An Essential Role for Adenosine Signaling in Alcohol Abuse

Christina      L. Ruby; Chelsea      A. Adams; Emily      J. Knight; Hyung      Wook Nam; Doo-Sup      Choi

doi:10.2174/1874473711003030163

Abstract

In the central nervous system (CNS), adenosine plays an important role in regulating neuronal activity and modulates signaling by other neurotransmitters, including GABA, glutamate, and dopamine. Adenosine suppresses neurotransmitter release, reduces neuronal excitability, and regulates ion channel function through activation of four classes of G protein-coupled receptors, A1, A2A, A2B, and A3. Central adenosine levels are largely controlled by nucleoside transporters, which transport adenosine across the plasma membrane. Adenosine has been shown to modulate cortical glutamate signaling and ventral-tegmental dopaminergic signaling, which are involved in several aspects of alcohol use disorders. Acute ethanol elevates extracellular adenosine levels by selectively inhibiting the type 1 equilibrative nucleoside transporter, ENT1. Raised adenosine levels mediate the ataxic and sedative/hypnotic effects of ethanol through activation of A1 receptors in the cerebellum, striatum, and cerebral cortex. Recently, we have shown that pharmacological inhibition or genetic deletion of ENT1 reduces the expression of excitatory amino acid transporter 2 (EAAT2), the primary regulator of extracellular glutamate, in astrocytes. These lines of evidence support a central role for adenosinemediated glutamate signaling and the involvement of astrocytes in regulating ethanol intoxication and preference. In this paper, we discuss recent findings on the implication of adenosine signaling in alcohol use disorders.

Keywords: Adenosine, alcoholism, signaling, ataxia, glutamate, neuro-glial interaction, pharmacology, genetics, neurotransmission, excitatory glutamatergic, Dysregulation, neuroglia interactions, serotonin, dopamine, acetylcholine, post-synaptic neurons, ecto-nucleotidases, xanthine oxidase, equilibrative nucleoside transporters (ENTs), nitrobenzylthioionosine, autoreceptors, hippocampus, ethylcarboxamidoadenosine, theophylline, Embryonic Kidney, antibodies, postsynaptic neuronal membranes, glutamatergic, incoordination, Presynaptic, dimerization, paradoxically, carboxamidoadenosine, enprophylline, intermediary, postsynaptic neurons, SNARE, striatum, homeostatic, deprivation, psychiatric disorders, manifestations, intoxication, N6-cyclohexyladenosine, Drosophila, cheapdate mutation, forskolin, heterodimerization, CREB-mediated, NMDA receptor antagonists, hippocampal, adenosinergic, remodeling, astrocyte-to-neuron