Mechanisms of the psychostimulant effects of caffeine: implications for substance use disorders

Abstract

Background: The psychostimulant properties of caffeine are reviewed and compared with those of prototypical psychostimulants able to cause substance use disorders (SUD). Caffeine produces psychomotor-activating, reinforcing, and arousing effects, which depend on its ability to disinhibit the brake that endogenous adenosine imposes on the ascending dopamine and arousal systems.

Objectives: A model that considers the striatal adenosine A2A-dopamine D2 receptor heteromer as a key modulator of dopamine-dependent striatal functions (reward-oriented behavior and learning of stimulus-reward and reward-response associations) is introduced, which should explain most of the psychomotor and reinforcing effects of caffeine.

Highlights: The model can explain the caffeine-induced rotational behavior in rats with unilateral striatal dopamine denervation and the ability of caffeine to reverse the adipsic-aphagic syndrome in dopamine-deficient rodents. The model can also explain the weaker reinforcing effects and low abuse liability of caffeine, compared with prototypical psychostimulants. Finally, the model can explain the actual major societal dangers of caffeine: the ability of caffeine to potentiate the addictive and toxic effects of drugs of abuse, with the particularly alarming associations of caffeine (as adulterant) with cocaine, amphetamine derivatives, synthetic cathinones, and energy drinks with alcohol, and the higher sensitivity of children and adolescents to the psychostimulant effects of caffeine and its potential to increase vulnerability to SUD.

Conclusions: The striatal A2A-D2 receptor heteromer constitutes an unequivocal main pharmacological target of caffeine and provides the main mechanisms by which caffeine potentiates the acute and long-term effects of prototypical psychostimulants.

Keywords: Adenosine; Alcohol; Caffeine; Dopamine; Drug abuse; Psychostimulants; Receptor heteromer.

Figure 1. Model of the striatal A_2A-D₂ receptor heteromer as a main mechanism for the psychomotor and reinforcing effects of psychostimulants

The relative thickness (and close number) of the red and green input arrows represents the degree of activation of the A_2A receptor (A2AR) and the D₂ receptor (D2R) that depends on the concentration of the corresponding neurotransmitter or exogenous ligands. Bold and colored A2AR and D2R represent dopamine denervation-induced up-regulated receptors. The thickness (and close number) of the red and green output arrows represent the intensity of A_2A and D₂ receptor signaling, respectively, which depends on the input signal for each receptor, on the sensitivity of each receptor (basal or up-regulated) and on the predominance of antagonistic allosteric and adenylyl-cyclase A_2A-D₂ receptor interactions (represented by horizontal arrows with a minus enclosed sign; in E, the broken line with double arrowhead indicates weak and non-predominant interactions). Predominant psychomotor activation or depression will result when subtraction of the A_2A receptor signaling from the D₂ receptor signaling gives a positive (also in green) or negative (also in red) result, respectively. A, resting condition; B, presence of rewarding stimulus or after administration of a direct or indirect dopamine receptor agonist without dopamine depletion; C, dopamine depletion; D, administration of a direct dopamine receptor agonist with dopamine depletion; E, administration of caffeine or and A_2A receptor antagonist with dopamine depletion; F, administration of caffeine or and A_2A receptor antagonist without dopamine depletion (see text).

Figure 2. Model of the striatal A_2A-D₂ receptor heteromer as a main mechanism for the rotational behavior in unilateral 6-OHDA-lesioned rats induced by direct and indirect dopamine receptor agonists and by caffeine

The circles represent striata from the dopamine denervated, lesioned site (L), and from the non-lesioned side (NL). Each letter indicates the condition of the striatum as defined in Fig. 1, under resting conditions, under aroused or with amphetamine (Amph) administration, and after apomorphine (Apo) or caffeine (Caff) administration. The output arrows are the result of either predominant A_2A or D₂ receptor signaling (red or green, respectively) from each striatum. A green arrow implies predominant D₂ receptor signaling and increased responsiveness for rewarding stimuli in the contralateral site and therefore a trend for turning behavior contralateral to the striatum. A red arrow implies predominant A_2A receptor signaling and decreased responsiveness for rewarding stimuli in the contralateral site and therefore a trend for turning behavior ipsilateral to the striatum. The thickness of each colored arrow represent the relative intensity (as in Fig. 1) of the final signaling from each striatum The black arrow points to the direction of the rotational behavior, ipsilateral or contralateral to L: either none or a trend for ipsilateral turning under resting conditions, ipsilateral turning when aroused or with Amph administration, and contralateral after Apo or Caff administration.

Figure 3. Model of the striatal A_2A-D₂ receptor heteromer as a main mechanism for caffeine-induced potentiation of the psychomotor activating and reinforcing effects of prototypical psychostimulants

The addition of caffeine or and A_2A receptor antagonist to an indirect dopamine receptor agonists, such amphetamine or cocaine (B), can potentially lead to the maximal psychomotor activation driven by the A_2A-D₂ receptor heteromer (G), as well as the consequences of repeated D₂ receptor-mediated activation, such as behavioral sensitization. See legend to Fig. 1 for details and text.