GPCRs as Therapeutic Targets: Dopamine Receptors: Neurotherapeutic Targets for Substance Use Disorders

The pivotal discovery of dopamine as a neurotransmitter in 1957 opened an entire field of basic and translational neuroscience to follow. Decades of brain research have revealed that dopamine signals in the brain via five distinct G protein-coupled receptors with important physiological functions in movement control, memory, attention, motivation, and reward. The dopamine hypothesis of addiction proposes that activation of dopamine neurotransmission is a critical mechanism underlying substance abuse and suggests pharmacologically modulating dopamine receptors with agonists or antagonists may prove therapeutic for treating various substance use disorders. In this chapter, a detailed review of the five dopamine receptors and their signaling and physiology is presented along with evidence that specific dopamine receptors control brain reward systems and behavioral responsiveness to drugs of abuse. Dopamine receptor ligands are also reviewed including structures, pharmacology, selective agonists, biased agonists, antagonists, and allosteric modulators. Activities of several dopamine receptor targeted drugs in preclinical studies and clinical trials are discussed, as are innovative approaches used to pharmacologically modulate the dopamine receptors.