p(HGNC:CHRM4)
In brain slices, VU10010 selectively potentiated mAChR-mediated reductions in glutamatergic, but not GABAergic, signaling in hippocampal neurons, indicating a key role for M4 in regulating hippocampal function, and possibly in modulating cognition. PubMed:24511233
The M4 receptor is highly expressed in the striatum, hippocampus, and neocortex,45,46 suggesting that this mAChR subtype is ideally located to modulate dopaminergic signaling. In support of this hypothesis, M4 KO mice exhibit a hyperdopaminergic phenotype that is resistant to mAChR agonist-induced attenuation of dopamine levels. PubMed:24511233
The M4 receptor is highly expressed in the striatum, hippocampus, and neocortex,45,46 suggesting that this mAChR subtype is ideally located to modulate dopaminergic signaling. In support of this hypothesis, M4 KO mice exhibit a hyperdopaminergic phenotype that is resistant to mAChR agonist-induced attenuation of dopamine levels. PubMed:24511233
The M4 receptor is highly expressed in the striatum, hippocampus, and neocortex,45,46 suggesting that this mAChR subtype is ideally located to modulate dopaminergic signaling. In support of this hypothesis, M4 KO mice exhibit a hyperdopaminergic phenotype that is resistant to mAChR agonist-induced attenuation of dopamine levels. PubMed:24511233
Conversely, the nonselective mAChR agonist BuTAC ([5R-(exo)]-6-[4-butylthio-1,2,5-thiadiazol-3-yl]-1-azabicyclo-[3.2.1]-octane) shows an antipsychotic profile when tested in numerous preclinical animal models. Administration of BuTAC reduces apomorphine-induced climbing and apomorphine-induced disruptions of prepulse inhibition78,79 and reduces conditioned avoidance responding in wild-type, but not M4 KO mice. PubMed:24511233
One example is xanomeline, an mAChR agonist with selectivity for the M1 and M4 subtypes. Xanomeline improves working memory in rodents and improves cognition and reduces psychotic episodes in AD patients, but it failed during phase-II clinical trial because of serious side-effects, probably due to simultaneous activation of M1 and M4 mAChRs (M4 > M1) PubMed:24590577
M4 mAChR is mainly expressed in the corpus striatum in the CNS and on various prejunctional nerve terminals in the periphery. M4 mAChR has been suggested to play a role in psychosis and to be a promising target for the treatment of schizophrenia[52]. Indeed, the mixed M1/M4 mAChR agonist xanomeline has antipsychotic effects, and M4 mAChR-knockout mice display increased sensitivity to the disruptive effects of phencyclidine, a drug of abuse PubMed:24590577
M4 mAChR is also involved in the pathology of Parkinson’s disease, which is associated with the loss of dopaminergic neurons projecting to the striatum and an imbalance between cholinergic and dopaminergic systems. In the corpus striatum, M4 mAChR is closely co-localized with dopamine receptors on striatal-projecting neurons and the striatal M4 mAChR inhibits dopamine D1 receptor function. Mice lacking M4 mAChR show increased locomotor activity and enhanced dopamine D1 receptor-mediated effects[55]. Consequently, selective M4 mAChR antagonists, such as benzoxazines, have been developed for the treatment of Parkinson’s disease PubMed:24590577
M4 mAChR is mainly expressed in the corpus striatum in the CNS and on various prejunctional nerve terminals in the periphery. M4 mAChR has been suggested to play a role in psychosis and to be a promising target for the treatment of schizophrenia[52]. Indeed, the mixed M1/M4 mAChR agonist xanomeline has antipsychotic effects, and M4 mAChR-knockout mice display increased sensitivity to the disruptive effects of phencyclidine, a drug of abuse PubMed:24590577
Conversely, the nonselective mAChR agonist BuTAC ([5R-(exo)]-6-[4-butylthio-1,2,5-thiadiazol-3-yl]-1-azabicyclo-[3.2.1]-octane) shows an antipsychotic profile when tested in numerous preclinical animal models. Administration of BuTAC reduces apomorphine-induced climbing and apomorphine-induced disruptions of prepulse inhibition78,79 and reduces conditioned avoidance responding in wild-type, but not M4 KO mice. PubMed:24511233
