Neurobiología de las metilxantinas

Abstract

ObjectiveIn this review we are going to see the pharmacological profile of the methylxanthines and that of their main components caffeine and theophiline. We will review their mechanisms of action, the implicated receptors, the distribution of these receptors within the Central Nervous System, their neuronal localization and their interaction with the dopamine receptors. Material and methodsThe distribution and the cellular localization of adenosine receptors A1 and A2a have been studied by single and double in situ hybridization. Behavioural and ligand binding studies together with FRET techniques have been used to study the interaction between the adenosinergic and dopaminergic systems as well as that of their receptors. ResultsMethylxanthines are psichostimulants that increase motor activity and arousal and decrease fatigue and sleep. Methylxanthines are non selective antagonists of adenosine receptors, mainly A1 and A2a receptors. Chronic use of methylxanthines produces dependency. A1 receptors inhibit adenylyl cyclase (AC) and are widely expressed in the brain (hippocampus, cortex, thalamus, striatum and globus pallidus). A2a receptors stimulates AC and are almost exclusively located in the striatum and olfactory tubercle. In the striatum, A1 receptors are colocalized with D1 receptors, while A2a colocalized with D2 receptors. Adenosine, by the activation of A1 and A2a receptors counteracts dopamine responses mediated by D1 and D2 receptors. This interaction occurs through intramembrane receptor-receptor interaction between A2a-D2 and A1-D1 receptors. These results have also been confirmed with the use of KO mice for each of the implicated receptors. ConclusionsMethylxantines are psychomotor stimulants that block adenosine receptors A1 and A2a. Adenosine opposes dopamine-mediated responses. In the striatum, A1 receptors colocalized with D1 receptors in direct pathway neurons while A2a receptors colocalized with D2 receptors in indirect pathway neurons. The interaction between dopaminergic and adenosinergic systems is taken place by the intramembrane receptors interaction between A1-D1 and between A2a-D2 receptors.