Recruitment of specific dopamine neuron sub-circuits by opioids

Opioids have strong addictive and rewarding effects, largely attributed to their interaction with the dopamine (DA) system. Within the ventral tegmental area (VTA), opioids increase DA neural activity by disinhibiting-or decreasing the tonic inhibition of-DA neurons. This disinhibition results in an increase in DA in the nucleus accumbens, which has been widely implicated in addiction. With recent developments suggesting rich VTA DA neuron heterogeneity, a key question is whether opioid exposure activates distinct DA neuron subsets. Here, we address (i) whether this activation is uniformly distributed across the midbrain or, alternatively, is enriched in specific anatomically restricted DA populations, and (ii) the specificity of projections of activated DA neurons, giving insight into the circuitry receiving DA following opioid administration. Using intersectional cFos-based labeling, we find that captured cells are biased towards the VTA over the substantia nigra pars compacta (SNc), specifically towards the Aldh1a1-rich paranigral region. We also find that the projection pattern of labeled cells is focused on the dorsomedial shell of the nucleus accumbens compared to the ventromedial shell, core, lateral shell, or dorsal striatum. Projections are also observed in the prefrontal cortex, olfactory tubercle, and basolateral amygdala. Our findings of pathway-specific opioid-induced recruitment of DA neurons provide potential for selective targeting of DA sub-circuits to decrease the addictive nature of opioids without disrupting overall DA function.