Nicotine, a major psychoactive component of tobacco smoke, alters GABA modulation of dopamine (DA) neurons in the ventral tegmental area (VTA). Changes in structural neuroplasticity can occur in GABAergic parvalbumin (PRV) positive neurons, which are enveloped by structures of the extracellular matrix called perineuronal nets (PNNs). In the current study, rats were trained to self-administer IV nicotine (0.03 mg/kg/infusion) for 21 days in 1-h daily sessions with an incrementing fixed ratio requirement; a control group received saline infusions. At either 45 min or 72 hr after the last session, immunofluorescence measurements for PNNs, PRV and c-Fos were conducted. In VTA, nicotine self-administration reduced the number of PRV+ cells surrounded by PNNs at 45 min, as well as reducing the intensity of PNNs, suggesting a remodeling of GABA interneurons in this region; the number of PRV+ cells surrounded by PNNs was also reduced at 72 hr. A similar reduction of PNNs occurred in orbitofrontal cortex (OFC), but not in medial prefrontal cortex (PrL or IL), 45 min after the last session; PNNs were not detected in nucleus accumbens (shell or core). The reduction of PNNs in VTA and OFC was unrelated to c-Fos+ cells, as the percent of WFA+ cells co-expressing c-Fos was decreased in OFC, but not in VTA. Thus, nicotine self-administration remodeled PNNs surrounding GABA interneurons in VTA and its indirect connections to OFC, suggesting a new possible molecular target where nicotine-induced neuroplasticity takes place. PNN manipulations may prevent or reverse the different stages of tobacco addiction.