Fig. 1.

Metabolic pathways and receptors of purinergic signaling involved in alcohol use disorders. In the cytosol, adenosine is synthesized from AMP by nucleotidase activity and transported to extracellular region via nucleoside transporter. Among several nucleoside transporters, ENT1 is known to regulate adenosine levels in response to ethanol. Adenosine is also converted from ATP extracellularly by ecto-nucleotidase activity. Extracellular adenosine binds to 4 different G-protein coupled adenosine receptors and is known to mediate ethanol-induced ataxia and sleep. ATP interacts with both ion channel named P2X receptors and G-protein coupled P2Y receptors. Among these, P2X4 receptors contain an ethanol-binding site (see Figure 2) and regulate ethanol drinking. cAMP, cyclic adenosine monophosphate; ENT, equilibrative nucleoside transporter; CNT, concentrative nucleoside transporter; VTA, ventral tegmental area.