Clozapine is a potent and selective muscarinic M4 receptor agonist

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

“…Clozapine has been reported to be: 1) a M 1/2 partial agonist (Fritze and Tilmann 1995;Michal et al 1999); 2) a M 2/3/5 receptor antagonist (Bymaster et al 1996); and 3) a M 4 receptor full (Zorn et al 1994;Zeng et al 1997) or partial agonist (Olianas et al 1997;Michal et al 1999). Clozapine and olanzapine may be relatively weaker M 1 receptor antagonists in vivo than in vitro (Bymaster and Falcone 2000).…”

“…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 role in both psychosis and reward (Davis et al 1991; Kalivas and Nakamura 1999).…”

“…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).…”

N-Desmethylclozapine, a Major Clozapine Metabolite, Acts as a Selective and Efficacious δ-Opioid Agonist at Recombinant and Native Receptors

“…An important feature of clozapine is its ability to bind with high affinity to acetylcholine (ACh) muscarinic receptors and to act as a mixed agonist/antagonist (Zorn et al, 1994;Zeng et al, 1997;Olianas et al, 1997Olianas et al, , 1999Michal et al, 1999). A similar property has recently been demonstrated for NDMC.…”

Towards a muscarinic hypothesis of schizophrenia

“…153 This position gained support from in vitro studies using functional assays in human muscarinic receptors expressed in cell cultures that suggested that clozapine is a full agonist at the muscarinic M 4 -receptor. [154][155][156] These findings were questioned by another study that failed to show an agonist effect of both clozapine and olanzapine on the M 4 receptor 157 and the failure to show agonist activity of clozapine at muscarinic M 4 -receptors in animal brain tissue. 155,158 The picture is further complicated by other data that suggest that clozapine is also a partial agonist at the M 1 , M 2 , and M 3 receptor.…”