The adenosine A_2A receptor agonist, CGS 21680, attenuates a probabilistic reversal learning deficit and elevated grooming behavior in BTBR mice

Restricted interests and repetitive behaviors (RRBs) are a defining feature of autism spectrum disorder (ASD). To date there are limited options for treating this core symptomology. Treatments that stimulate adenosine A_2A receptors may represent a promising approach for reducing RRBs in ASD. This is because A_2A receptors are expressed on striatal neurons of the basal ganglia indirect pathway. Under activation of this pathway has been associated with RRBs while activation of A_2A receptors leads to increased activity of the indirect basal ganglia pathway. The present studies investigated whether acute, systemic treatment with CGS21680, an A_2A receptor agonist attenuates elevated self-grooming and a probabilistic reversal learning deficit in the BTBR T+ Itpr3^tf/J (BTBR) mouse model of idiopathic autism. The effects of this treatment were also investigated in C57BL/6J (B6) mice as a comparison strain. Using a spatial reversal learning test with 80/20 probabilistic feedback, comparable to one in which ASD individuals exhibit deficits, CGS 21680 (0.005 and 0.01mg/kg) attenuated a reversal learning deficit in BTBR mice. Enhancement in probabilistic reversal learning performance resulted from CGS 21680 improving the consistent maintenance of new adaptive behavioral choice patterns after reversal. CGS 21680 at 0.01 mg, but not 0.005 mg, also reduced self-grooming behavior in BTBR mice. CGS 21680 did not affect self-grooming or reversal learning in B6 mice. These findings demonstrate that A_2A receptor agonists may be a promising receptor target in the treatment of RRBs in ASD. Autism Res 2018, 11: 223–233.