Pharmacological Blockade of Adenosine A but Not A Receptors Enhances Goal-Directed Valuation in Satiety-Based Instrumental Behavior.

The balance and smooth shift between flexible, goal-directed behaviors and repetitive, habitual actions are critical to optimal performance of behavioral tasks. The striatum plays an essential role in control of goal-directed versus habitual behaviors through a rich interplay of the numerous neurotransmitters and neuromodulators to modify the input, processing and output functions of the striatum. The adenosine receptors (namely AR and AR), with their high expression pattern in the striatum and abilities to interact and integrate dopamine, glutamate and cannabinoid signals in the striatum, may represent novel therapeutic targets for modulating instrumental behavior.

Habit Formation after Random Interval Training Is Associated with Increased Adenosine A Receptor and Dopamine D Receptor Heterodimers in the Striatum.

Striatal adenosine A receptors (ARs) modulate striatal synaptic plasticity and instrumental learning, possibly by functional interaction with the dopamine D receptors (DRs) and metabotropic glutamate receptors 5 (mGluR5) through receptor-receptor heterodimers, but evidence for these interactions is lacking. Using proximity ligation assay (PLA), we studied the subregional distribution of the AR-DR and AR-mGluR5 heterodimer complexes in the striatum and their adaptive changes over the random interval and random ratio training of instrumental learning. After confirming the specificity of the PLA detection of the AR-DR heterodimers with the AR knockout and DR knockout mice, we detected a heterogeneous distribution of the AR-DR heterodimer complexes in the striatum, being more abundant in the dorsolateral than the dorsomedial striatum.

Aberrant adenosine A2A receptor signaling contributes to neurodegeneration and cognitive impairments in a mouse model of synucleinopathy.

Synucleinopathy is characterized by abnormal accumulation of misfolded α-synuclein (α-Syn)-positive cytoplasmic inclusions and by neurodegeneration and cognitive impairments, but the pathogenesis mechanism of synucleinopathy remains to be defined. Using a transmission model of synucleinopathy by intracerebral injection of preformed A53T α-Syn fibrils, we investigated whether aberrant adenosine A2A receptor (A2AR) signaling contributed to pathogenesis of synucleinopathy. We demonstrated that intra-hippocampal injection of preformed mutant α-Syn fibrils triggered a striking and selective induction of A2AR expression which was closely co-localized with pSer129 α-Syn-rich inclusions in neurons and glial cells of hippocampus.