The M4 receptor is highly expressed in the striatum, hippocampus, and neocortex,45,46 suggesting that this mAChR subtype is ideally located to modulate dopaminergic signaling. In support of this hypothesis, M4 KO mice exhibit a hyperdopaminergic phenotype that is resistant to mAChR agonist-induced attenuation of dopamine levels. PubMed:24511233
The M4 receptor is highly expressed in the striatum, hippocampus, and neocortex,45,46 suggesting that this mAChR subtype is ideally located to modulate dopaminergic signaling. In support of this hypothesis, M4 KO mice exhibit a hyperdopaminergic phenotype that is resistant to mAChR agonist-induced attenuation of dopamine levels. PubMed:24511233
The M4 receptor is highly expressed in the striatum, hippocampus, and neocortex,45,46 suggesting that this mAChR subtype is ideally located to modulate dopaminergic signaling. In support of this hypothesis, M4 KO mice exhibit a hyperdopaminergic phenotype that is resistant to mAChR agonist-induced attenuation of dopamine levels. PubMed:24511233
The M4 receptor is highly expressed in the striatum, hippocampus, and neocortex,45,46 suggesting that this mAChR subtype is ideally located to modulate dopaminergic signaling. In support of this hypothesis, M4 KO mice exhibit a hyperdopaminergic phenotype that is resistant to mAChR agonist-induced attenuation of dopamine levels. PubMed:24511233
In brain slices, VU10010 selectively potentiated mAChR-mediated reductions in glutamatergic, but not GABAergic, signaling in hippocampal neurons, indicating a key role for M4 in regulating hippocampal function, and possibly in modulating cognition. PubMed:24511233
M4 mAChR is mainly expressed in the corpus striatum in the CNS and on various prejunctional nerve terminals in the periphery. M4 mAChR has been suggested to play a role in psychosis and to be a promising target for the treatment of schizophrenia[52]. Indeed, the mixed M1/M4 mAChR agonist xanomeline has antipsychotic effects, and M4 mAChR-knockout mice display increased sensitivity to the disruptive effects of phencyclidine, a drug of abuse PubMed:24590577
M4 mAChR is mainly expressed in the corpus striatum in the CNS and on various prejunctional nerve terminals in the periphery. M4 mAChR has been suggested to play a role in psychosis and to be a promising target for the treatment of schizophrenia[52]. Indeed, the mixed M1/M4 mAChR agonist xanomeline has antipsychotic effects, and M4 mAChR-knockout mice display increased sensitivity to the disruptive effects of phencyclidine, a drug of abuse PubMed:24590577
M4 mAChR is also involved in the pathology of Parkinson’s disease, which is associated with the loss of dopaminergic neurons projecting to the striatum and an imbalance between cholinergic and dopaminergic systems. In the corpus striatum, M4 mAChR is closely co-localized with dopamine receptors on striatal-projecting neurons and the striatal M4 mAChR inhibits dopamine D1 receptor function. Mice lacking M4 mAChR show increased locomotor activity and enhanced dopamine D1 receptor-mediated effects[55]. Consequently, selective M4 mAChR antagonists, such as benzoxazines, have been developed for the treatment of Parkinson’s disease PubMed:24590577
M4 mAChR is also involved in the pathology of Parkinson’s disease, which is associated with the loss of dopaminergic neurons projecting to the striatum and an imbalance between cholinergic and dopaminergic systems. In the corpus striatum, M4 mAChR is closely co-localized with dopamine receptors on striatal-projecting neurons and the striatal M4 mAChR inhibits dopamine D1 receptor function. Mice lacking M4 mAChR show increased locomotor activity and enhanced dopamine D1 receptor-mediated effects[55]. Consequently, selective M4 mAChR antagonists, such as benzoxazines, have been developed for the treatment of Parkinson’s disease PubMed:24590577
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