Activation of PPARγ 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 antidiabetic 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␥ (Ϫ/Ϫ)) and their littermate wild-type (PPAR␥ (ϩ/ϩ)) 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␥ (ϩ/ϩ)) 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.

The (Poly)Pharmacology of Cannabidiol in Neurological and Neuropsychiatric Disorders: Molecular Mechanisms and Targets

“…Domi et al [ 131 ] investigated the role of PPARγ in anxiety and stress response in mice, showing that its activation prevents the anxiogenic effect of acute stress, while its ablation or the administration of a specific antagonist exacerbates basal anxiety and enhances sensitivity to stress. These results, combined with other studies including preclinical and clinical trials [ 133 , 134 , 135 , 136 , 137 ], demonstrate the therapeutic potential of PPARγ agonists for various neuropsychiatric disorders and drug dependencies. Interestingly, since CBD is a selective PPARγ agonist [ 19 , 138 ], many of its therapeutic effects in alleviating neuropsychiatric disorders could be mediated by PPARγ signaling and by its regulation of the mesolimbic DA activity [ 139 ].…”

Effects of Embryonic Inflammation and Adolescent Psychosocial Environment on Cognition and Hippocampal Staufen in Middle-Aged Mice

“…RNAscope in situ hybridization was performed as previously described ( Domi et al, 2019 ; Gavini et al, 2020 ). The RNAscope assay was performed on formalin-fixed, paraffin-embedded (FFPE) tissue.…”

Therapeutic Potential of Peroxisome Proliferator-Activated Receptor (PPAR) Agonists in Substance Use Disorders: A Synthesis of Preclinical and Human Evidence

“…One recent study found that PPAR-γ activation may play a role in nicotine withdrawal. Administration of pioglitazone prior to assessment of nicotine withdrawal attenuated somatic and anxiety-like signs of withdrawal in rats and in wild-type mice with intact PPAR-γ, but not in conditional neuronal PPAR-γ KO mice [42]. In addition, the effect of pioglitazone on both somatic and anxiety-like signs of nicotine withdrawal was blocked by pre-treatment with the PPAR-γ antagonist GW9662 in WT mice [42].…”