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 and synthetic cathinones and energy drinks with alcohol; and the higher sensitivity of children and adolescents to the psychostimulants effects of caffeine and its possible increase in the vulnerability to develop 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.

Caffeine, a common active adulterant of cocaine, enhances the reinforcing effect of cocaine and its motivational value

“…It is more likely that caffeine, by its antagonism of A2AR in striatal pathways, would facilitate the adenylate cyclase inhibition induced by DA D2 activation (Ferré 2008). More recently, the same author highlighted the role of the striatal A2A-D2 receptor heteromer as the main target of caffeine and by which caffeine potentiates the acute and long-term effects of prototypical psychostimulants (Ferré 2016).…”

Trajectories of energy drink consumption and subsequent drug use during young adulthood

“…Earlier research showed an association between caffeine administration and dose-dependent increases in self-administration of stimulants (Schenk et al, 1996). The effect of caffeine on dopamine receptors has been suggested as a mechanism underlying its potentiation of other psychostimulants (Cauli and Morelli, 2005; Ferré, 2016). …”

“…Third, neurobiological evidence supports the possibility that frequent ED consumption might contribute to an increased risk for SUD due to caffeine’s ability to potentiate the addictive properties of other substances (Ferré, 2016). Laboratory studies have shown that caffeine enhances nicotine’s reinforcing and analgesic effects and potentiates the addictive properties of other stimulant drugs (Jones and Griffiths, 2003; O’Neill et al, 2015; Sigmon and Griffiths, 2011; Tanda and Goldberg, 2000).…”

Caffeine-induced Plasticity of Grey Matter Volume in Healthy Brains: A placebo-controlled multimodal within-subject study

“…Caffeine is the most commonly used psychostimulant worldwide and mainly consumed in forms of coffee, tea, energy drink, and soda [1][2][3][4] . Although caffeine is mostly considered to be non-addictive, the observed physical and psychological dependence 5,6 consolidate its regular consumption [7][8][9] through the caffeineinduced reinforcing effects 10 , as well as the motive to resist withdrawal symptoms 11 and to increase alertness 12 . Higher alertness after acute caffeine intake 13 mirrors a reduced homeostatic sleep pressure, which is also evident in a reduced depth of sleep 14 .…”