A Subpopulation of Neuronal M4 Muscarinic Acetylcholine Receptors Plays a Critical Role in Modulating Dopamine-Dependent Behaviors

Acetylcholine (ACh) regulates many key functions of the CNS by activating cell surface receptors referred to as muscarinic ACh receptors (M1–M5 mAChRs). Like other mAChR subtypes, the M4 mAChR is widely expressed in different regions of the forebrain. Interestingly, M4 mAChRs are coexpressed with D1 dopamine receptors in a specific subset of striatal projection neurons. To investigate the physiological relevance of this M4 mAChR subpopulation in modulating dopamine-dependent behaviors, we used Cre/loxP technology to generate mutant mice that lack M4 mAChRs only in D1 dopamine receptor-expressing cells. The newly generated mutant mice displayed several striking behavioral phenotypes, including enhanced hyperlocomotor activity and increased behavioral sensitization following treatment with psychostimulants. These behavioral changes were accompanied by a lack of muscarinic inhibition of D1 dopamine receptor-mediated cAMP stimulation in the striatum and an increase in dopamine efflux in the nucleus accumbens. These novel findings demonstrate that a distinct subpopulation of neuronal M4 mAChRs plays a critical role in modulating several important dopamine-dependent behaviors. Since enhanced central dopaminergic neurotransmission is a hallmark of several severe disorders of the CNS, including schizophrenia and drug addiction, our findings have substantial clinical relevance.

• Publication year

  2010

• Venue

  Journal of Neuroscience

• Publication date

  2010-02-10

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1523/JNEUROSCI.3843-09.2010PMID 20147565PMCID PMC2824442
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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• The neuroscience of addiction

  2005cited by this paper
• Muscarinic receptor subtype pharmacology and physiology.

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• Phenotypic analysis of dopamine receptor knockout mice; recent insights into the functional specificity of dopamine receptor subtypes.

  2004influential reference
• Muscarinic acetylcholine receptor subtypes in cerebral cortex and hippocampus.

  2004cited by this paper
• M4 muscarinic receptors regulate the dynamics of cholinergic and dopaminergic neurotransmission: relevance to the pathophysiology and treatment of related central nervous system pathologies

  2004cited by this paper
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• Muscarinic receptors as a target for drugs treating schizophrenia.

  2002influential reference
• Effects of Newer Antipsychotics on Extrapyramidal Function

  2002cited by this paper
• Efficient FLP recombination in mouse ES cells and oocytes

  2001influential reference
• Elucidating the role of muscarinic receptors in psychosis.

  2001cited by this paper
• Molecular basis of long-term plasticity underlying addiction

  2001cited by this paper
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  2001cited by this paper
• Therapeutic opportunities for muscarinic receptors in the central nervous system.

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• G OLFa Mediates Dopamine D 1 Receptor Signaling

  2000influential reference
• GOLFα Mediates Dopamine D1 Receptor Signaling

  2000cited by this paper
• G(olf)alpha mediates dopamine D1 receptor signaling.

  2000cited by this paper
• Regulation of Neurotransmitter Interactions in the Ventral Striatum

  1999cited by this paper
• Use of SHIRPA and discriminant analysis to characterise marked differences in the behavioural phenotype of six inbred mouse strains.

  1999cited by this paper
• Enhancement of D1 dopamine receptor-mediated locomotor stimulation in M(4) muscarinic acetylcholine receptor knockout mice.

  1999cited by this paper
• Neuroscience of addiction.

  1998cited by this paper
• The tumor suppressor SMAD4/DPC4 is essential for epiblast proliferation and mesoderm induction in mice.

  1998cited by this paper
• International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors.

  1998cited by this paper
• Differential expression of D1 and D2 dopamine and m4 muscarinic acetylcholine receptor proteins in identified striatonigral neurons

  1997cited by this paper
• The Neurobiology of Addiction

  1997influential reference
• Effects of clozapine on rat striatal muscarinic receptors coupled to inhibition of adenylyl cyclase activity and on the human cloned m4 receptor

  1997cited by this paper
• Behavioral and functional analysis of mouse phenotype: SHIRPA, a proposed protocol for comprehensive phenotype assessment

  1997influential reference
• Neurobiology of addiction.

  1996cited by this paper
• Fibroblast growth factor receptor 3 is a negative regulator of bone growth.

  1996cited by this paper
• Molecular biology of muscarinic acetylcholine receptors.

  1996cited by this paper
• Development of Selective Antisera for Muscarinic Cholinergic Receptor Subtypes

  1995cited by this paper
• D1 dopamine receptor immunoreactivity in human and monkey cerebral cortex: predominant and extrasynaptic localization in dendritic spines.

  1994cited by this paper
• Modulatory functions of neurotransmitters in the striatum: ACh/dopamine/NMDA interactions.

  1994influential reference
• Immunological localization of m1-m5 muscarinic acetylcholine receptors in peripheral tissues and brain.

  1993cited by this paper
• Advances and limitations of the molecular neuroanatomy of cholinergic receptors: the example of multiple muscarinic receptors.

  1993influential reference
• Phenotypical characterization of the rat striatal neurons expressing muscarinic receptor genes

  1992cited by this paper
• Identification and localization of muscarinic acetylcholine receptor proteins in brain with subtype-specific antibodies

  1991cited by this paper
• The current status of the dopamine hypothesis of schizophrenia.

  1988cited by this paper
• Comprehensive observational assessment: Ia. A systematic, quantitative procedure for assessing the behavioral and physiologic state of the mouse

  1968cited by this paper

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