Adenosine and Kynurenic Acid Interactions: Possible Relevance for Schizophrenia Treatment?

Schizophrenia is a severe and chronic mental disorder, mainly characterized by the presence of the so-called “positive” (delusions, hallucinations, disorganized thinking) and “negative” (anhedonia, blunted affect, social withdrawal) symptoms, as well as cognitive dysfunctions. Although several interrelated causes have been associated with the development of the pathology, it is generally accepted that the hyperfunction of dopaminergic and/or hypofunction of glutamatergic transmission (i.e., the so-called “combined glutamate/dopamine hypothesis of schizophrenia”) might underlie the symptoms of schizophrenia (Howes et al., 2015; Snyder and Gao, 2020). Clinical indications demonstrate that positive symptoms respond well to conventional antipsychotic medications, which mainly act as dopamine D2 receptor (D2R) antagonists, while negative symptoms and cognitive impairments are more difficult to be counteracted. Several non-D2R related mechanisms of action of antipsychotic drugs have been proposed over the last decades, but none has conclusively been proven effective. Furthermore, while the newer antipsychotic drugs produce fewer motor side effects than conventional “first generation” drugs, safety and tolerability concerns about weight gain and endocrinopathies often limit their use (Li et al., 2016). Thus, there is an urgent necessity for more effective and better-tolerated antipsychotic drugs, as well as to identify new molecular targets and develop mechanistically novel compounds that can address the various symptom dimensions of schizophrenia. Due to the complexity of the pathology, it seems likely, however, that a multi-target strategy, i.e., the use of multifunctional drugs or a combination of drugs affecting distinct targets, will lead to more effective therapeutic approaches. Based on this background and recent findings, the present opinion paper was conceived to critically review possible interactions between adenosine and kynurenic acid (KYNA) in this context. These two neuromodulators may be pathophysiologically associated with schizophrenia, and a deeper understanding of their interactions may lead to the development of innovative strategies for the treatment of schizophrenia. Adenosine and Schizophrenia It is well recognized that, beside dopamine and glutamate systems, the purinergic system may be also involved in the pathophysiology of schizophrenia (Lara and Souza, 2000; Krugel, 2016; Cheffer et al., 2018). In fact, the so-called “adenosine hypothesis of schizophrenia” (Lara et al., 2006; Boison et al., 2012; Hirota and Kishi, 2013; Rial et al., 2014) postulates that a reduced adenosine tone is involved in the dysregulation of glutamatergic and dopaminergic activity in schizophrenia patients. Accordingly, based on informative studies in experimental animals, adenosine receptor agonists may act as atypical antipsychotic drugs (Krugel, 2016). Adenosine A2A receptors (A2ARs), which are highly expressed in the striatum and the olfactory tubercle, exert fine regulation of individual synapses (Hines and Haydon, 2014; Krugel, 2016), and their activation facilitates glutamate release and potentiates N-methyl-D-aspartate (NMDA) receptor function. As a consequence, A2ARs regulate synaptic plasticity by promoting adequate (or aberrant) adaptive responses in neuronal circuits (Azdad et al., 2009; Boison and Aronica, 2015; Krugel, 2016). In general, adenosine and A2AR agonists induce behavioral effects similar to those of dopamine receptor (DR) antagonists used as antipsychotics (Rimondini et al., 1997; Wardas, 2008; Shen et al., 2012; Borroto-Escuela et al., 2020). In fact, A2AR agonists inhibit hyperlocomotion and sensorimotor gating deficits induced by DR agonists and/or NMDA receptor channel blockers in rodents (Krugel, 2016). More specifically, converging evidence suggests that heteroreceptor complexes containing AR and DR protomers, especially adenosine A2AR-D2R heteroreceptor complexes, exert strong inhibitory