Effects of the Partial M1 Muscarinic Cholinergic Receptor Agonist CDD-0102A on Stereotyped Motor Behaviors and Reversal Learning in the BTBR Mouse Model of Autism

Int J Neuropsychopharmacol. 2022 Jan 12;25(1):64-74. doi: 10.1093/ijnp/pyab079.


Background: Autism spectrum disorders (ASD) are a set of neurodevelopmental disorders marked by a lack of social interaction, restrictive interests, and repetitive behaviors. There is a paucity of pharmacological treatments to reduce core ASD symptoms. Various lines of evidence indicate that reduced brain muscarinic cholinergic receptor activity may contribute to an ASD phenotype.

Methods: The present experiments examined whether the partial M1 muscarinic receptor agonist, 5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine hydrochloride (CDD-0102A), alleviates behavioral flexibility deficits and/or stereotyped motor behaviors in the BTBR mouse model of autism. Behavioral flexibility was tested using a reversal learning test. Stereotyped motor behaviors were measured by eliciting digging behavior after removal of nesting material in a home cage and by measuring repetitive grooming.

Results: CDD-0102A (0.2 and 0.6 mg/kg but not 1.2 mg/kg) injected prior to reversal learning attenuated a deficit in BTBR mice but did not affect performance in B6 mice. Acute CDD-0102A treatment (1.2 and 3 mg/kg) reduced self-grooming in BTBR mice and reduced digging behavior in B6 and BTBR mice. The M1 muscarinic receptor antagonist VU0255035 (3 mg/kg) blocked the effect of CDD-0102A on grooming behavior. Chronic treatment with CDD-0102A (1.2 mg/kg) attenuated self-grooming and digging behavior in BTBR mice. Direct CDD-0102A infusions (1 µg) into the dorsal striatum reduced elevated digging behavior in BTBR mice. In contrast, CDD-0102A injections in the frontal cortex were not effective.

Conclusions: The results suggest that treatment with a partial M1 muscarinic receptor agonist may reduce repetitive behaviors and restricted interests in autism in part by stimulating striatal M1 muscarinic receptors.

Keywords: Autism; BTBR; behaviors; learning; repetitive muscarinic receptor.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Autism Spectrum Disorder / drug therapy*
  • Cholinergic Agents
  • Disease Models, Animal
  • Female
  • Grooming / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Oxadiazoles
  • Pyrimidines
  • Receptor, Muscarinic M1 / agonists*
  • Reversal Learning / drug effects*
  • Stereotyped Behavior / drug effects*


  • Cholinergic Agents
  • Oxadiazoles
  • Pyrimidines
  • Receptor, Muscarinic M1
  • 5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine