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.