African-Specific Variability in the Acetylcholine Muscarinic Receptor M4: Association with Cocaine and Heroin Addiction

Levran, Orna; Randesi, Matthew; Peles, Einat; Rosa, Joel Correa da; Ott, Jürg; Rotrosen, John; Adelson, Miriam; Kreek, Mary Jeanne

doi:10.2217/pgs-2016-0028

Cited by 11 publications

(7 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The M4Rs on D1R-expressing neurons could be interesting as pharmacological targets, as they exert control over a broad array of behaviors related to addiction pathology; including locomotor sensitization, impulsivity, drug seeking and reinstatement of drug-seeking behavior after extinction. In line with this, a recent study on genetic polymorphisms within the M4R gene revealed a link to both cocaine and heroin addiction in human subjects (Levran et al, 2016 ).…”

Section: Discussionmentioning

confidence: 75%

Muscarinic M4 Receptors on Cholinergic and Dopamine D1 Receptor-Expressing Neurons Have Opposing Functionality for Positive Reinforcement and Influence Impulsivity

Klawonn

Wilhelms

Lindström

et al. 2018

Front. Mol. Neurosci.

View full text Add to dashboard Cite

The neurotransmitter acetylcholine has been implicated in reward learning and drug addiction. However, the roles of the various cholinergic receptor subtypes on different neuron populations remain elusive. Here we study the function of muscarinic M4 receptors (M4Rs) in dopamine D1 receptor (D1R) expressing neurons and cholinergic neurons (expressing choline acetyltransferase; ChAT), during various reward-enforced behaviors and in a “waiting”-impulsivity test. We applied cell-type-specific gene deletions targeting M4Rs in D1RCre or ChATCre mice. Mice lacking M4Rs in D1R-neurons displayed greater cocaine seeking and drug-primed reinstatement than their littermate controls in a Pavlovian conditioned place preference (CPP) paradigm. Furthermore, the M4R-D1RCre mice initiated significantly more premature responses (PRs) in the 5-choice-serial-reaction-time-task (5CSRTT) than their littermate controls, indicating impaired waiting impulse control. In contrast, mice lacking M4Rs in cholinergic neurons did not acquire cocaine Pavlovian conditioning. The M4R-ChATCre mice were also unable to learn positive reinforcement to either natural reward or cocaine in an operant runway paradigm. Immediate early gene (IEG) expression (cFos and FosB) induced by repeated cocaine injections was significantly increased in the forebrain of M4R-D1RCre mice, whereas it remained normal in the M4R-ChATCre mice. Our study illustrates that muscarinic M4Rs on specific neural populations, either cholinergic or D1R-expressing, are pivotal for learning processes related to both natural reward and drugs of abuse, with opposing functionality. Furthermore, we found that neurons expressing both M4Rs and D1Rs are important for signaling impulse control.

show abstract

Section: Discussionmentioning

confidence: 75%

Muscarinic M4 Receptors on Cholinergic and Dopamine D1 Receptor-Expressing Neurons Have Opposing Functionality for Positive Reinforcement and Influence Impulsivity

Klawonn

Wilhelms

Lindström

et al. 2018

Front. Mol. Neurosci.

View full text Add to dashboard Cite

show abstract

“…M4Rs on D1R neurons exert control over a broad array of behaviors related to addiction pathology, including locomotor sensitization, impulsivity, drug-seeking and relapse behavior after extinction. In line with this notion, a recent study on genetic polymorphisms within the M4R gene revealed a link to both cocaine and heroin addiction in human subjects (Levran et al, 2016).…”

Section: M4r Function In Learning and Motivation -Can We Really Tell?mentioning

confidence: 76%

“…Moreover, the conditional deletion of M4 receptors from D1-receptor expressing neurons leads to increased locomotor responses to psychostimulants, as well as an elevated dopamine efflux in the striatum upon amphetamine injections (Jeon et al, 2010). A recent study on genetic polymorphisms within the M4R gene revealed a link to both cocaine and heroin addiction in human subjects (Levran et al, 2016).…”

