title: Dual role of PPAR-γ in induction and expression of behavioral sensitization to cannabinoid receptor agonist WIN55,212-2.
abstract: Behavioral sensitization (B.S.) is a pathophysiological animal model for stimulant-induced psychosis and addiction. Accumulated evidence indicates that inflammatory processes are involved in psychostimulants effects in the CNS. Cannabinoids like WIN55,212-2 act as potential activators of PPAR-γ and affects the inflammatory status of the CNS. The purpose of this study is to determine PPAR-γ role in induction and expression of B.S. and the coincident inflammatory responses developed by WIN55,212-2 (WIN). Using open-field test, locomotor activity was monitored in animals treated with intraperitoneal low-dose WIN single or repeated injections. Concurrent striatal COX-2 and TNF-α levels and PPAR-γ activity were determined by immunoblotting assay. Effects of concomitant chronic or acute PPAR-γ pharmacological inhibition (with GW9662) were then investigated on behavioral and biochemical variables. WIN enhanced locomotor activity and while administered chronically augmented cytosolic COX-2 and TNF-α and also PPAR-γ nuclear levels. GW9662 co-administration completely prevented the induction of sensitizing effects of chronic WIN and altered the inflammatory responses. However, the expression of B.S. was intensified with GW9662 as assessed by increased locomotion after WIN challenge following 48 h withdrawal. Neuroinflammation and locomotor excitability in animals received just a single-dose WIN were also escalated with GW9662. Our findings conclude that PPAR-γ could play different key roles during B.S. development by WIN. Although PPAR-γ is mostly known for neuroprotective and anti-inflammatory effects, our data indicate that it mediates the B.S. induction by chronic WIN. However, while the B.S. was induced, PPAR-γ could play a homeostatic role opposing the expressed B.S. escalation.
authors.affiliation: Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, 19615-1178, Tehran, Iran.
authors.forename: Leili
authors.initials: L
authors.lastname: Enayatfard
authors.forename: Farzaneh
authors.initials: F
authors.lastname: Rostami
authors.forename: Sanaz
authors.initials: S
authors.lastname: Nasoohi
authors.forename: Shahrbanoo
authors.initials: S
authors.lastname: Oryan
authors.forename: Abolhassan
authors.initials: A
authors.lastname: Ahmadiani
authors.forename: Leila
authors.initials: L
authors.lastname: Dargahi
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology*; D015415:Biomarkers; D002186:Cannabinoids / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D008124:Locomotion / Q000187:drug effects; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology*; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011595:Psychomotor Agitation / Q000209:etiology*; D051381:Rats; D017208:Rats, Wistar; D043882:Receptors, Cannabinoid / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D048588:Benzoxazines; D015415:Biomarkers; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; D047495:PPAR gamma; D043882:Receptors, Cannabinoid; D014409:Tumor Necrosis Factor-alpha; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat