Efficacy of Risperidone in an Insulin-Resistant Mouse Model of Hyperactivity and Deficient Sociability

Background: Many patients with autism are given risperidone, an atypical antipsychotic, to control restrictive-repetitive behaviors, impulsivity and aggression. Risperidone has tranquilizing properties, mediated primarily by its actions as an antagonist at dopamine D₂ receptors, and risperidone does little to promote social interaction behavior in most patients. Unfortunately, long-term use of risperidone often produces serious metabolic side-effects including increased appetite, obesity, and early onset of type II diabetes.    In doing so, risperidone may also modify the dopaminergic response of patients by elevating their insulin levels.  This is because insulin enhances the function of dopamine transporters, making them more efficient at removing dopamine from brain extracellular fluid.

Objectives: We hypothesize that elevated insulin levels will enhance the expression and function of dopamine transporters and D₂ receptors, and mute behavioral responses to risperidone treatment.  This hypothesis was tested in mice with natural mutations that alter circulating levels of insulin.  Since autism is 5x more prevalent in males than in females, and because insulin levels in male mice were more responsive to these genetic modulators, only male mice were used in this study. 

Methods: Black-and-tan Brachyury Tufted (BTBR T+Itpr³tf/J mice, crossed with C57BL/6 mice yield F1 hybrid offspring that are socially impaired and insulin resistant.  The F1 mice have increased abdominal adiposity, and elevated insulin levels relative to either parent strain by 10 weeks of age.  Levels of insulin are greatest in F1 hybrids > BTBR > C57BL/6 mice.  These mice were treated acutely with risperidone (0.01 mg/kg) or vehicle and behaviorally tested in three-chamber sociability and marble burying tests.  Their social dominance was also compared in a tube test.  Brains from naïve mice were also used in-vitro in radioligand binding and uptake studies for the dopamine transporter and D2 receptor to compare binding site density and functional response in mice within a physiologically-relevant range of insulin levels.

Results: F1 mice were socially deficient in three-chamber tests, and were more impulsive than either parent strain in a social dominance test. Their social and repetitive behavior was not improved by risperidone administered acutely. In fact, risperidone treatment was less effective in BTBR and F1 hybrid mice at reducing marble burying than it was in C57BL/6 mice.  [³H] WIN 35,428 binding to dopamine transporters was similar among strains, but [³H] dopamine uptake was significantly increased in BTBR mice. [³H] dopamine binding sites were higher in BTBR and F1 hybrids than in C57BL/6 mice.

Conclusions: Dopamine transmission may be suppressed in F1 and BTBR mice by elevated insulin levels, which may alter their responsiveness to risperidone. As evidence of this, marble burying in F1 mice was unaffected by an acute risperidone treatment, while the same dose of risperidone reduced this in C57BL/6 mice. The BTBRxBL6 F1 mouse appears to be a useful physiological model for investigation of long-term drug treatment effects on the social brain and on glucose metabolism.