title: Deficient adolescent social behavior following early-life inflammation is ameliorated by augmentation of anandamide signaling.
abstract: Early-life inflammation has been shown to exert profound effects on brain development and behavior, including altered emotional behavior, stress responsivity and neurochemical/neuropeptide receptor expression and function. The current study extends this research by examining the impact of inflammation, triggered with the bacterial compound lipopolysaccharide (LPS) on postnatal day (P) 14, on social behavior during adolescence. We investigated the role that the endocannabinoid (eCB) system plays in sociability after early-life LPS. To test this, multiple cohorts of Sprague Dawley rats were injected with LPS on P14. In adolescence, rats were subjected to behavioral testing in a reciprocal social interaction paradigm as well as the open field. We quantified eCB levels in the amygdala of P14 and adolescent animals (anandamide and 2-arachidonoylglycerol) as well as adolescent amygdaloid cannabinoid receptor 1 (CB1) binding site density and the hydrolytic activity of the enzyme fatty acid amide hydrolase (FAAH), which metabolizes the eCB anandamide. Additionally, we examined the impact of FAAH inhibition on alterations in social behavior. Our results indicate that P14 LPS decreases adolescent social behavior (play and social non-play) in males and females at P40. This behavioral alteration is accompanied by decreased CB1 binding, increased anandamide levels and increased FAAH activity. Oral administration of the FAAH inhibitor PF-04457845 (1mg/kg) prior to the social interaction task normalizes LPS-induced alterations in social behavior, while not affecting social behavior in the control group. Infusion of 10ng PF-04457845 into the basolateral amygdala normalized social behavior in LPS injected females. These data suggest that alterations in eCB signaling following postnatal inflammation contribute to impairments in social behavior during adolescence and that inhibition of FAAH could be a novel target for disorders involving social deficits such as social anxiety disorders or autism.
authors.affiliation: Hotchkiss Brain Institute, Cumming School of Medicine, Mathison Center for Mental Health, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada; Department of Neuroscience, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada. Electronic address: vdoenni@ucalgary.ca.
authors.forename: V M
authors.initials: VM
authors.lastname: Doenni
authors.affiliation: Hotchkiss Brain Institute, Cumming School of Medicine, Mathison Center for Mental Health, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada.
authors.forename: J M
authors.initials: JM
authors.lastname: Gray
authors.affiliation: Hotchkiss Brain Institute, Cumming School of Medicine, Mathison Center for Mental Health, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada.
authors.forename: C M
authors.initials: CM
authors.lastname: Song
authors.affiliation: Department of Psychiatry, Vanderbilt School of Medicine, Vanderbilt Brain Institute, Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, 1211 Medical Center Dr, Nashville, TN 37232, United States.
authors.forename: S
authors.initials: S
authors.lastname: Patel
authors.affiliation: Hotchkiss Brain Institute, Cumming School of Medicine, Mathison Center for Mental Health, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada.
authors.forename: M N
authors.initials: MN
authors.lastname: Hill
authors.affiliation: Hotchkiss Brain Institute, Cumming School of Medicine, Mathison Center for Mental Health, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada.
authors.forename: Q J
authors.initials: QJ
authors.lastname: Pittman
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000679:Amygdala / Q000378:metabolism*; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001522:Behavior, Animal; D063388:Endocannabinoids / Q000378:metabolism*; D005260:Female; D005989:Glycerides / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000523:psychology*; D008070:Lipopolysaccharides; D008297:Male; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D011724:Pyridazines / Q000008:administration & dosage; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D015398:Signal Transduction; D012919:Social Behavior; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; D008070:Lipopolysaccharides; D053284:Polyunsaturated Alkamides; D011724:Pyridazines; D043884:Receptor, Cannabinoid, CB1; D014508:Urea; D000099252:Fatty Acid Amide Hydrolases; C560620:N-pyridazin-3-yl-4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzylidene)piperidine-1-carboxamide; C094503:glyceryl 2-arachidonate; C078814:anandamide
keywords: Amygdala; Anxiety; Autism; Early-life inflammation; Endocannabinoid; FAAH; LPS; Social behavior