Drug-induced changes in connectivity to midbrain dopamine cells revealed by rabies monosynaptic tracing

Addictive drugs cause long-lasting changes in connectivity from inputs onto ventral tegmental area dopamine cells (VTADA) that contribute to drug-induced behavioral adaptations. However, it is not known which inputs are altered. Here we used a rabies virus (RABV)-based mapping strategy to quantify RABV-labeled inputs to VTA cells after a single exposure to one of a variety of misused drugs - cocaine, amphetamine, methamphetamine, morphine, and nicotine - and compared the relative global input labeling across conditions. We observed that all tested addictive drugs elicited similar input changes onto VTADA cells, in particular onto DA cells projecting to the lateral shell of the nucleus accumbens and amygdala. In addition, repeated administration of ketamine/xylazine to induce anesthesia induces a change in inputs to VTADA cells that is similar to but different from those elicited by a single exposure to addictive drugs, suggesting that caution should be taken when using ketamine/xylazine-based anesthesia in rodents when assessing motivated behaviors. Furthermore, comparison of viral tracing data to an atlas of gene expression in the adult mouse brain showed that the basal expression patterns of several gene classes, especially calcium channels, were highly correlated with the extent of both addictive drug- or ketamine/xylazine-induced changes in RABV-labeled inputs to VTADA cells. Reducing expression levels of the voltage-gated calcium channel Cacna1e in cells in the nucleus accumbens lateral shell reduced RABV-mediated input labeling of these cells into VTADA cells. These results directly link genes controlling cellular excitability and the extent of input labeling by RABV.