Abstract
Repetitive behaviors with restricted interests is one of the core criteria for the diagnosis of autism spectrum disorder (ASD). Current pharmacotherapies that target the dopaminergic or serotonergic systems have limited effectiveness in treating repetitive behaviors. Previous research has demonstrated that administration of muscarinic cholinergic receptor (mAChR) antagonists can exacerbate motor stereotypies while mAChR agonists reduce stereotypies. The present study determined whether the mAChR agonist, oxotremorine affected repetitive behaviors in the BTBR T+ tf/J (BTBR) mouse model of autism. To test the effects of oxotremorine on repetitive behaviors, marble burying and grooming behavior were measured in BTBR mice and compared to that in C57BL/6J (B6) mice. The effects of oxotremorine on locomotor activity was also measured. Thirty minutes before each test, mice received an intraperitoneal (ip) injection of saline, 0.001 mg or 0.01 mg of oxotremorine methiodide. Saline- treated BTBR mice exhibited increased marble burying and self-grooming behavior compared to that of saline-treated B6 mice. Oxotremorine significantly reduced marble burying and self-grooming behavior in BTBR mice, but had no significant effect in B6 mice. In addition, oxotremorine did not affect locomotor activity in BTBR mice, but significantly reduced locomotor activity in B6 mice at the 0.01 mg dose. These findings demonstrate that activation of mAChRs reduces repetitive behavior in the BTBR mouse and suggest that treatment with a mAChR agonist may be effective in reducing repetitive behaviors in ASD.
Highlights
Autism spectrum disorders (ASDs) represent a cluster of neurodevelopmental disorders characterized by social and communicative impairments, as well restricted interests and repetitive behaviors (RRBs)
Comparable to that observed in ASD, BTBR mice exhibited increased repetitive behaviors compared to that of B6 mice
The increased repetitive behaviors in BTBR mice included both elevated self-grooming and marble burying as observed in past studies (Yang et al, 2007; Silverman et al, 2010; Gould et al, 2011; Pearson et al, 2011; Amodeo et al, 2012)
Summary
Autism spectrum disorders (ASDs) represent a cluster of neurodevelopmental disorders characterized by social and communicative impairments, as well restricted interests and repetitive behaviors (RRBs). Lower order RRBs involve repetitive manipulation of objects, stereotyped movements or repetitive self-injurious behavior (Lam and Aman, 2007). Atypical antipsychotics have food and drug administration (FDA) indications for treating irritability but not the core features of ASD (McPheeters et al, 2011). Recent gene networks that confer risk for ASD include genes related to cholinergic transmission and these are highly expressed in the brain (Voineagu et al, 2011; Ben-David and Shifman, 2012; Lee et al, 2012). Anti-psychotic treatments which have significant muscarinic receptor antagonism, e.g., quetiapine, can exacerbate symptoms in ASD (Martin et al, 1999; Hardan et al, 2005). Treatments that increase muscarinic cholinergic receptor (mAChR) transmission may reduce core symptoms in ASD
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