The role of adenosine receptors in mood and anxiety disorders

Abstract

Adenosine receptor subtypes, first described 40 years ago, are known to regulate diverse biological functions and have a role in various conditions, such as cerebral and cardiac ischemia, immune and inflammatory disorders and cancer. In the brain, they limit potentially dangerous over excitation, but also regulate mechanisms essential in sleep and psychiatric disorders. In this review, we discuss the role of adenosine receptors in mood and anxiety disorders. Activation of A 2A receptors is associated with increased depression-like symptoms, while increased A 1 receptors signaling elicits rapid antidepressant effects. Indeed, several lines of evidence demonstrate that the therapeutic effects of different non-pharmacological treatments of depression, like sleep deprivation and electroconvulsive therapy are mediated by A 1 receptor up-regulation or activation. In addition, A 1 receptors may also play a role in the antidepressant effects of transcranial direct current stimulation and deep brain stimulation. As a potential downstream mechanism, which facilitates the antidepressant effects of A 1 receptors, we propose a crosstalk between adenosinergic and glutamatergic systems mediated via synaptic plasticity protein Homer1a and a-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid receptors. Moreover, adenosine receptors are also involved in the control of circadian rhythms, sleep homeostasis and some neuroimmunological mechanisms, all of them implicated in mood regulation. Antagonists of adenosine receptors such as caffeine have general anxiogenic effects. In particular, A 2A receptors appear to have an important role in the pathophysiology of anxiety disorders. Taken together, the results discussed here indicate that the adenosinergic system is involved in both the etiology and the treatment of mood and anxiety disorders.

Purinergic Signaling and Related Biomarkers in Depression

“…The impact of adenosine on brain function is mainly dependent on the activity of A1 and A2A receptors, while limited action on central nervous system (CNS) functions has been shown for A2B and A3 receptors [14]. A1 receptors are the most abundant and homogenously distributed in the brain [7], with high expression levels in the cerebellum, hippocampus, cortex, and thalamus, whereas A2A receptors are highly expressed in striatopallidal neurons, with a lower presence in other brain regions [15,16]. The primary function of adenosine seems to be inhibitory neuromodulation, linked with a negative feedback to excitatory activity of glutamatergic synapses [17].…”

“…The primary function of adenosine seems to be inhibitory neuromodulation, linked with a negative feedback to excitatory activity of glutamatergic synapses [17]. Presynaptic A1 receptors inhibit the release of neurotransmitters, including glutamate, dopamine, serotonin, and acetylcholine, while postsynaptic receptors reduce neuronal signaling by hyperpolarization and excitability via regulation of potassium channels [16]. A2A receptors may enable adaptive responses in the regulation of synaptic plasticity.…”

Exercise-Induced Adaptations to the Mouse Striatal Adenosine System

“…Reductions to A 1 R and A 2A R protein expression Neural Plasticity could contribute to reduced efficacy of adenosine-mediated inhibition of dopamine activity in the striatum, which should be followed up in more detail by future studies. Indeed, changes in A 1 Rs and A 2A Rs that are dependent on physical activity status could affect therapeutic approaches for psychiatric and neurological diseases that involve abnormal dopamine signaling in the striatum, including addiction, depression, Parkinson's disease, and Huntington's disease, among many others [94][95][96][97][98][99][100][101][102][103][104]. Therefore, the current findings could be of importance for understanding the mechanisms contributing to exercise-improved cognitive function, as well as the prevention and treatment of mental health and neurobiological disorders that involve the striatum.…”

Rapid anti‐depressant‐like effects of ketamine and other candidates: Molecular and cellular mechanisms

“…Reviewing data from human, animal and neuronal cell, both low‐dose SD and ketamine could regulate circadian rhythms 150 . It is hypothesized that A1R ameliorates the depression‐like behaviours through regulating cycle genes and then affecting synaptic homeostasis 151 . However, we still lack evidence for that so far (Figure 4).…”