employing the CGI definition of responders (CGIp3) the patients treated with xanomeline did significantly better than the placebo treated group. Interestingly, even though gastrointestinal side effects were observed, they occurred to a considerably lesser extent than in the Alzheimer patient study (Bodick et al, 1997).…”

Section: Discussionmentioning

confidence: 61%

“…However, potent parasympatomimetic side effects confound the clinical use of nonselective cholinergic receptor agonists. More recently, it has been reported that acetylcholinesterase inhibitors as well as the muscarinic M 1 /M 4 preferring receptor agonist xanomeline reduce psychoticlike symptoms in patients with Alzheimer's disease (Bodick et al, 1997;Cummings, 2000;White and Cummings, 1996). Even though these newer compounds have considerably less parasympatomimetic side effects, nausea and vomiting have been reported in Alzheimer patients taking these drugs (Doody et al, 2001;Bodick et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

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

Andersen

Fink-Jensen

Peacock

et al. 2003

Neuropsychopharmacol

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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.

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Section: Discussionmentioning

confidence: 61%

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

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“…In fact muscarinic agonists like xanomeline, BuTAC, and PTAC (which are relatively devoid of D 2 activity) have been shown to be very active in CAR (Bymaster et al, , 2002 and xanomeline has been shown to have antipsychotic and pro-cognitive efficacy in humans (Bodick et al, 1997). However in the case of NDMC, in the dose range tested, it did not effectively inhibit CAR at the 20-90-min time point where other M 1 agonists/partial agonists have inhibited CAR significantly after s.c. administration .…”

Section: Discussionmentioning

confidence: 99%

Evaluation of N-Desmethylclozapine as a Potential Antipsychotic—Preclinical Studies

Natesan

Reckless

Barlow

et al. 2006

Neuropsychopharmacol

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There is growing interest in N-desmethylclozapine (NDMC), the major metabolite of clozapine, as a unique antipsychotic because it acts in vitro as a 5-HT 2 antagonist and as a partial agonist to dopamine D 2 and muscarinic receptors. To explore this, we compared NDMC to a typical (haloperidol), atypical (clozapine), and partial-agonist atypical (aripiprazole) antipsychotic in preclinical models. The comparison was carried out using: brain D 2 and 5-HT 2 receptor occupancy; animal models predictive of antipsychotic efficacy (amphetamine-induced hyperlocomotion (AIL) and conditioned avoidance response (CAR) models); measures predictive of side effects (catalepsy and prolactin elevation); and molecular markers predictive of antipsychotic action (striatal Fos induction). NDMC (10-60 mg/kg/s.c.) showed high 5-HT 2 (64-79%), but minimal D 2 occupancy (o15% at 60 mg/kg) 1 h after administration. In contrast to other antipsychotics, NDMC was not very effective in reducing AIL or CAR and showed minimal induction of Fos in the nucleus accumbens. However, like atypical antipsychotics, it showed no catalepsy, prolactin elevation, and minimal Fos in the dorsolateral striatum. It seems unlikely that NDMC would show efficacy as a stand-alone antipsychotic, however, its freedom from catalepsy and prolactin elevation, and its unique pharmacological profile (muscarinic agonism) may make it feasible to use this drug as an adjunctive treatment to existing antipsychotic regimens.

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“…M 1 receptor agonists have been reported to improve working memory in animals (Aura et al 1997;McDonald et al 1998) and xanomeline, a M 1 receptor agonist with minimal M 2 receptor blockade Shannon et al 1994Shannon et al , 2000, has also improved cognition, and decreased hallucinatory and delusional symptoms in Alzheimer's disease (Bodick et al 1997;Bymaster et al 1997) and perhaps schizophrenia, whereas M 1 receptor antagonists may worsen working memory in patients with schizophrenia (McEvoy 1987;Spohn and Strauss 1989;King 1990) and in animals (Bymaster et al 1993;Aura et al 1997;Roldan et al 1997). The atypical APD-induced cortical ACh release would be expected to increase M 1 receptor stimulation by diminishing M 1 receptor antagonism where it exists.…”

