Oxotremorine treatment reduces repetitive behaviors in BTBR T+ tf/J mice

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.

Neurobiology of rodent self-grooming and its value for translational neuroscience

“…The inbred BTBR T + Itpr3 tf / J (BTBR) mouse strain, which exhibits agenesis of the corpus callosum, displays several aberrant behaviours that resemble symptoms of ASD, including social deficits, anxiety and general behavioural inflexibility 19,95,41–43 . Peer rearing with a different (‘non-ASD’) strain improved social deficits in BTBR mice but did not improve their repetitive self-grooming 96 , raising the possibility that different ASD behavioural domains may be regulated by distinct brain mechanisms.…”

“…However, increased self-grooming in these animals can be corrected pharmacologically. For example, cholinergic agents (which may be useful in correcting postulated cholinergic deficits in ASD 97,98 and/or some of its clinical symptoms 99 ) reduce self-grooming 19 and other ASD-like behaviours 100 in BTBR mice. Furthermore, repetitive self-grooming behaviour in BTBR mice is rescued by the inhibition of glutamatergic metabotropic mGluR5 receptors 90,101 and by the stimulation of NMDA receptors by d -cycloserine 102 (which has also been shown to ameliorate some behavioural deficits in individuals with ASD 103,104 ).…”

“…For example, mice that lack both the ephrin A2 and the ephrin A3 receptors display robust repetitive self-grooming in addition to motor retardation, increased prepulse inhibition and social deficits (impaired social interaction and preference), thereby paralleling in their phenotypes some of the clinical symptoms of ASD 115 . The search for novel molecular anti-ASD drug targets is a recognized priority 19,93,106,116,117 , and the utility of grooming-based analyses for exploring novel candidate pathways of this disorder (for example, ephrin A receptor agonists) continues to emerge.…”

“…Some of these may be useful in modelling self-grooming-related symptoms of OCD, including compulsive hand-washing 19,22,25 and obsessive hair-pulling 126–128,129 (TABLE 2). For example, serotonergic drugs that are effective in treating some symptoms of clinical OCD 71 are also successful in reducing aberrant self-grooming phenotypes in some of these mutant mice (TABLE 3).…”

Behavioral and Neuroanatomical Phenotypes in Mouse Models of Autism

“…Repetitive behaviors in mice include unusually long bouts of self-grooming, digging, and burying foreign objects such as marbles. High levels of stereotyped or repetitive behaviors have been reported in mice with mutations in genes including Shank3 [15], 16p11.2 deletion [28,54], Cntnap2 [17], and Ephrin-A [27] in the inbred strains of BTBR [6,[55][56][57], C58/J [58], and in deer mice [59].…”