Despite diverse molecular mechanisms of action, drugs of abuse affect distinct yet partially overlapping neurocircuitries. We have demonstrated that craving for psychoactive substances relates to the activation of specific brain-wide networks, yet the underlying neurobiology remains elusive. In this SP, we apply mathematical modelling and simulations to investigate how acute and chronic exposure to different drugs (alcohol, nicotine, D9THC, heroin, and cocaine) changes cellular activity, particularly in terms of short-term and adaptive alterations in neurotransmitter concentrations.