The reasons for the preferable use of A2A receptor antagonists for improvement of locomotor activity and learning

Previously, we hypothesized that dopamine, as well as antagonists of muscarinic and adenosine receptors, enhances locomotor activity due to modulation of the efficacy of cortical inputs to striatal spiny cells and synergistic disinhibition of neurons of the thalamus and cortex via the direct and indirect pathways in the basal ganglia [Silkis, 2001]. It was shown that the occurrence of a pause in the responses of cholinergic interneurons of the striatum to sensory stimuli promotes this disinhibition due to weakening of the activation of muscarinic receptors on spiny cells. We proposed a hypothetical mechanism for the appearance of this pause, which includes afferent inhibition and activation of D2 receptors [Silkis, 2004]. Current studies support this mechanism. In this study, we propose that a decrease in the activity of cholinergic neurons results in the enhancement of the excitation of spiny cells by cortical afferents due to weakening of their inhibition by inhibitory striatal interneurons that express nicotinic receptors. We put forward a hypothesis that the use of antagonists of A2A receptors is preferable for the improvement of locomotor activity, treatment of Parkinson's disease, learning, and the choice of actions that results in better reinforcement because only these antagonists promote the occurrence of a pause in the responses to cholinergic interneurons and a decrease in their activity. Due to the same reason the treatment of mental diseases by antagonists of D2 receptors should additionally include antagonists of A2A receptors. Although antagonists of A1 receptors promote the disinhibition of neurons of the thalamus and cortex via the direct pathway in the basal ganglia, their use is undesirable because it may lead to an increase in the activity of cholinergic interneurons and prevent a pause in their responses. In addition, after systemic administration of antagonists of A2A receptors, they should predominantly influence the functioning of the striatum, where they are predominantly located, whereas A1 receptors are widely expressed in the brain and systemic administration of their antagonists may result in unpredictable side effects.