Elucidating the role of muscarinic receptors in psychosis

The unique profile of clozapine cannot be fully explained either by its 5HT receptors (7) as these characteristics are shared by other drugs (8).Clozapine has a promiscuous pharmacology, interacts with many G protein-coupled receptors, and has nanomolar affinity for all five cloned muscarinic receptors (M1-M5) (8, 9).

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Furthermore, 0 of 4 SNPs within CHRM1 previously deduced from sequencing of the human genome were found in this study despite a prediction that a majority of such inferred SNPs are accurate.

The consensus sequence of CHRM1 obtained in our study differs from the deposited reference sequence (AC NM_000738) in 2 adjacent nucleotides, leading to a V173M change, suggesting a sequencing error in the reference sequence.

There is currently growing enthusiasm in both academia and the pharmaceutical industry about the M4 muscarinic receptor as a novel target for treating schizophrenia.

His research is focused on determining the molecular mechanisms whereby the M4 receptor mediates anti-psychotic like effects, information that will be of critical importance as compounds targeting this receptor start moving towards clinical trials. Foster is also very excited about preliminary data recently gathered suggesting that compounds developed at Vanderbilt that target the M4 receptor display robust efficacy in reducing excessive grooming in mice, a phenotype observed in numerous preclinical animal models of obsessive compulsive disorder (OCD) as well as autism spectrum disorders (ASDs).

The molecular and neuronal substrates conferring on clozapine its unique and superior efficacy in the treatment of schizophrenia remain elusive.

The interaction of clozapine with many G protein-coupled receptors is well documented but less is known about its biologically active metabolite, -desmethylclozapine was shown to dose-dependently potentiate NMDA receptor currents in CA1 pyramidal cells by 53% at 100 n M, an effect largely mediated by activation of muscarinic receptors.

Furthermore, in addition to its efficacy in reducing positive and negative symptoms while causing very few extrapyramidal side effects (2), clozapine has been reported to favorably impact most impaired cognitive functions (3) and to reduce the risk of suicide (4) in schizophrenia patients.

Although effective, atypical anti-psychotics like risperidone and olanzapine do not appear to have a therapeutic spectrum that is as broad as clozapine (2, 3, 5).

Future studies will focus on the changes in developmental neurobiology and brain plasticity that occur in preclinical models of schizophrenia, OCD, and ASD and will examine the potential utility of our novel M4-selective compounds as a novel therapeutic approach to modulate disease associated changes in neurotransmission and behavior.

These studies will inform and assist ongoing drug discovery efforts and have the potential to lead to much needed novel therapeutic strategies to help patients suffering from these conditions.

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