Implication of the purinergic system in alcohol use disorders

In the central nervous system, adenosine and adenosine 5'-triphosphate (ATP) play an important role in regulating neuronal activity as well as controlling other neurotransmitter systems, such as, GABA, glutamate, and dopamine. Ethanol increases extracellular adenosine levels that regulate the ataxic and hypnotic/sedative effects of ethanol. Interestingly, ethanol is known to increase adenosine levels by inhibiting an ethanol-sensitive adenosine transporter, equilibrative nucleoside transporter type 1 (ENT1). Ethanol is also known to inhibit ATP-specific P2X receptors, which might result in such similar effects as those caused by an increase in adenosine. Adenosine and ATP exert their functions through P1 (metabotropic) and P2 (P2X-ionotropic and P2Y-metabotropic) receptors, respectively. Purinergic signaling in cortex-striatum-ventral tegmental area (VTA) has been implicated in regulating cortical glutamate signaling as well as VTA dopaminergic signaling, which regulates the motivational effect of ethanol. Moreover, several nucleoside transporters and receptors have been identified in astrocytes, which regulate not only adenosine-ATP neurotransmission, but also homeostasis of major inhibitory-excitatory neurotransmission (i.e., GABA or glutamate) through neuron-glial interactions. This review will present novel findings on the implications of adenosine and ATP neurotransmission in alcohol use disorders.