Caffeine is the most consumed psychoactive drug in the world. As a psychostimulant, it shows all the pharmacological properties of classical psychostimulants, such as cocaine and amphetamine. Those properties include arousal, motor activation, and reinforcing effects. Nevertheless, those effects are milder for caffeine, which depends on its unique mechanism of action, adenosine receptor antagonism. Classical psychostimulants produce a direct potentiation of central dopaminergic, noradrenergic, and serotoninergic neurotransmission, by acting on catecholamine and serotonin transporters. Caffeine, instead, indirectly activates those and several other ascending neurotransmitter systems (cholinergic, histaminergic, and orexinergic) by removing an inhibitory presynaptic adenosinergic tone, mediated by the effect of endogenous adenosine on adenosine A1 receptors. Caffeine-induced modulation of the dopaminergic system also depends on postsynaptic mechanisms that depend on assemblies of adenosine and dopamine receptors (A1-D1 and A2A-D2 receptor heteromers) (for review see Ref.
1).