Section: Discussionmentioning

confidence: 99%

Atypical, but Not Typical, Antipsychotic Drugs Increase Cortical Acetylcholine Release without an Effect in the Nucleus Accumbens or Striatum

Ichikawa

2002

Neuropsychopharmacology

228

124

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The role of acetylcholine (ACh) in the action of antipsychotic drugs (APDs) was studied by microdialysis, without AChesterase inhibition, to facilitate the interpretation of any observed drug effects. The atypical APDs, (Perry et al. 1999) and working memory (Winkler et al. 1995), and thus, may be important to either the cognitive dysfunction of schizophrenia or the ability of antipsychotic drugs (APDs) to improve some or all aspects of that cognitive deficit (Meltzer and McGurk 1999). The atypical APDs, clozapine, olanzapine, risperidone, and quetiapine, have, in fact, been reported to improve some domains of cognitive dysfunction (see Meltzer and McGurk 1999; Purdon 1999 for reviews), in addition to psychopathology (Leucht et al. 1999) in schizophrenia, more so than typical APDs, e.g., haloperidol and phenothiazines. The basis for these advantages is unclear.The atypical APDs share in common a relatively more potent antagonist action at serotonin (5-HT) 2A NO . 3 al. 1989;Schotte et al. 1996) and ␣ 1 -and ␣ 2 -adrenoceptors (Hertel et al. 1999). These features have been related to their ability to increase DA release in the mPFC (Hertel et al. 1999; Kuroki et al. 1999; Ichikawa et al. 2001). However, a possible role for ACh in mediating these effects is receiving increasing attention. Clozapine and olanzapine, but not risperidone, quetiapine, ziprasidone, or iloperidone (Schotte et al. 1996;Bymaster et al. 1999), have significant direct agonist or antagonist effects upon various subtypes of muscarinic ACh receptors (mAChRs) (Tandon 1999), whereas the typical APDs, thioridazine and mesoridazine, are also potent mAChR antagonists (Niedzwiecki et al. 1989a,b;Bolden et al. 1992). Furthermore, trihexyphenidyl and biperiden (Bolden et al. 1992), mAChR antagonists which reduce typical APD-induced extrapyramidal symptoms (EPS), have been reported to cause complex clinical effects in patients with schizophrenia, e.g., working memory impairment (King 1990) and worsening of psychosis while decreasing negative symptoms (Tandon et al. 1992). It is possible that clozapine and olanzapine influence clinical symptoms in schizophrenia via a direct effect upon main cholinergic transmission (Zorn et al. 1994; Bymaster et al. 1996).As has been demonstrated in rodents (Everitt and Robbins 1997) and primates (Mrzljak et al. 1995), the nucleus basalis magnocellularis (NBM) or the basal forebrain consisting of the substantia innominata, the nucleus of Meynert, and the horizontal limb of the diagonal band, project cholinergic neurons to the cortex, whereas cholinergic interneurons exist mostly in the striatum (STR) and nucleus accumbens (NAC) (Kawaguchi et al. 1995). These three regions are involved in various actions of APDs (Ichikawa and Meltzer 1999): 1) the medial prefrontal cortex (mPFC) has been suggested to be involved in the neural circuitry important for negative symptoms and cognition, e.g., working memory (Goldman-Rakic and Selemon 1997); 2) the STR is centrally involved in motor function; and 3) the NAC plays a key ...

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Effects of Xanomeline, a Selective Muscarinic Receptor Agonist, on Cognitive Function and Behavioral Symptoms in Alzheimer Disease

Cited by 574 publications

References 47 publications

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

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

Evaluation of N-Desmethylclozapine as a Potential Antipsychotic—Preclinical Studies

Atypical, but Not Typical, Antipsychotic Drugs Increase Cortical Acetylcholine Release without an Effect in the Nucleus Accumbens or Striatum

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