Abstract: Addiction has been extensively studied on many levels: from the molecular level, with various “omics” approaches (Natividad et al., 2018; Grecco et al., 2021), to the clinical level, with psychotherapy and MRI imaging (Ceceli et al., 2022). These approaches have identified brain regions central to addictive processes and reward behavior such as the nucleus accumbens (NA) and the ventral tegmental area. Particularly, the NA exhibits significant volume changes as a consequence of chronic alcohol, heroin, or cigarette abuse as measured by voxel-based morphometry with magnetic resonance imaging in human patients. However, the underlying cellular basis for such large-scale changes is not well understood. Studies in animal models suggest that cellular correlates of volume changes are dependent on alterations in spine/synapse densities and synapse volumes, rather than cell numbers (Keifer et al., 2015). In the NA, substantial spine loss on medium spiny neurons occurs upon withdrawal from various substances of abuse, including alcohol and cocaine (Spiga et al., 2014). Loss of spines is also likely accompanied by a loss of presynaptic boutons; additionally, regional alterations in dendritic arborization could also play a substantial role in the volume changes. While some of these changes may arise as secondary downstream effects due to toxicity after extended substance abuse, morphological changes are beginning to emerge as an important mediator of the effects of substances of abuse on the brain (Russo et al., 2010). Recently, Knabbe et al. (2022) found increased spine turnover and bouton loss in neocortical neurons of somatosensory and motor areas in live mice following a single ethanol administration. This study thus showed that drug-induced morphological changes can occur in brain areas not directly associated with drug-related behavior. If and how such observed morphological changes are critical to the development of addiction is not clear. In the following, we discuss how morphological plasticity processes akin to learning could lead to addiction.