Electronic nicotine delivery systems disrupt brain plasticity and inflammatory signalling in the mesocorticolimbic system

Tobacco use disorder remains a major public health concern despite advances in pharmacological and behavioural cessation strategies, partly due to the limited effectiveness of current methods and the rising popularity of electronic devices. Electronic Nicotine Delivery Systems (ENDS), including electronic cigarettes (ECs) and Heat-not-Burn (HnB) products, have emerged as widely used alternatives marketed as reduced-risk options. However, their neurobiological impact on reward-related brain circuits and their potential neurotoxicity remain poorly understood. This thesis investigates the molecular and cellular consequences of repeated ENDS exposure on neuroplasticity and neuroinflammation within the mesocorticolimbic system. In the first experimental aim, EC mainstream exposure was investigated in male rats to examine its impact on neuronal adaptations underlying nicotine addiction, with focus on oligodendrogenesis-related pathways in the Ventral Tegmental Area (VTA) and Nucleus Accumbens (NAc). Results revealed selective upregulation of Bdnf/Trkb, increased Dynorphin/KOR signalling, positive regulators of oligodendroglial differentiation, and elevated OLIG2 expression in the VTA. Moreover, significant modifications in neurofilament protein levels indicated cytoskeletal remodelling, suggesting maladaptive myelination and impaired axonal integrity. These findings suggest that prolonged EC exposure alters oligodendrogenesis modulators in the VTA. The second aim evaluated the neurotoxicity of HnB in the prefrontal cortex (PFC), VTA, and NAc. Exposure triggered excessive production of reactive radical species, elevated expression of pro-inflammatory cytokines, and dysregulation of nuclear transcription factors NRF2 and NF-κB. Additionally, changes in Ppars and Kdm6a expression, together with altered PTEN/AKT/ERK signalling, highlighted the involvement of epigenetic and metabolic regulators in ENDS-induced neurotoxicity. Evidence of oxidative DNA damage and CYP450 dysregulation further underlined long-term vulnerability to neuronal dysfunction. These findings show that ENDS selectively modulate signalling pathways in the mesocorticolimbic system, driving neuroinflammatory processes linked to addictive behaviours. Moreover, these results provide novel insights into the cellular mechanisms underlying nicotine use disorder and point to potential long-term effects on brain function.