Cocaine’s powerful addictive properties have been linked by a number of studies to dopamine, a crucial neurotransmitter with wide-ranging effects on motivation and mood. This link was an important discovery, but not specific enough to open the way for addiction medication. Two studies in the August issue of Neuron, conducted by Dr. Larry Zweifel and Dr. David Engblom, use genetically altered KO mice to explore precisely how cocaine and dopamine interact to form addictive behavior.

Dr. Zweifel’s experiment focused on the chain of chemical processes that leads to the strengthening of dopamine connections. If brain plasticity is necessary for addiction to take root, then knocking out a link anywhere in this chain would protect the brain from drugs. Dr. Zweifel’s mice lacked the NMDA receptors needed to complete the neural strengthening process. While their initial neural and motor responses to cocaine looked normal, they did not display the long-term symptoms of addiction, like dependence and withdrawal. This is strong evidence that cocaine’s powerful grip relies on rewiring the brain.

Dr. Engblom’s work further refines our knowledge of the ways that dopamine plasticity contributes to addiction. His mice each lacked one of the subunit dopamine receptors, either GluR1, GluR2, or NR1. The absence of GluR2 did not affect plasticity, but mice missing GluR1 and NR1 did not develop the strengthened transmission normally observed after cocaine exposure. These mice still learned to prefer locations where cocaine was most commonly offered, but they did not develop long-term addictive behaviors. GluR1-lacking mice did not show extinction of drug-seeking behavior and NR1-lacking mice did not show reinstatement.

Both of these studies establish that dopamine plasticity is responsible for many of the long-term aspects of addiction. This understanding may lead to medications that can prevent cocaine, and other drugs, from grabbing hold of the brain and rewiring it to encourage future drug-seeking. Freed from the trap of malfunctioning reward circuitry, many more patients might be able to desist from drug use with resolve and help from a therapist.