, Volume 216, Issue 3, pp 367–378

Increased cocaine self-administration in M4 muscarinic acetylcholine receptor knockout mice

  • Lene S. Schmidt
  • Morgane Thomsen
  • Pia Weikop
  • Ditte Dencker
  • Jürgen Wess
  • David P. D. Woldbye
  • Gitta Wortwein
  • Anders Fink-Jensen
Original Investigation



The reinforcing effects of cocaine are mediated by the mesolimbic dopamine system. Behavioral and neurochemical studies have shown that the cholinergic muscarinic M4 receptor subtype plays an important role in regulation of dopaminergic neurotransmission.


Here we investigated for the first time the involvement of M4 receptors in the reinforcing effects of cocaine using chronic intravenous cocaine self-administration in extensively backcrossed M4 receptor knockout (M4−/−) mice.


We evaluated acquisition of cocaine self-administration in experimentally naïve mice. Both cocaine self-administration and food-maintained operant behavior were evaluated under fixed ratio 1 (FR 1) and progressive ratio (PR) schedules of reinforcement. In addition, cocaine-induced dopamine release and cocaine-induced hyperactivity were evaluated.


M4−/− mice earned significantly more cocaine reinforcers and reached higher breaking points than their wild-type littermates (M4+/+) at intermediate doses of cocaine under both FR 1 and PR schedules of reinforcement. Under the PR schedule, M4−/− mice exhibited significantly higher response rates at the lowest liquid food concentration. In accordance with these results, cocaine-induced dopamine efflux in the nucleus accumbens and hyperlocomotion were increased in M4−/− mice compared to M4+/+ mice.


Our data suggest that M4 receptors play an important role in regulation of the reward circuitry and may serve as a new target in the medical treatment of drug addiction.


Acetylcholine Muscarinic M4 Knockout Self-administration Cocaine 

Supplementary material

213_2011_2225_MOESM1_ESM.doc (48 kb)
Supplemental Table 1Behavioral phenotype assessment, primary screen (SHIRPA). Body weight, body length, and locomotor activity (bb, beam breaks) are group means ± SEM. Other data are group medians with range in parenthesis. Groups sizes, n = 1921. There was no significant effect of genotype in any of the measures. (DOC 47 kb)


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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Lene S. Schmidt
    • 1
  • Morgane Thomsen
    • 3
  • Pia Weikop
    • 1
  • Ditte Dencker
    • 1
  • Jürgen Wess
    • 4
  • David P. D. Woldbye
    • 1
    • 2
  • Gitta Wortwein
    • 1
  • Anders Fink-Jensen
    • 1
    • 5
  1. 1.Laboratory of NeuropsychiatryRigshospitalet University HospitalCopenhagenDenmark
  2. 2.Department of Neuroscience and PharmacologyUniversity of CopenhagenCopenhagenDenmark
  3. 3.Alcohol and Drug Abuse Research CenterMcLean Hospital, Harvard Medical SchoolBelmontUSA
  4. 4.Molecular Signaling Section, Laboratory of Bioorganic ChemistryNIDDK, NIHBethesdaUSA
  5. 5.Laboratory of Neuropsychiatry and Psychiatric Centre CopenhagenUniversity of CopenhagenCopenhagenDenmark

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