In search of opioid sensitive GABA afferents to midbrain dopamine neurons

Dopamine neurons in the ventral tegmental area (VTA) and substantia nigra regulate motivation and reward, and their disinhibition by opioids is a critical step in addiction. Using optogenetics and whole-cell recordings, we examined opioid sensitivity of GABA inputs to midbrain dopamine neurons from VTA interneurons, nucleus accumbens (NAc), and rostromedial tegmental nucleus (RMTg). RMTg inputs showed strong μ-opioid receptor-mediated inhibition, NAc inputs moderate inhibition, and VTA interneurons minimal inhibition. Striatal inputs exhibited mixed μ- and κ-opioid sensitivity. These findings identify RMTg as a major source of opioid-sensitive inhibition, providing insight into mechanisms underlying opioid-induced dopamine activation.