Adenosine Signaling in Anxiety

Adenosine is a ubiquitous nucleoside that acts as a neuromodulator in the central nervous system (CNS), controlling neuronal excitability, modulating neurotransmitter release, and regulating ion channel function through four subtypes of G-protein-coupled receptors (GPCRs), A1, A2A, A2B, and A3. Adenosine receptor agonists are anxiolytic while adenosine A1 and A2A receptor antagonists such as caffeine can cause anxiety. Pharmacological and genetic manipulation of A1 and A2A receptors suggests that each contributes separately to the regulation of anxious states. However, a growing body of evidence argues for a particularly important role of the A2A receptor. Single nucleotide polymorphisms (SNPs) in the A2A receptor gene (ADORA2A) are associated with anxiety in psychiatric disorders and in response to stimulants. Additionally, genetic knockout of the type 1 equilibrative nucleoside transporter (ENT1), which plays an essential role in controlling adenosine levels in the brain, reduces anxiety in rodents, while inhibition of ENT1 may mediate the anxiolytic effects of benzodiazepines and alcohol. In this chapter, we discuss the emerging role of adenosine signaling in anxiety, with special focus on the A1 and A2A receptors and ENT1. This chapter also includes how caffeine and alcohol regulate anxiety through adenosine signaling.