Fig. 3: Schematic illustration of brain circuits implicated in depression and addictive drug abuse.

Addictive drug exposure induces widespread neuroadaptations across multiple brain regions, altering glutamatergic, dopaminergic, and GABAergic signaling and contributing to vulnerability to depressive symptoms. a Depictive summary of the classical neural circuits involved in major depression and stress-related depressive phenotypes, including dysregulation within monoaminergic pathways, neuroinflammatory signaling, and reduced neurotrophic support (e.g., BDNF–TrkB pathways); b schematic representation of the core reward- and motivation-related neurocircuitry underlying addiction. This panel is not intended to represent depression-specific circuits, but rather the canonical pathways involved in reinforcement learning and drug seeking. These addiction circuits partially overlap with depressive circuits (e.g., PFC–NAc), providing a mechanistic basis for comorbidity, while also containing addiction-specific nodes (e.g., LH, VP). Norepinephrine (NA), interleukin-8 (IL-8), tropomyosin receptor kinase B (TrkB), nuclear factor kappa-B (NF-κB), hypothalamus (Hyp), amygdala (Amy), lateral hypothalamic area (LHA), ventral tegmental area (VTA), lateral habenula (LHb), ventral pallidum (VP), basolateral amygdala (BLA), lateral hypothalamus (LH), mediodorsal thalamus (MDT). (Figure created with Adobe Illustrator 2023).