Activation of PPAR? Attenuates the Expression of Physical and Affective Nicotine Withdrawal Symptoms through Mechanisms Involving Amygdala and Hippocampus Neurotransmission.

ABSTRACT: An isoform of peroxisome proliferator-activated receptors (PPARs), PPAR?, is the receptor for the thiazolidinedione class of anti-diabetic medications including pioglitazone. Neuroanatomical data indicate PPAR? 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? manipulation on nicotine withdrawal in male Wistar rats and in male mice with neuron-specific PPAR? deletion (PPAR?(-/-)) and their littermate wild-type (PPAR?(+/+)) 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? during nicotine withdrawal. Brain site-specific microinjections of the PPAR? agonist pioglitazone were performed to explore the role of this system on nicotine withdrawal at a neurocircuitry level. Results showed that activation of PPAR? by pioglitazone abolished the expression of somatic and affective nicotine withdrawal signs in rats and in (PPAR?(+/+)) mice. This effect was blocked by the PPAR? antagonist GW9662. During early withdrawal and protracted abstinence, the expression of PPAR? 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? in nicotine withdrawal and indicates that activation of PPAR? may offer an interesting strategy for smoking cessation.SIGNIFICANCE STATEMENT Smoking cessation leads the occurrence of physical and affective withdrawal symptoms representing a major burden to quit tobacco use. Here, we show that activation of PPAR? prevents the expression of both somatic and affective signs of nicotine withdrawal. At molecular levels results show that PPAR? expression increases in GABAergic cells in the hippocampus and in GABA- and glutamate-positive cells in the basolateral amygdala. Hippocampal microinjections of pioglitazone reduce the insurgence of the physical withdrawal signs, whereas anxiety linked to protracted abstinence is attenuated by pioglitazone injected into the amygdala. Our results demonstrate the implication of neuronal PPAR? in nicotine withdrawal and suggest that PPAR? agonism may represent a promising treatment to aid smoking cessation.

SUBMITTER: Domi E 

PROVIDER: S-EPMC6891057 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature