Cocaine-Induced\nRemodeling of the Rat Brain\nPeptidome: Quantitative Mass\nSpectrometry Reveals Anatomically Specific Patterns of Cocaine-Regulated\nPeptide Changes

Addiction to psychostimulants, including cocaine, causes\nwidespread\nmorbidity and mortality and is a major threat to global public health.\nCurrently, no pharmacotherapies can successfully treat psychostimulant\naddiction. The neuroactive effects of cocaine and other psychostimulants\nhave been studied extensively with respect to their modulation of\nmonoamine systems (particularly dopamine); effects on neuropeptide\nsystems have received less attention. Here, we employed mass spectrometry\n(MS) methods to characterize cocaine-induced peptidomic changes in\nthe rat brain. Label-free peptidomic analysis using liquid chromatography\ncoupled with tandem MS (LC–MS/MS) was used to describe the\ndynamic changes of endogenous peptides in five brain regions (nucleus\naccumbens, dorsal striatum, prefrontal cortex, amygdala, and hypothalamus)\nfollowing an acute systemic cocaine challenge. The improved sensitivity\nand specificity of this method, coupled with quantitative assessment,\nenabled the identification of 1376 peptides derived from 89 protein\nprecursors. Our data reveal marked, region-specific changes in peptide\nlevels in the brain induced by acute cocaine exposure, with peptides\nin the cholecystokinin and melanin-concentrating hormone families\nbeing significantly affected. These findings offer new insights into\nthe region-specific effects of cocaine and could pave the way for\ndeveloping new therapies to treat substance use disorders and related\npsychiatric conditions.