Introduction
Addiction is a disorder of the brain's reward and learning systems. At its core, it involves the hijacking of neural circuits that evolved to motivate survival behaviors -- eating, social bonding, reproduction -- by substances or activities that produce supranormal dopamine signals. Understanding the pharmacology of addiction means understanding how drugs change the brain at the molecular, cellular, and circuit levels, and why these changes are so resistant to reversal. This understanding also reveals why psychedelics and other novel compounds may offer fundamentally different therapeutic approaches.
The Mesolimbic Dopamine Pathway
The brain's reward circuitry centers on the mesolimbic dopamine pathway: a projection from dopamine neurons in the ventral tegmental area (VTA) to the nucleus accumbens (NAc), with additional projections to the prefrontal cortex, amygdala, and hippocampus. When we encounter something rewarding, VTA neurons fire and release dopamine into the NAc, producing the sensation of pleasure and, more importantly, signaling that the behavior is worth repeating.
Natural rewards (food, social interaction) produce modest, transient increases in NAc dopamine -- typically 50-100% above baseline. Drugs of abuse produce dramatically larger signals. Cocaine can increase NAc dopamine by 300-400% above baseline. Methamphetamine can produce increases of over 1,000%. This supranormal signaling overwhelms the system's calibration, setting in motion a cascade of adaptive changes.
Nora Volkow, Director of the National Institute on Drug Abuse, and George Koob, Director of the National Institute on Alcohol Abuse and Alcoholism, have been instrumental in characterizing these changes through decades of neuroimaging and neuroscience research.
