ACTIVATION OF PPAR ATTENUATES ALCOHOL DRINKING AND EXERTS POTENT ANTISTRESS ACTIONS: POSSIBLE INVOLVEMENT OF GABA-MEDIATED MECHANISMS

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Ciccocioppo, R1, Domi, E1,2, Stopponi, S1, Fotio, Y1, Cippitelli, A1, Casarola, F1, Brunori, G1, Domi, A1, Borruto, AM1,  Soverchia, l1, Ubaldi, M1,

 

1School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, Italy

2 Department of Clinical and Experimental Medicine, Linkopings University, Linkoping, Sweden

 

Peroxisome Proliferator-Activated Receptors γ (PPARγ) is one of the three isoforms of the PPARs nuclear receptor family. Activation of PPARγ by the synthetic ligands pioglitazone and rosiglitazone attenuate alcohol self-administration and stress-induced relapse to alcohol seeking in the rat.  Moreover, chronic administration of pioglitazone during binge alcohol intoxication attenuates the expression of withdrawal symptoms, blunts rebound anxiety and protects from alcohol-induced neuronal damage and cognitive deficits. Results also show that pioglitazone, despite being unable to modify basal anxiety markedly attenuates the anxiogenic effect of  restraint stress in rodents. Using mice carrying a genetic ablation of neuronal PPARγ (PPARγNestinCre), we demonstrate that a lack of receptors, specifically in neurons, exacerbates basal anxiety and enhances stress sensitivity.  Consistently, administration of GW9662, a selective PPARg antagonist, elicits a marked anxiogenic response in PPARγ wild-type (Wt) but not in PPARγNestinCre KO mice.  Between Wt and KO mice no differences were noted in hypothalamic regions responsible for hormonal response to stress nor in blood corticosterone levels, suggesting that the stress-attenuating properties of PPARγ is unrelated to modulation of hormonal response to acute stress.  The anxiogenic response elicited by stress is instead selectively abolished by site-specific  microinjection of pioglitazone, into the amygdala. No drug effect was observed following microinjection into the hippocampus. Immunoistochemical results also revealed that in the central amygdala  PPARg heavily co-localizes with GABAergic neurons supporting the possibility that the anti-stress and alcohol reducing properties of  PPARγ agonists may be linked to their ability to modulate GABAergic transmission in this brain area.

(Support: RO1 AA017447)

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