Pharmacological Treatment of Repetitive Behavior in the Context of Development

Background: Repetitive behavior is a diagnostic criterion of Autism Spectrum Disorder that presents is a variety of ways, including motor stereotypy, insistence on sameness, and circumscribed interests. Our work utilizes mouse models of repetitive behavior in order to elucidate the neuropathology that mediates the behavioral disorder and to find novel drug targets for treatment. These models include the inbred C58 mouse (Mus) and the outbred deer mouse (Peromyscus). These models share a robust repetitive behavior phenotype that includes hindlimb jumping and backward somersaulting. Data from both of these models have revealed reduced activation of the indirect basal ganglia pathway. We have created a drug cocktail that specifically targets a heteromeric receptor complex found only on indirect basal ganglia pathway neurons of the striatum, made up of a dopamine D2 receptor antagonist, an adenosine A2a agonist, and a glutamate mGluR5 positive allosteric modulator. We have shown previously that acute and chronic administrations of this drug cocktail reduce repetitive behavior in both adult C58 mice and adult deer mice, whereas single or double drug combinations do not.

Objectives: To test the efficacy of the drug cocktail to reduce repetitive behavior in young mice, we administered subcutaneous injections of the drug cocktail each day for 13 days in two cohorts of mice. One cohort began treatment the day following weaning (PND 22); the other cohort began treatment during adolescence (PND 42). An additional objective was to determine whether early and repeated drug treatment could alter the developmental trajectory of the repetitive behavior and to confirm that early drug exposure had no adverse consequences on body weight.

Methods: Experiment 1: Deer mice were administered either vehicle (peanut oil) or the triple drug cocktail each morning for 13 days starting on PND 22. The drug cocktail was made up of L-421,626 (D2 antagonist) at 5 mg/kg, CGS21680 (A2a agonist) at 0.3 mg/kg, and CDPPB (mGluR5 positive allosteric modulator) at 15 mg/kg. Mice were tested for their repetitive behavior on PNDs 22, 25, 28, 31, 34, 42, 49, 56, and 63. Experiment 2: Deer mice were administered either vehicle or the triple drug cocktail each morning for 13 days starting on PND 42. Mice were tested for their repetitive behavior on PNDs 42, 45, 48, 51, 54, 56, and 63.

Results: Experiment 1: The triple drug cocktail significantly and selectively reduced repetitive behavior on each of the testing days during the 13 day repeated drug treatment phase. In addition, a continued reduction in repetitive behavior was seen in the previously-treated group for up to 21 days following discontinuation. Experiment 2: The triple drug cocktail significantly reduced repetitive behavior in the adolescent mice during the 13 day treatment phase. This effect, unfortunately, did not last beyond the repeated drug treatment phase. Body weights were not different between groups for either experiment.

Conclusions: We can successfully and selectively treat repetitive behavior in young mice with our triple drug cocktail without adverse change in body weight. Very early drug treatment can also change the trajectory of repetitive behavior development.