title: A role for 2-arachidonoylglycerol and endocannabinoid signaling in the locomotor response to novelty induced by olfactory bulbectomy.
abstract: Bilateral olfactory bulbectomy (OBX) in rodents produces behavioral and neurochemical changes associated clinically with depression and schizophrenia. Most notably, OBX induces hyperlocomotion in response to the stress of exposure to a novel environment. We examined the role of the endocannabinoid system in regulating this locomotor response in OBX and sham-operated rats. In our study, OBX-induced hyperactivity was restricted to the first 3 min of the open field test, demonstrating the presence of novelty (0-3 min) and habituation (3-30 min) phases of the open field locomotor response. Levels of the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide were decreased in the ventral striatum, a brain region deafferented by OBX, whereas cannabinoid receptor densities were unaltered. In sham-operated rats, 2-AG levels in the ventral striatum were negatively correlated with distance traveled during the novelty phase. Thus, low levels of 2-AG are reflected in a hyperactive open field response. This correlation was not observed in OBX rats. Conversely, 2-AG levels in endocannabinoid-compromised OBX rats correlated with distance traveled during the habituation phase. In OBX rats, pharmacological blockade of cannabinoid CB(1) receptors with either AM251 (1 mg kg(-1) i.p.) or rimonabant (1 mg kg(-1) i.p.) increased distance traveled during the habituation phase. Thus, blockade of endocannabinoid signaling impairs habituation of the hyperlocomotor response in OBX, but not sham-operated, rats. By contrast, in sham-operated rats, effects of CB(1) antagonism were restricted to the novelty phase. These findings suggest that dysregulation in the endocannabinoid system, and 2-AG in particular, is implicated in the hyperactive locomotor response induced by OBX. Our studies suggest that drugs that enhance 2-AG signaling, such as 2-AG degradation inhibitors, might be useful in human brain disorders modeled by OBX.
authors.affiliation: Neuroscience and Behavior Program, Department of Psychology, University of Georgia, Athens, GA 30602-3013, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Eisenstein
authors.forename: Jason R
authors.initials: JR
authors.lastname: Clapper
authors.forename: Philip V
authors.initials: PV
authors.lastname: Holmes
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Hohmann
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000502:physiology*; D001345:Autoradiography; D063385:Cannabinoid Receptor Modulators / Q000502:physiology*; D002851:Chromatography, High Pressure Liquid; D003511:Cyclohexanols; D003720:Densitometry; D004298:Dopamine / Q000502:physiology; D063388:Endocannabinoids; D004777:Environment; D005989:Glycerides / Q000502:physiology*; D008032:Limbic System / Q000502:physiology; D050356:Lipid Metabolism / Q000502:physiology; D008297:Male; D013058:Mass Spectrometry; D009043:Motor Activity / Q000502:physiology*; D009830:Olfactory Bulb / Q000502:physiology*; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D019275:Radiopharmaceuticals; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000502:physiology; D000077285:Rimonabant; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D003511:Cyclohexanols; D063388:Endocannabinoids; D005989:Glycerides; D010880:Piperidines; D011720:Pyrazoles; D019275:Radiopharmaceuticals; D043884:Receptor, Cannabinoid, CB1; C103505:AM 251; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; C094503:glyceryl 2-arachidonate; D000077285:Rimonabant; D004298:Dopamine