In laboratory animals, repeated administration of drugs of abuse, such as cocaine, morphine or alcohol, causes sensitization (reverse tolerance) to their stimulant and rewarding effects. Neuroadaptations underlying sensitization could be related to those that contribute to addictive behaviors. An increased understanding of the molecular mechanisms of sensitization could lead to improved treatments for addiction. Here, we review evidence that the ability of drugs of abuse to elevate levels of the GluR1 subunit of AMPA glutamate receptors in the ventral tegmental area (VTA) of the midbrain is crucial for the development of sensitization. Even transient increases in GluR1 levels within VTA neurons can trigger complex cascades of other molecular adaptations in these neurons and, within larger neural circuits, can cause enduring changes in the responses of the brain to drugs of abuse. However, there is ongoing debate over whether elevated levels of GluR1 in the VTA are a primary cause, or secondary effect, of the neurobiological underpinnings of sensitization.