Implication of the purinergic system in alcohol use disorders

Abstract

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.

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.

Fig. 2

Molecular model of the rat P2X4R reveals a putative ethanol and IVM pocket. The model was built by threading the edited primary sequence onto the X-ray crystal structure of zebra fish P2X4R (Kawate et al., 2009). (A) A side view of the rat P2X4R showing the ectodomain and the six alpha helices of TM1 and TM2 segments of 3 different P2X4R subunits. Residues W46, W50 in the first alpha helix of one subunit as well as D331 and M336 in the final alpha helix of the adjacent subunit form a pocket that demonstrates a good fit for a molecule of ethanol (in pink) at the same scale. (B) A similar view of the rat P2X4R, but with a model of IVM (rendered in balls and sticks) inserted into a putative binding site in a position between the alpha helices like that described in nicotinic acetylcholine receptors (Sattelle et al., 2009). Figure taken from (Asatryan et al., 2010).