modulation of dorsal and ventral striato-pallidal GABA neurons (Ferre et al., 1991; Fuxe et al., 2008; Borroto-Escuela et al., 2018; Borroto-Escuela et al., 2020). Thus, A2AR agonists reduce D2R recognition and function by acting on the A2A-D2 heteroreceptor complexes located in the dorsal and ventral striato-pallidal anti-reward GABA pathway. Upon activation of this pathway, the brain circuit involved increases the glutamate drive to the frontal cortex from the medial dorsal thalamic nucleus, and transfer of anti-reward information takes place (Fuxe et al., 2008; Borroto-Escuela et al., 2017; Borroto-Escuela et al., 2018; Borroto-Escuela et al., 2020). Thus, it was suggested more than a decade ago (Fuxe et al., 2008) and recently demonstrated (Borroto-Escuela et al., 2020; Valle-Leon et al., 2020) that drugs promoting A2AR-D2R heteromer formation might constitute an alternative strategy for the treatment of schizophrenia. Furthermore, A2AR agonists can allow a reduction of the dose of the D2R antagonists which should reduce the side effects of classical and atypical antipsychotic drugs. These findings moved A2AR agonists into the focus of interest for adenosinergic therapeutic options in the disease. The adenosine A1 receptor (A1R), too, has been proposed as a potential antipsychotic drug target (Ossowska et al., 2020). A1Rs are coupled to the Gi/o family of G-proteins, are abundantly present throughout the central nervous system, and appear to generally exert an inhibitory and neuroprotective ‘tone’ (Chen et al., 2014; Krugel, 2016). Activation of presynaptic A1Rs inhibits the release of neurotransmitters (e.g., glutamate, GABA, dopamine, serotonin and acetylcholine) and depresses postsynaptic neuronal signaling by inducing hyperpolarization (Paul et al., 2011). Notably, pre- and post-synaptic A1R activation, leading to reduced glutamate and GABA release as well as impaired NMDA receptor and D1R function, respectively, plays a major role in the “adenosine hypothesis” of schizophrenia (Fuxe et al., 2008; Krugel, 2016). Thus, as the pathophysiologically significant NMDA receptor hypofunction in the disease can be traced mainly to fast-spiking GABA neurons (Nakazawa and Sapkota, 2020), a reduction of A1R signaling should benefit critical neuronal circuits and consequently have positive effects on schizophrenia symptoms. In line with this view, A2AR agonists might exert part of their antipsychotic action by activating the A2AR protomer in a prejunctional A1-A2A receptor complex. Through this antagonistic receptor-receptor interaction, A2AR agonists could lower the affinity of the A1R protomer and thus the inhibitory action of the A1R protomer on glutamate release (Ciruela et al., 2006; Franco et al., 2008; Borroto-Escuela et al., 2020). Antagonists of A1R receptors have indeed been shown to reduce memory impairment in experimental animals (Boison et al., 2012). On the other hand, since activation of A1Rs on dopaminergic nerve terminals inhibits dopamine release (Paul et al., 2011; Zhang and Sulzer, 2012), A1R agonists, too, may counteract schizophrenia symptoms. In fact, preclinical findings have indicated that stimulation of A1Rs may have antipsychotic effects, although cognitive dysfunctions must be expected to be associated with the treatment (Ossowska et al., 2020). Specifically, recent studies demonstrated that the selective A1R agonist 5-Chloro-5′-deoxy-N6-(±)-(endo-norborn-2-yl)adenosine (5′-Cl-5′-deoxy-ENBA) reduces the hyperlocomotion caused by amphetamine or the non-competitive NMDA receptor antagonist dizolcipine (MK-801; Eyjolfsson et al., 2006; Ossowska et al., 2020). Inhibition of amphetamine- and MK-801-mediated hyperlocomotion may also be caused by allosteric interaction of D1R signaling in the A1R-D1R heteroreceptor complex, which is located in striato-nigral and striato-entopeduncular GABA neurons as well as in D1R-rich GABA neurons in the nucleus accumbens (Rimondini et al., 1997; Fuxe et al., 2007; Fuxe et al., 2008; Fuxe et al., 2020; Franco et al., 2008; Perez-de-la-Mora et al., 2020).