Pharmacological interactions between adenosine A_2A receptor antagonists and different neurotransmitter systems

While Parkinson's disease (PD) is traditionally characterized by dopaminergic neuron degeneration, several neurotransmitters and neuromodulators besides dopamine are also involved in the onset and progression of the disease and its symptoms. The other principal neurotransmitters/neuromodulators known to control basal ganglia functions and, in particular, motor functions, are GABA, glutamate, serotonin (5-HT), noradrenaline, acetylcholine, adenosine and endocannabinoids. Among these, adenosine is the most relevant, acting through its adenosine A_2A receptor. Work in experimental models of PD has established the effects of A_2A receptor antagonists, including the alleviation of disrupted dopamine functions and improved efficacy of dopamine replacement therapy. Moreover, positive interactions between A_2A receptor antagonists and both D₂ and D₁ receptor agonists have been described in vitro at the receptor-receptor level or in more complex in vivo models of PD, respectively. In addition, the interactions between A_2A receptor antagonists and glutamate ionotropic GluN_2B-containing N-Methyl-d-aspartic acid receptors, or metabotropic glutamate (mGlu) receptors, including both mGlu₅ receptor inhibitors and mGlu₄ receptor activators, have been reported in both in vitro and in vivo animal models of PD, as have positive interactions between A_2A and endocannabinoid CB₁ receptor antagonists. At the same time, a combination of A_2A receptor antagonists and 5-HT_1A-5-HT_1B receptor agonists have been described to modulate the expression of dyskinesia induced by chronic dopamine replacement therapy.