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).