The adenosine hypothesis of schizophrenia into its third decade: From neurochemical imbalance to early life etiological risks

Abstract

The adenosine hypothesis of schizophrenia was conceptualized about two decades ago in an attempt to integrate two prominent theories of neurochemical imbalance that attribute the pathogenesis of schizophrenia to hyperfunction of the mesocorticolimbic dopamine neurotransmission and hypofunction of cortical glutamate neurotransmission. Given its unique position as an endogenous modulator of both dopamine and glutamate signaling in the brain, adenosine was postulated as a potential new drug target to achieve multiple antipsychotic actions. This new strategy may offer hope for improving treatment, especially in alleviating negative symptoms and cognitive deficits of schizophrenia that do not respond to current medications. To date, however, the adenosine hypothesis has yet led to any significant therapeutic breakthroughs. Here, we address two possible reasons for the impasse. First, neither the presence of adenosine functional deficiency in people with schizophrenia nor its causal relationship to symptom production has been satisfactorily examined. Second, the lack of novel adenosine-based drugs also impedes progress. This review updates the latest preclinical and clinical data pertinent to the construct validity of the adenosine hypothesis and explores novel molecular processes whereby dysregulation of adenosine signaling could be linked to the etiology of schizophrenia. It is intended to stimulate and revitalize research into the adenosine hypothesis towards the development of a new and improved generation of antipsychotic drugs that has eluded us for decades.

Adenosine Receptor mRNA Expression in Frontal Cortical Neurons in Schizophrenia

“…In recent years, attention has turned to the adenosine system and its potential neuromodulatory role in the pathophysiology of schizophrenia [ 8 , 15 , 32 , 45 ], as well as the potential for adenosine receptors specifically as therapeutic substrates for this disorder [ 45 , 46 ]. The adenosine receptors are expressed throughout the human brain [ 47 ], with most studies focusing on changes in receptor expression and function in the striatum and striatal–dopamine neurons in schizophrenia [ 7 , 10 , 11 , 29 , 30 , 31 ]. Much less is known about adenosine receptor expression in the neurons of other frontal cortical brain regions, like the ACC, that are implicated in schizophrenia.…”

“…Conversely, negative symptoms such as apathy, social isolation, and anhedonia, as well as cognitive symptoms, like memory impairments and problem-solving, are often associated with dysfunction of the glutamatergic system [ 6 ]. The adenosine hypothesis of schizophrenia plays a crucial role in integrating the dopamine and glutamate hypotheses of this disorder, proposing that the dysregulation of these systems is the result of a hypo-adenosinergic state [ 7 ].…”

“…As a neuromodulator, adenosine exerts its influence on dopamine and glutamate neurotransmission via a complex system of receptors, enzymes, and transporters found throughout the brain on neurons and glial cells [ 8 ]. The central effects of adenosine at physiological concentrations are primarily mediated by the activation of two high-affinity G protein-coupled adenosine receptors: the inhibitory A 1 receptor (A 1 R) and the excitatory A 2A receptor (A 2A R) [ 7 ]. These receptors play a pivotal role in fine-tuning synaptic transmission and serve as key regulators of neurotransmitter release [ 9 ].…”

“…Of particular interest in schizophrenia are the A 2A Rs that are predominantly expressed at post-synaptic neurons in the striatum and hippocampus, as well as at intermediate levels in the frontal cortex [ 7 , 10 , 11 ]. Activation of A 2A Rs promotes neural excitability, synaptic plasticity, and long-term potentiation, which are widely believed to underlie forms of learning and memory [ 12 ].…”

“…Inhibitory A 1 Rs have a widespread distribution in the brain, including in the frontal cortex [ 7 , 10 , 11 ]. The activation of A 1 Rs inhibits the release of dopamine and glutamate by post-synaptic hyperpolarization [ 19 , 20 , 21 ].…”