Cocaine addiction-like behaviors are associated with long-term changes in gene regulation, energy metabolism, and GABAergic inhibition within the amygdala
Zhou, J. L.; de Guglielmo, G.; Ho, A. J.; Kallupi, M.; Li, H.-R.; Chitre, A. S.; Carrette, L. L. G.; George, O.; Palmer, A. A.; McVicker, G. P.; Telese, F.
Show abstract
The amygdala processes positive and negative valence and contributes to the development of addiction, but the underlying cell type-specific gene regulatory programs are unknown. We generated an atlas of single nucleus gene expression and chromatin accessibility in the amygdala of outbred rats with low and high cocaine addiction-like behaviors following prolonged abstinence. Between rats with different addiction indexes, we identified thousands of cell type-specific differentially expressed genes enriched for energy metabolism-related pathways that are known to affect synaptic transmission and action potentials. Rats with high addiction-like behaviors showed enhanced GABAergic transmission in the amygdala, which, along with relapse-like behaviors, were reversed by inhibition of Glyoxalase 1, which metabolizes the GABAA receptor agonist methylglyoxal. Finally, we identified thousands of cell type-specific chromatin accessible sites and transcription factor (TF) motifs where accessibility was associated with addiction index, most notably at motifs for pioneer TFs in the Fox, Sox, helix-loop-helix, and AP1 families.
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