Adenosine and Dopamine / part 2

Adenosine receptor subtypes present in the brain include A₁, A_2A, A_2B, and A₃. The binding affinities of A_2BAR and A₃AR are in the micromolar range, making it unlikely that they play a major role in neurotransmission under physiologic conditions. In contrast, the ligand-binding affinities of A₁AR and A_2AAR are both in the physiologically relevant nanomolar range. As a result, A₁AR and A_2AAR are viewed as the predominant targets of caffeine-induced AR antagonism in brain. A₁AR and A_2AAR are distributed differently throughout the brain. A₁AR are highly expressed in hippocampus, cortex, and cerebellum, with relatively low expression in the basal ganglia, whereas A_2AAR are expressed primarily in striatum, nucleus accumbens, and olfactory tubercle.

A₁AR are coupled to inhibitory G protein (G_i). When stimulated, they inhibit adenylyl cyclase (AC), promote potassium efflux, promote hyperpolarization of neuronal membranes, restrict calcium influx, and reduce neuronal excitability. Most of the A₁AR in striatum are located presynaptically and act to modulate the release of glutamate and dopamine. Blockade and stimulation of A₁AR respectively augments and reduces glutamate release in striatum. A₁AR suppress dopamine release directly and through an indirect effect on glutamate-induced dopamine release and thereby modulate the extracellular dopamine concentration and D₁R- and D₂R-mediated dopaminergic neurotransmission.
In striatum, presynaptic A_2AAR modulate glutamate release.
However, striatal A_2AAR are predominantly postsynaptic, are coupled to excitatory G protein (G_olf) and act to promote neuronal activity. A selective A_2AAR agonist promotes the phosphorylation of postsynaptic targets of AC-cAMP-protein kinase A (PKA) in striatal slices in a time- and dose-dependent manner, whereas presynaptic PKA substrates are unresponsive, consistent with the postsynaptic localization of A_2AAR. Furthermore, in vivo administration of caffeine, a nonselective AR antagonist, reduces phosphorylation of postsynaptic proteins.
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