Role of the central ascending neurotransmitter systems in the psychostimulant effects of caffeine

Abstract

Caffeine is the most consumed psychoactive drug in the world. It is a non-selective adenosine receptor antagonist that in the brain targets mainly adenosine A1 and A2A receptors. The same as classical psychostimulants, caffeine produces motor-activating, reinforcing and arousing effects. This depends on the ability of caffeine to counteract multiple effects of adenosine in the central ascending neurotransmitter systems. Motor and reinforcing effects depend on the ability of caffeine to release pre- and postsynaptic brakes that adenosine imposes on the ascending dopaminergic system. By targeting A1-A2A receptor heteromers in striatal glutamatergic terminals and A1 receptors in striatal dopaminergic terminals (presynaptic brake), caffeine induces glutamate-dependent and glutamate-independent release of dopamine. These presynaptic effects of caffeine are potentiated by the release of the postsynaptic brake imposed by antagonistic interactions in the striatal A2A-D2 and A1-D1 receptor heteromers. Arousing effects of caffeine depend on the blockade of multiple inhibitory mechanisms that adenosine, as an endogenous sleep-promoting substance, exerts on the multiply interconnected ascending arousal systems. Those mechanisms include a direct A1-receptor mediated modulation of the corticopetal basal forebrain system and an indirect A2A-receptor mediated modulation of the hypothalamic histaminergic and orexinergic systems.

Fig. 1.

Caffeine targets in the striatal spine modules of the GABAergic enkephalinergic neuron (a) and GABAergic dynorphinergic neuron (b). Adenosine A2A-dopamine D2 receptor heteromers are localized in the dendritic spines of the GABAergic enkephalinergic neuron and adenosine A1-dopamine D1 receptor heteromers are localized in the dendritic spines of the GABAergic dynorphinergic neurons. Presynaptic A2A receptors form heteromers with A1 receptors and are localized in the striatal glutamatergic terminals that make contact with the dendritic spines of the GABAergic dynorphinergic neuron. A1 receptors are also localized in a fraction of dopaminergic terminals (modified from ref. [16]).

Fig. 2.

Scheme of the highly interconnected multiple ascending arousal systems, which are all targets of caffeine (see text). BF: area of origin of the corticopetal basal forebrain system; LC: locus coeruleus; LDT and PPT: laterodorsal and pedunculopontine nuclei; TM: tuberomammillary nucleus; Orx: area of origin of the orexinergic system; Thal: thalamus.