Future Perspective
Despite significant advances over several decades in the development of effective pharmacotherapies, the societal concerns of addiction remain the same. As considered in this review, adenosine is a robust homeostatic molecule with an ability to regulate several neuronal pathways, culminating in a neuroprotective function. Aiming to circumvent the peripheral side effects of adenosine, novel drug delivery techniques including stem cell implants, adenosine releasing synthetic polymers, focal paracrine delivery of adenosine from encapsulated cells and so on, were designed to continuously release adenosine and thus suppress the ongoing pathological conditions. However, clinical trials with selective adenosine-related therapies or combination therapies should be started in complementary or synergistic fashions to disseminate the impending therapeutic potential of this bioenergetic molecule.
Furthermore, existing pharmacological agents for the treatment of addiction and related withdrawal behavior have not been proven to be free from adverse effects and, moreover, they are only able to control certain transient symptoms based on their glutamatergic or dopaminergic pathways. On the other hand, the neuronal signaling regulated by the neuromodulatory effect of adenosine in connection with other neurotransmitters needs more focus based on its varied functional activities in different pathways of addiction phenomenon including the ventral tegmental area and the striatum. Under neuronal insults such as drug withdrawal, there is an enhanced turnover of excitatory amino acids that bind to kainate and/or quisqualate receptors and depolarize neurons sufficiently to overcome the voltage-dependent Mg block of NMDA receptors. The subsequent NMDA receptor activation and massive influx of Ca leads to the production of free radicals and eventual lipid peroxidation, mitochondrial damage and cell death. In this context, the neuromodulatory functions of adenosine conferring neuroprotection needs to be evaluated to prevent neuronal overexcitation and reduce neuronal cell death.
The research outcomes on the behavioral aspects of drug addiction, especially drug withdrawal, have been positive, but still require more investigation. The behavioral abnormalities, such as cognitive dysfunction, emotional instability, and some severe manifestations such as seizures, aggressiveness and anxiety in drug-withdrawn patients, demand many improved treatment options. Despite the availability of several pharmacological agents, many addicts still do not completely benefit from them. Numerous studies have shown the beneficial effects of adenosine and its analogs in varied behavioral abnormalities such as seizures, depression, anxiety, cognitive dysfunction apart from the amelioration of addiction reward and reinforcement. The current scenario demands the translation of these concepts from basic preclinical science to treatment developments. More experimental studies focusing on the efficiency of adenosinergic drugs on behavioral treatments are warranted in the context of translational studies. These efforts to link findings from basic research with treatment development would yield new insights that will help to make drug abuse and withdrawal-related abnormalities not only controllable but also curable.
Variations in gene loci encoding endogenous opioidergic, serotonergic, dopaminergic and other primary neuronal pathways, have been proposed in higher animals, such as primates, in the pathophysiology of alcohol dependence. Similarly, based on the potent neuroprotective and neuromodulatory actions of adenosine, variation in the human adenosine receptor genes can also be conceived in their physiological relevance. Investigation of the existence of these variations in the non-human primate adenosine receptor gene would determine whether non-human primates can model genotype/phenotype associations in the adenosinergic system of relevance with humans. The cloning of adenosine receptors in non-human primates and their characterization in heterogeneously expressing cell lines would allow characterization and exploration of several dependence-related parameters. Thus the genotype-specific molecular characterizations in higher animals may provide a potential target for the development of newer pharmacological interventions in human drug dependence.
Many preclinical and clinical reports over the last few decades have discovered profound endogenous therapeutic properties of adenosine, exerted by a complex interplay among receptors, transporters and metabolizing enzymes. These results have to be translated into new clinical approaches based on adenosinergic principles and, therefore, the introduction of adenosine-based drug therapies may finally offer novel therapeutic strategies for the drug withdrawal syndrome.