TH and nicotine dependence: Although the activation of VTA dopaminergic neurons, which enhances locus coeruleus (LC) noradrenergic neuron firing via prefrontal cortex-LC circuitry, is a recognized mechanism underlying DA-NE system synergy in reward and stress processing [62], the biochemical pathway from tyrosine hydroxylase (TH) to DA synthesis has been underexplored in nicotine addiction research.