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

Abstract

Repetitive behaviors are diagnostic for autism spectrum disorder (ASD) and commonly observed in other neurodevelopmental disorders. Currently, there are no effective pharmacological treatments for repetitive behavior in these clinical conditions. This is due to the lack of information about the specific neural circuitry that mediates the development and expression of repetitive behavior. Our previous work in mouse models has linked repetitive behavior to decreased activation of the subthalamic nucleus, a brain region in the indirect and hyperdirect pathways in the basal ganglia circuitry. The present experiments were designed to further test our hypothesis that pharmacological activation of the indirect pathway would reduce repetitive behavior. We used a combination of adenosine A1 and A2A receptor agonists that have been shown to alter the firing frequency of dorsal striatal neurons within the indirect pathway of the basal ganglia. This drug combination markedly and selectively reduced repetitive behavior in both male and female C58 mice over a six-hour period, an effect that required both A1 and A2A agonists as neither alone reduced repetitive behavior. The adenosine A1 and A2A receptor agonist combination also significantly increased the number of Fos transcripts and Fos positive cells in dorsal striatum. Fos induction was found in both direct and indirect pathway neurons suggesting that the drug combination restored the balance of activation across these complementary basal ganglia pathways. The adenosine A1 and A2A receptor agonist combination also maintained its effectiveness in reducing repetitive behavior over a 7-day period. These findings point to novel potential therapeutic targets for development of drug therapies for repetitive behavior in clinical disorders.

A Multi-Target and Multi-Channel Mechanism of Action for Jiawei Yinhuo Tang in the Treatment of Social Communication Disorders in Autism: Network Pharmacology and Molecular Docking Studies

“…e activation balance of complementary basal ganglia pathways is related to FOS expression in the dorsal striatum. Reduced activation causes repetitive ASD behavior, which includes decreased glutamatergic neurotransmitter transmission, decreased metabolic activity of neurons in the subthalamic nucleus, and decreased dendritic spine density [51,52]. CASP3 (caspase-3) is a protease that can cleave DNA and promote cell apoptosis.…”

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).…”

Adenosine Receptors in Neuropsychiatric Disorders: Fine Regulators of Neurotransmission and Potential Therapeutic Targets

“…However, when the two agonists were used in combination, a significant reduction in repetitive behavior was observed [100]. This effect was accompanied by an increase in Fos transcription in the dorsal striatum, wherein Fos transcription was used as an index of neuronal activity in both direct and indirect pathway neurons [100]. The reduction of repetitive behavior with the co-administration of CGS 21680 and CPA was previously reported in deer mice, which develop high levels of repetitive motor behaviors when reared in a standard laboratory environment [101].…”

“…In C58 mice, the administration of the A 1 AR agonist CPA or the A 2A AR agonist CGS 21680 did not reduce repetitive behavior. However, when the two agonists were used in combination, a significant reduction in repetitive behavior was observed [100]. This effect was accompanied by an increase in Fos transcription in the dorsal striatum, wherein Fos transcription was used as an index of neuronal activity in both direct and indirect pathway neurons [100].…”