Targeting Dopamine D₂, Adenosine A_2A, and Glutamate mGlu₅ Receptors to Reduce Repetitive Behaviors in Deer Mice

Abstract

Repetitive behaviors are seemingly purposeless patterns of behavior that vary little in form and are characteristic of many neurodevelopmental, psychiatric, and neurologic disorders. Our work has identified an association between hypofunctioning of the indirect basal ganglia pathway and the expression of repetitive behavior in the deer mouse model. In this study, we targeted indirect pathway cells of the striatum with single drugs and drug combinations that bind to dopamine D 2 , adenosine A 2A , and glutamate mGlu 5 receptors. These receptors function both individually and as receptor heteromers. We found that only the triple drug cocktail (L-741,6261CGS216801CDPPB) that was designed to increase striatal indirect basal ganglia pathway cell function reduced repetitive behavior in adult male deer mice. No single drug or double drug combinations were effective at selectively reducing repetitive behavior. We found this triple drug cocktail reduced repetitive behavior in both short-acting and long-acting formulations and was effective throughout 7 days of daily administration. Conversely, another triple drug cocktail (quinpirole1SCH582611MTEP) that was designed to further reduce striatal indirect basal ganglia pathway cell function caused a significant increase in repetitive behavior. Significant and behaviorally selective effects on repetitive behavior were only achieved with the triple drug cocktails that included doses of L-741,626 and quinpirole that have off-target effects (e.g., dopamine D 3 receptors). These data further a role for decreased indirect basal ganglia pathway activation in repetitive behavior and suggest that targeting these receptors and/or heteromeric complexes on the indirect pathway neurons of the striatum may offer pharmacotherapeutic benefit for individuals with repetitive behavior disorders.

Reduction of repetitive behavior by co-administration of adenosine receptor agonists in C58 mice

“…Our previous findings using two mouse models, deer mice and C58 mice, have implicated reduced STN activation in the mediation of repetitive behavior (Lewis et al, 2018;Lewis et al, 2019;Tanimura et al, 2011;Tanimura et al, 2010). In Tanimura et al (2010) and Lewis et al (2019), we provided evidence for pharmacological agents selected to increase indirect basal ganglia pathway activity to reduce repetitive behavior in deer mice. The present findings provide important generalizability to our findings by showing that the adenosine A1 and A2A receptor agonist combination substantially reduced repetitive behavior in C58 mice.…”

Drug development for Autism Spectrum Disorder (ASD): Progress, challenges, and future directions

“…Activation of the ACC and inferior frontal gyrus discriminated between minimal versus clinical improvement in repetitive behavior with citalopram in two cases ( Dichter et al, 2010 ). Preclinical data suggest deficits in basal ganglia indirect pathway activation are related to RRBs ( Lewis et al, 2019 ), but clinical studies have not examined possible relationships between RRBs and metabolite concentrations, despite accumulating evidence of reduced regional cortical GABA concentrations in ASD in most ( Rojas et al, 2014 ; Drenthen et al, 2016 ; Port et al, 2017 ; Puts et al, 2017 ) but not all studies ( Carvalho Pereira et al, 2018 ). Probes of basal ganglia-mediated inhibitory control deficits may emerge as intermediate targets for RRBs.…”

Differential consequences of habitual responding in a mouse model of repetitive behavior.

“…For example, previous studies in animal models of RRB implicate hypoactivation of the STN in the expression of repetitive motor behavior using cytochrome oxidase and dendritic spine density as measures (Bechard et al, 2016; Lewis et al, 2018). Recent studies also suggest that pharmacologically increasing indirect pathway function markedly reduces repetitive motor behavior in C58 and deer mouse models (Lewis, Primiani, & Muehlmann, 2019; Lewis, Rajpal, & Muehlmann, 2019). Moreover, there is evidence from multiple studies suggesting that habitual responding is altered by the indirect pathway signaling (Furlong, Supit, Corbit, Killcross, & Balleine, 2017; O’Hare et al, 2016; Vicente, Galvão-Ferreira, Tecuapetla, & Costa, 2016; Yin et al, 2009).…”