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African-specific variability in the acetylcholine muscarinic receptor M4: association with cocaine and heroin addiction.

ABSTRACT: This study was designed to determine whether polymorphisms in acetylcholine receptors contribute to opioid dependence and/or cocaine dependence.The sample (n = 1860) was divided by drug and ancestry, and 55 polymorphisms (nine genes) were analyzed.Of the 20 SNPs that showed nominally significant associations, the association of the African-specific CHRM4 SNP rs2229163 (Asn417=) with cocaine dependence survived correction for multiple testing (Pcorrected = 0.047). CHRM4 is located in a region of strong linkage disequilibrium on chromosome 11 that includes genes associated with schizophrenia. CHRM4 SNP rs2229163 is in strong linkage disequilibrium with several African-specific SNPs in DGKZ and AMBRA1.Cholinergic receptors' variants may contribute to drug addiction and have a potential role as pharmacogenetic markers.

SUBMITTER: Levran O

PROVIDER: S-EPMC4996315 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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African-specific variability in the acetylcholine muscarinic receptor M4: association with cocaine and heroin addiction.

Levran Orna O Randesi Matthew M Peles Einat E Correa da Rosa Joel J Ott Jurg J Rotrosen John J Adelson Miriam M Kreek Mary Jeanne MJ

Pharmacogenomics 20160607 9

<h4>Aim</h4>This study was designed to determine whether polymorphisms in acetylcholine receptors contribute to opioid dependence and/or cocaine dependence.<h4>Patients & methods</h4>The sample (n = 1860) was divided by drug and ancestry, and 55 polymorphisms (nine genes) were analyzed.<h4>Results</h4>Of the 20 SNPs that showed nominally significant associations, the association of the African-specific CHRM4 SNP rs2229163 (Asn417=) with cocaine dependence survived correction for multiple testing ...[more]

PMID: 27269905

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Project description:Accumulating evidence suggests that selective M4 muscarinic acetylcholine receptor (mAChR) activators may offer a novel strategy for the treatment of psychosis. However, previous efforts to develop selective M4 activators were unsuccessful because of the lack of M4 mAChR subtype specificity and off-target muscarinic adverse effects. We recently developed VU0152100, a highly selective M4 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 M4 on region-specific brain activation, VU0152100 alone and in combination with amphetamine were evaluated using pharmacologic magnetic resonance imaging (phMRI). Key neural substrates of M4-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 M4 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 M4 PAMs as a new approach to the treatment of psychosis and cognitive impairments associated with psychiatric disorders such as schizophrenia.

Dataset Information

African-specific variability in the acetylcholine muscarinic receptor M4: association with cocaine and heroin addiction.

Publications

African-specific variability in the acetylcholine muscarinic receptor M4: association with cocaine and heroin addiction.

Similar Datasets

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