Indirect basal ganglia pathway mediation of repetitive behavior: attenuation by adenosine receptor agonists

Repetitive behaviors are diagnostic for autism and common in related neurodevelopmental disorders. Despite their clinical importance, underlying mechanisms associated with the expression of these behaviors remain poorly understood. Our lab has previously shown that the rates of spontaneous stereotypy in deer mice (Peromyscus maniculatus) were negatively correlated with enkephalin content, a marker of striatopallidal but not striatonigral neurons. To investigate further the role of the indirect basal ganglia pathway, we examined neuronal activation of the subthalamic nucleus (STN) using cytochrome oxidase (CO) histochemistry in high- and low-stereotypy mice. CO activity in STN was significantly lower in high-stereotypy mice and negatively correlated with the frequency of stereotypy. In addition, exposure to environmental enrichment, which attenuated stereotypy, normalized the activity of STN. Co-administration of the adenosine A(2A) receptor agonist CGS21680 and the A(1) receptor agonist CPA attenuated stereotypy dose-dependently. The significant reduction associated with the lowest dose of the drug combination tested was due to its effects on mice with lower baseline levels of stereotypy. Higher doses of the drug combination were required to show robust behavioral effects, and presumably requisite activation of the indirect pathway, in high-stereotypy mice. These findings support that decreased indirect pathway activity is linked to the expression of high levels of stereotypy in deer mice and that striatal A(1) and A(2A) receptors may provide promising therapeutic targets for the treatment of repetitive behaviors in neurodevelopmental disorders.