Figure 3.

Representation of the hypothesized pharmacological mechanism underlying a therapeutic response in schizophrenia based on human and animal studies. Therapeutic doses of antipsychotic drugs (APDs) block about 70% of striatal D₂ receptors. APDs mostly block heteroreceptors, which are more often D_2L than D_2S, as well as a smaller proportion of autoreceptors (which are more often D_2S than D_2L). APDs also block the dopamine transporter (DAT). The combined blockade of D_2L heteroreceptors and DAT causes synaptic accumulation of dopamine that allows stimulation of spare D_2S receptors. Phasic release of dopamine in response to environmental changes will trigger an enduring autoinhibition since extracellular dopamine levels are already elevated. We hypothesize that the autoinhibition triggered by a phasic discharge of dopamine during antipsychotic treatment is the mechanism underlying a therapeutic antipsychotic response.