Prolonged nicotine exposure, via electronic cigarettes, selectively enhances the transcription of Bdnf/TrkB and elevates dynorphin peptide and OLIG2 levels in the rat VTA

Different drugs of abuse affect CNS neuronal networks and reshape the expression of neuroplasticity-related genes in crucial parts of the mesocorticolimbic reward circuitry, such as the ventral tegmental area (VTA) and the nucleus accumbens (NAc). Recent evidence suggests that neuronal activity and life experience, including repeated drug exposure, can modulate oligodendrogenesis thus altering neuronal myelination. This study aimed to investigate whether the prolonged exposure to nicotine, via electronic cigarettes, affects oligodendrocyte differentiation. To this end, male Sprague-Dawley rats were exposed to nicotine via a commercially available e-cigarette device for four weeks. Subsequently, the VTA and NAc were collected for gene and protein expression analyses to assess the Bdnf/Trkb and DYN/KOR systems, OLIG2 (a marker of oligodendrogenesis), its epigenetic regulator Kdm6b, as well as neurofilament protein levels, given their critical role in maintaining axonal integrity. Results showed that exposure to nicotine mainstream enhances the expression of OLIG2 (p< 0.05), a transcription factor essential for oligodendrocyte differentiation, in the rat VTA. This effect was associated with increased mRNA levels of the epigenetic enzyme Kdm6b (p < 0.05), which is involved in regulating OLIG2 expression and synaptic plasticity. In the same brain region, nicotine increased Bdnf (p< 0.05) and Trkb gene expression (p< 0.01), as well as dynorphin peptide levels (p < 0.01), without notable changes in KOR protein expression (p>0.05). These data suggest adaptive /maladaptive alterations in oligodendrocyte regulation, potentially contributing to addiction-related neurobiology. Noteworthy, these molecular changes occurred alongside a reduction in neurofilament light levels (p< 0.01), suggesting potential axonal remodelling associated with enhanced oligodendrogenesis. No significant changes in investigated parameters were detected in the NAc (p> 0.05), thus suggesting that oligodendrogenesis and associated molecular alterations selectively occurred in the VTA. Protein correlation analysis revealed that prolonged nicotine exposure primarily affects neuroplasticity-related protein networks within this area. Overall, these findings suggest that prolonged nicotine exposure, through electronic cigarettes, induces oligodendrogenesis and BDNFergic dynorphinergic alterations specifically within the VTA. These molecular changes may impact axonal conduction velocity and reward circuitry connectivity, promoting neuronal adaptations ultimately contributing to the development of addictive behaviour.