Section: The Muscarinic Acetylcholine Receptor M4mentioning

confidence: 99%

Molecular Mechanisms of Reward and Aversion

Klawonn¹

2018

Linköping University Medical Dissertations

View full text Add to dashboard Cite

“…The sample includes subjects with opioid addiction (OD) and controls and was described in detail elsewhere 14 . Briefly, OD subjects (cases) were recruited at several opiate treatment programs in the US (e.g., Manhattan Campus of VA NY Harbor Health Care System, Weill Medical College of Cornell University, and Dr. Miriam and Sheldon G. Adelson Clinic for Drug Abuse Treatment and Research, in Las Vegas) or at the Rockefeller University.…”

Section: Methodsmentioning

confidence: 99%

“…All cases had a history of at least 1 year of multiple daily uses of heroin and were on methadone maintenance treatment at the time of recruitment. The European American (EA) sample included subjects with >50% European/Middle Eastern ancestry contributions, based on structure or PC analysis as described 14 , 15 (OD, n = 545; Controls, n = 196). The African American (AA) sample included subjects with >50% African ancestry contribution (OD, n = 308; Controls, n = 190); self-identified Hispanics were excluded.…”

Section: Methodsmentioning

confidence: 99%

OPRD1 SNPs associated with opioid addiction are cis-eQTLs for the phosphatase and actin regulator 4 gene, PHACTR4, a mediator of cytoskeletal dynamics

et al. 2021

Self Cite

View full text Add to dashboard Cite

Several OPRD1 intronic variants were associated with opioid addiction (OD) in a population-specific manner. This follow-up study aims to further characterize the OPRD1 haplotype pattern of the risk variants in different populations and apply in silico analysis to identify potential causal variants. A population-specific haplotype pattern was revealed based on six OPRD1 eQTL SNPs and five common haplotypes were identified in a sample of European ancestry (CEU). A European-specific haplotype (‘Hap 3’) that includes SNPs previously associated with OD and is tagged by SNP rs2236861 is more common in subjects with OD. It is quite common (10%) in CEU but is absent in the African sample (YRI) and extends upstream of OPRD1. SNP rs2236857 is most probably a non-causal variant in LD with the causal SNP/s in a population-specific manner. The study provides an explanation for the lack of association in African Americans, despite its high frequency in this population. OD samples homozygous for ‘Hap 3’ were reanalyzed using a denser coverage of the region and revealed at least 25 potentially regulatory SNPs in high LD. Notably, GTEx data indicate that some of the SNPs are eQTLs for the upstream phosphatase and actin regulator 4 (PHACTR4), in the cortex, and others are eQTLs for OPRD1 and the upstream lncRNA ENSG00000270605, in the cerebellum. The study highlights the limitation of single SNP analysis and the sensitivity of association studies of OPRD1 to a genetic background. It proposes a long-range functional connection between OPRD1 and PHACTR4. PHACTR4, a mediator of cytoskeletal dynamics, may contribute to drug addiction by modulating synaptic plasticity.

show abstract

African-Specific Variability in the Acetylcholine Muscarinic Receptor M4: Association with Cocaine and Heroin Addiction

Abstract: Cholinergic receptors' variants may contribute to drug addiction and have a potential role as pharmacogenetic markers.

Cited by 11 publications

References 57 publications

Muscarinic M4 Receptors on Cholinergic and Dopamine D1 Receptor-Expressing Neurons Have Opposing Functionality for Positive Reinforcement and Influence Impulsivity

Muscarinic M4 Receptors on Cholinergic and Dopamine D1 Receptor-Expressing Neurons Have Opposing Functionality for Positive Reinforcement and Influence Impulsivity

Molecular Mechanisms of Reward and Aversion

OPRD1 SNPs associated with opioid addiction are cis-eQTLs for the phosphatase and actin regulator 4 gene, PHACTR4, a mediator of cytoskeletal dynamics

Contact Info

Product

Resources

About