Drug-evoked synaptic plasticity: beyond metaplasticity

- Addictive drugs alter synaptic plasticity in the VTA through a common mechanism.
- Changes in the VTA are permissive for later mesocorticolimbic circuit remodeling.
- Mesocorticolimbic circuit remodeling may underlie addiction-related behaviors.
- Reversing drug-induced plasticity may ultimately suppress addiction-related behavior.

Addictive drugs such as cocaine induce synaptic plasticity in the ventral tegmental area and its projection areas, which may represent the cellular correlate of an addiction trace. Cocaine induces changes in excitatory transmission primarily in the VTA, which persists for days after a single exposure. These initial alterations in synaptic transmission represent a metaplasticity that is permissive for late stages of remodeling throughout the mesocorticolimbic circuitry, specifically in the NAc. Specific synaptic and cellular changes in the NAc persist following prolonged exposure to cocaine, and this remodeling may contribute to altered behavior. By manipulating synaptic activity in the NAc, it may be possible to reverse pathological synaptic transmission and its associated abnormal behavior following exposure to addictive drugs.