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Activation of peroxisome proliferator-activated receptor γ reduces alcohol drinking and seeking by modulating multiple mesocorticolimbic regions in rats.

ABSTRACT: Peroxisome proliferator-activated receptor γ (PPARγ) is an intracellular transcription factor whose signaling activation by the selective agonist pioglitazone reduces alcohol drinking and alcohol-seeking behavior in rats. The present study utilized the two-bottle choice and operant self-administration procedures to investigate neuroanatomical substrates that mediate the effects of PPARγ agonism on alcohol drinking and seeking in msP rats. Bilateral infusions of pioglitazone (0, 5, and 10 μg/μl) in the rostromedial tegmental nucleus (RMTg) decreased voluntary alcohol drinking and alcohol self-administration. Microinjections of pioglitazone in the ventral tegmental area (VTA), central amygdala (CeA), and nucleus accumbens (NAc) shell had no such effect. Notably, water, food, and saccharin consumption was unaltered by either treatment. The yohimbine-induced reinstatement of alcohol seeking was prevented by infusions of pioglitazone (0, 2.5, 5, and 10 μg/μl) in the CeA, VTA, and RMTg but not in the NAc shell. These results emphasize the involvement of mesocorticolimbic circuitries in mediating the effects of PPARγ agonists on alcohol drinking and seeking. These results will facilitate future studies that investigate the pathophysiological role of PPARγ in alcohol use disorder and help clarify the mechanisms by which the activation of this receptor decreases the motivation for drinking.

SUBMITTER: Fotio Y

PROVIDER: S-EPMC7852659 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Activation of peroxisome proliferator-activated receptor γ reduces alcohol drinking and seeking by modulating multiple mesocorticolimbic regions in rats.

Fotio Yannick Y Borruto Anna Maria AM Benvenuti Federica F Demopulos Gregory G Gaitanaris George G Roberto Marisa M Ciccocioppo Roberto R

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20200701 2

Peroxisome proliferator-activated receptor γ (PPARγ) is an intracellular transcription factor whose signaling activation by the selective agonist pioglitazone reduces alcohol drinking and alcohol-seeking behavior in rats. The present study utilized the two-bottle choice and operant self-administration procedures to investigate neuroanatomical substrates that mediate the effects of PPARγ agonism on alcohol drinking and seeking in msP rats. Bilateral infusions of pioglitazone (0, 5, and 10 μg/μl) ...[more]

PMID: 32610339

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Project description:BackgroundPeroxisome proliferator-activated receptor gamma (PPARγ) signaling has been shown to regulate lipogenesis and lipid accumulation. Previous studies have shown that hepatic PPARγ is up-regulated in steatotic liver of both animal and human. However, the effects of hepatic PPARγ signaling on alcoholic liver disease (ALD) remain elusive.MethodsTo determine the role of hepatic PPARγ signaling on ALD, wild-type (WT) and hepatocyte-specific PPARγ knockdown (PPARγ∆Hep) mice were fed a modified Lieber-DeCarli alcohol or isocaloric maltose dextrin control liquid diet for 8 weeks to induce ALD. Blood parameters, hepatic steatosis, and inflammation were measured after 8-week alcohol feeding.ResultsAlcohol feeding to WT mice resulted in liver damage (alanine aminotransferase [ALT], 94.68 ± 17.05 U/L; aspartate aminotransferase [AST], 55.87 ± 11.29 U/L), which was significantly alleviated by hepatic PPARγ knockdown (ALT, 57.36 ± 14.98 U/L; AST, 38.06 ± 3.35 U/L). Alcohol feeding led to marked lipid accumulation and up-regulation of lipogenic genes including fatty acid transport protein 1 (FATP1), acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN), lipin1 (LIPIN1), diacylglycerol acyltransferase 1 (DGAT1), and diacylglycerol acyltransferase 2 (DGAT2) in the livers of WT mice. Knockdown of hepatic PPARγ significantly alleviated alcohol-induced lipid accumulation and abolished the up-regulation of FASN, DGAT1, and DGAT2. Silencing of PPARγ in FL83B cells significantly decreased ethanol (EtOH)-, linoleic acid-, and EtOH plus linoleic acid-induced lipid accumulation. Knockdown of hepatic PPARγ also significantly reduced alcohol-induced inflammatory chemokine (monocyte chemotactic protein 1 [MCP1], keratinocyte-derived chemokine [KC], interferon gamma-induced protein 10 [IP-10]) and inflammatory infiltration (lymphocyte antigen 6 complex, locus G [Ly6G], and F4/80).ConclusionsThe results suggest that hepatic PPARγ signaling contributes to alcohol-induced liver injury by promoting hepatic steatosis and inflammation.

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Activation of peroxisome proliferator-activated receptor γ reduces alcohol drinking and seeking by modulating multiple mesocorticolimbic regions in rats.

Publications

Activation of peroxisome proliferator-activated receptor γ reduces alcohol drinking and seeking by modulating multiple mesocorticolimbic regions in rats.

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