The neurotransmitter dopamine is involved in a wide variety of neuroendocrine, emotional, cognitive and locomotor functions. These activities of dopamine are mediated by a group of 5 G protein coupled receptors, 2 of which (D1 and D5) couple to Gs and 3 of which (D2 , D3 , D4) couple to Gi. The D4 receptor is highly polymorphic, particularly in the third cytoplasmic loop, which contains from 2 to 7 repeats of 16 amino acids. Individuals with 7 repeats have increased risk of developing ADHD. Mice engineered to lack D4 have reduced locomotor activity, increased sensitivity to drugs of abuse that elevate dopamine (cocaine, methamphetamine and ethanol), and reduced response to novelty.