An essential role for adenosine signaling in alcohol abuse

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, A(1), A(2A), A(2B), and A(3). Central adenosine are largely controlled by nucleoside transporters, which transport adenosine levels 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 A(1) 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 adenosine-mediated 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.

Fig. 1

Adenosine-mediated glutamate signaling in the striatum. In astrocytes, adenosine (Ado) is synthesized from AMP (from ATP breakdown) by endo-nucleotidase (endo-NTase) activity and transported to the extracellular region via equilibrative nucleoside transporters (ENTs). ATP released by neurons or astrocytes can also be converted to adenosine extracellularly by ecto-nucleotidase (ecto-NTase) activity. Adenosine binds to G-protein coupled receptors, including presynaptic A₁ receptors (A₁R), known to inhibit glutamate release. A₁ and A_2A adenosine receptors are also located postsynaptically, where they modulate neuronal excitability. Presynpatic neurons synthesize glutamate (Glu) from glutamine (Gln), via glutaminase and then package glutamate into vesicles for release using vesicular glutamate transporters (VGLUTs). Once released into synaptic clefts, glutamate activates ionotropic (iGluR) and metabotropic (mGluR) receptors, and is removed within a few milliseconds by excitatory amino acid transporters (EAATs) located in astrocytes. Astrocytes then convert glutamate into glutamine via glutamine synthetase, and recycle it back to presynaptic neurons.

Fig. 2

Altered glutamate signaling in ENT1 null mice. Deletion or inhibition of ENT1 increases extracellular glutamate levels by inhibiting presynaptic adenosine A1 receptors (A₁R) and/or astrocytic excitatory amino acid transporter type 2 (EAAT2). Our recent behavioral, biochemical, and microdialysis studies suggest that increased resistance to acute ethanol intoxication is related to increased glutamate signaling in ENT1 null mice. Resultant decreases in CREB activity might be associated with increased ethanol drinking in mice lacking ENT1.