Consequences of cannabinoid and monoaminergic system disruption in a mouse model of autism spectrum disorders

Abstract

Autism spectrum disorders (ASDs) are heterogenous neurodevelopmental disorders characterized by impairment in social, communication skills and stereotype behaviors. While autism may be uniquely human, there are behavioral characteristics in ASDs that can be mimicked using animal models. We used the BTBR T+tf/J mice that have been shown to exhibit autism-like behavioral phenotypes to 1). Evaluate cannabinoid-induced behavioral changes using forced swim test (FST) and spontaneous wheel running (SWR) activity and 2). Determine the behavioral and neurochemical changes after the administration of MDMA (20 mg/kg), methamphetamine (10 mg/kg) or MPTP (20 mg/kg). We found that the BTBR mice exhibited an enhanced basal spontaneous locomotor behavior in the SWR test and a reduced depressogenic profile. These responses appeared to be enhanced by the prototypic cannabinoid, Δ(9)-THC. MDMA and MPTP at the doses used did not modify SWR behavior in the BTBR mice whereas MPTP reduced SWR activity in the control CB57BL/6J mice. In the hippocampus, striatum and frontal cortex, the levels of DA and 5-HT and their metabolites were differentially altered in the BTBR and C57BL/6J mice. Our data provides a basis for further studies in evaluating the role of the cannabinoid and monoaminergic systems in the etiology of ASDs.

Keywords: Autism; BTBR T+tf/J mice.; Behavior; Cannabinoid; MPTP; Monoamines; Psychostimulants; Δ9-THC.

Fig. (1).

The effects of psychostimulants (d-amphetamine, Methamphetamine and MDMA), and disruption of monoaminergic system by the neurotoxin (MPTP), in a mouse model of autism spectrum disorders. Panel A shows the basal motor activity of male and female BTBR and C57BL/J mice in the spontaneous wheel running (SWR) monitors; panel B is the effect of acute 10 min treatment with d-amphetamine (5.0 mg/kg) on the performance of male BTBR and the male controls, S129 and C57BL/6J mice. Panel C shows the effects of acute administration of methamphetamine (10 mg/kg), MDMA (20.0 mg/kg) and MPTP (20 mg/kg) in both male and female BTBR and C57BL/6J mice in comparison to their respective controls. The duration of the wheel running behavior was accessed over a 10 min period in all animals tested. * or ¶ represents statistical significance at p<0.05 as compared to the same gender.

Fig. (2).

Behavioral effects of BTBR, C57BL/6J and S129 mouse strains in the FST. Panel A shows the basal levels of performance indicated by the time and number of immobility by the three mouse strains in the forced swim test model. Panel B is time and number of immobility after acute treatment of the mouse strains with Δ⁹-THC (1 and 10 mg/kg) in comparison to vehicle treated controls. Panel C shows the influence of acute treatment of the mouse strains with Δ⁹-THC (1 and 10 mg/kg) in the spontaneous wheel running activity monitors. * or + represents statistical significance at p<0.05 with strains and drug treatment in the behavioral measures.

Fig. (3).

Neurochemical analysis of dopamine (DA) and serotonin (5HT) levels in striatum and frontal cortex in BTBR and C57BL/6J male and female mice following a single day three times administration of either saline, methamphetamine (10 mg/kg), MDMA (20 mg/kg) or MPTP (20 mg/kg). Regional brain areas were dissected 2 days later. Since there were no significant sex differences the data was collapsed on the variable sex. Panel A is the striatal dopamine level in BTBR relative to C57BL/6J mice. Panel B is the frontal cortex dopamine level in the two strains of mice. Panel C is the striatal serotonin level. *Represents statistical significance at p<0.05 using a least squares means analysis. Significance tests were performed between the two strains of mice for each of the treatments independently.