An isoform of peroxisome proliferator-activated receptors (PPARs), PPAR gamma, is the receptor for the thiazolidinedione class of antidiabetic medications including pioglitazone. Neuroanatomical data indicate PPAR gamma localization in brain areas involved in drug addiction. Preclinical and clinical data have shown that pioglitazone reduces alcohol and opioid self-administration, relapse to drug seeking, and plays a role in emotional responses. Here, we investigated the behavioral effect of PPAR gamma manipulation on nicotine withdrawal in male Wistar rats and in male mice with neuron-specific PPAR gamma deletion (PPAR gamma(()(+/+)())) and their littermate wild-type (PPAR gamma((-/-))) controls. Real-time quantitative RT-PCR and RNAscope in situ hybridization assays were used for assessing the levels of expression and cell-type localization of PPAR gamma function, Memory, Mortality, Older subjects, Structural brain abnormalities during nicotine withdrawal. Brain site-specific microinjections of the PPAR gamma agonist pioglitazone were performed to explore the role of this system on nicotine withdrawal at a neurocircuitry level. Results showed that activation of PPAR gamma by pioglitazone abolished the expression of somatic and affective nicotine withdrawal signs in rats and in (PPAR gamma(()(+/+)())) mice. This effect was blocked by the PPAR gamma antagonist GW9662. During early withdrawal and protracted abstinence, the expression of PPAR gamma increased in GABAergic and glutamatergic cells of the amygdala and hippocampus, respectively. Hippocampal microinjections of pioglitazone reduced the expression of the physical signs of withdrawal, whereas excessive anxiety associated with protracted abstinence was prevented by pioglitazone microinjection into the amygdala. Our results demonstrate the implication of the neuronal PPAR gamma in nicotine withdrawal and indicates that activation of PPAR gamma may offer an interesting strategy for smoking cessation.