Spatial multiomic insights into acute cocaine exposure

Abstract

Recent studies provide compelling evidence that cocaine-induced neurotoxicity begins within hours of a single acute cocaine exposure. Despite this, a comprehensive understanding of the molecular alterations occurring in vivo within the reward system following such an exposure has been lacking. In this study, we developed an analytical workflow that combines desorption electrospray ionization mass spectrometry imaging of metabolites at different temperatures with microscale proteomics of brain regions. We present a multiomic perspective on the molecular consequences of acute cocaine exposure on the principal areas of the reward system and the hippocampus. Our findings include distinct region-specific alterations in the tricarboxylic acid cycle and lipid synthesis within the reward circuitry highlighting a significant energy depletion in mice 24 hours post-cocaine injections. Additionally, we linked widespread reductions in key neurotransmitters across the reward system and calcium level alterations, to changes in synaptic plasticity and mitochondrial dysfunction. Mitochondrial dysfunction and energy metabolism disruption were evident through imbalances in the mitochondrial ATP production and electron transport chain components, increased susceptibility to oxidative stress, disturbances in mitochondrial transport proteins, and fluctuations in creatine and taurine levels. Among the brain regions within the reward circuitry, the prefrontal cortex exhibited the most pronounced effects. This study provides a holistic overview of the intricate interplay between proteins and metabolites, unveiling molecular mechanisms within the reward circuitry regions affected during the onset of cocaine-induced neurotoxicity.