Pharmacological Treatment of Repetitive Behavior in Deer Mice: Targeting Striatal Heteromeric Receptor Complexes

Background: Restricted repetitive behaviors are extremely common in many neurodevelopmental disorders and are one of the three diagnostic criteria for autism. The deer mouse (Peromyscus maniculatus) model of repetitive behavior is a particularly useful model because the repetitive motor behavior develops early, persists through much of the lifetime of the animal, and occurs spontaneously (i.e. without a specific pharmacological or environmental challenge). Preliminary evidence from our laboratory indicates that the repetitive motor behavior exhibited by these mice is a result of a neurobiological imbalance of activation between the direct and indirect pathways of the basal ganglia. The direct and indirect basal ganglia pathways are thought to work in an antagonistic fashion; activation of the direct pathway enhances basal ganglia output and promotes motor behavior whereas activation of the indirect pathway reduces basal ganglia output and inhibits movement. The imbalance between the direct and indirect pathways in the deer mice seems to be caused by decreased activation of the indirect pathway that allows direct pathway activation to over-excite the cortex. On neurons of the direct and indirect pathways there are heteromeric complexes of receptors that exhibit further antagonistic relationships. These receptor complexes include dopamine D1 and adenosine A1 receptors on direct pathway neurons and dopamine D2, adenosine A2A, and glutamate mGluR5 receptors on indirect pathway neurons. 

Objectives: 1) to assess whether drugs affecting these individual dopamine, adenosine, or glutamate receptor subtypes are effective at reducing repetitive behavior in deer mice; 2) to determine whether combinations of these drugs are more effective at reducing repetitive behavior (and hence increasing indirect pathway activation) than any of the drugs are alone; 3) to improve our understanding of the individual roles of dopamine D2, adenosine A2A, and glutamate mGluR5 receptors in the functioning of the indirect basal ganglia pathway.

Methods: We examined the effects of an adenosine A2A agonist (CGS21680), a dopamine D2 antagonist (L-741,626), and a glutamate mGluR5 positive allosteric modulator (CDPPB) individually and in combination on repetitive behavior in deer mice.

Results: When administered individually, the adenosine A2A agonist, the dopamine D2 antagonist, and the mGluR5 positive allosteric modulator do not significantly reduce repetitive behavior in deer mice. When co-administered, however, the A2A agonist and D2 antagonist significantly decrease the rate of stereotypy in deer mice. We are presently continuing this series of experiments by adding the mGluR5 positive allosteric modulator to the drug cocktail to assess whether there is a further reduction in repetitive behavior.

Conclusions: These data further suggest that decreased indirect pathway activation may mediate the expression of repetitive behavior and that targeting the heteromeric receptor complexes on the indirect pathway neurons may offer pharmacotherapeutic benefit for individuals with neurodevelopmental disorders who exhibit restrictive repetitive behavior.