Influence of stimulant-induced hyperactivity on social approach in the BTBR mouse model of autism

Abstract

Translational research is needed to discover pharmacological targets and treatments for the diagnostic behavioral domains of autism spectrum disorders. Animal models with phenotypic relevance to diagnostic criteria offer clear experimental strategies to test the efficacy and safety of novel treatments. Antagonists of mGluR5 receptors are in clinical trials for Fragile X syndrome and under investigation for the treatment of autism spectrum disorders. However, in preclinical studies of mGluR5 compounds tested in our laboratory and others, increased locomotion following mGluR5 modulation has been observed. Understanding the influence of general activity on sociability and repetitive behaviors will increase the accuracy of interpretations of positive outcomes measured from pharmacological treatment that produces locomotor activating or sedating effects. In the present studies, dose-response curves for d-amphetamine (AMPH)-induced hyperlocomotion were similar in standard B6 mice and in the BTBR mouse model of autism. AMPH produced significant, robust reductions in the high level of repetitive self-grooming that characterizes BTBR, and also reduced the low baseline grooming in B6, indicating that AMPH-induced hyperlocomotion competes with time spent engaged in self-grooming. We then tested AMPH in B6 and BTBR on the 3-chambered social approach task. One component of sociability, the time spent in the chamber with the novel mouse, in B6 mice was reduced, while the sniffing time component of sociability in BTBR mice was enhanced. This finding replicated across multiple cohorts treated with AMPH and saline vehicle. In-depth analysis revealed that AMPH increased the number and decreased the duration of sniffing bouts in BTBR, suggesting BTBR treated with AMPH mostly engaged in brief sniffs rather than true social interactions with the novel mouse during the social approach task. Our data suggest that compounds with stimulant properties may have some direct benefits on reducing repetitive behaviors in autism spectrum disorders, particularly in the subset of autistic individuals with hyperactivity.

Repetitive behavior profile and supersensitivity to amphetamine in the C58/J mouse model of autism

“…Further, supersensitive responses to amphetamine challenge can reveal underlying abnormalities in dopamine function induced by genetic vulnerability, environmental stressors, or repeated exposure to psychostimulants [53–56]. Increased locomotor responses to amphetamine have been observed in mouse models of neurodevelopmental disorders, such as the BTBR T+ tf /J strain [57], and in mice with conditional expression of a human DISC1 mutation [58]. In addition, we have previously reported supersensitivity to amphetamine effects on acoustic startle amplitudes and prepulse inhibition in Grin1 neo/neo mice [27].…”

Anxiety- and depression-like behavior in mice lacking the CD157/BST1 gene, a risk factor for Parkinson's disease

“…The open field test measures locomotion and anxious behaviors (Silverman et al, 2013). The open field box consisted of a square box (600 × 600 × 200 mm), covered with polypropylene sheets inside the wooden box.…”

The BTBR mouse model of idiopathic autism – Current view on mechanisms

“…Several psychostimulant drugs, acting at the dopaminergic circuitry, affect the behavior of BTBR mice. D-amphetamine increased the number but decreased the duration of social sniffing and reduced the excessive grooming (Silverman et al 2013 b). 3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) as well as methamphetamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, a neurotoxin destroying dopaminergic neurons) did not affect BTBR locomotor activity, while (−)-trans-Δ9-tetrahydrocannabinol (THC) reduced spontaneous, repetitive wheel running in this strain (Onaivi et al 2011).…”