title: Cannabinoid exposure in pubertal rats increases spontaneous ethanol consumption and NMDA receptor associated protein levels.
abstract: Recent evidence suggests an involvement of the endocannabinoid system in the regulation of emotional behaviour and ethanol intake. Here we investigated age-specific acute behavioural effects of the cannabinoid receptor agonist WIN 55,212-2 (WIN) on anxiety-related behaviour and voluntary ethanol consumption in rats. Animals were treated with WIN (1.2 mg/kg)/vehicle at puberty onset on postnatal day (PD) 40, or at adulthood (PD 100). Animals were tested in the elevated plus-maze (EPM) and the light/dark emergence test (EMT) and for the initial response to alcohol in a free-choice ethanol consumption paradigm. Acute WIN treatment increased anxiety-related behaviours, and this effect was found to be partially more pronounced in pubertal than adult rats. Additionally, increased intake of higher ethanol solutions after cannabinoid treatment was only observed in pubertal rats. These drug-induced behavioural changes during puberty are paralleled by induction of the NR1 subunit of the NMDA receptor in the medial prefrontal cortex and the striatum. Moreover, pubertal but not adult WIN administration increased the levels of the scaffold protein Homer in these brain regions. Enhanced CB₁ receptor levels in the reinforcement system were also observed in pubertal compared to adult rats. These data support the notion that puberty is a highly vulnerable period for the aversive effects of cannabinoid exposure. In particular, augmented ethanol intake in pubertal cannabinoid-exposed animals might be related to some extent to increased emotional behaviour and in particular to enhanced NMDA and CB₁ receptor signalling.
authors.affiliation: Translational Neuroscience Facility, Department of Physiology, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Matthias
authors.initials: M
authors.lastname: Klugmann
authors.forename: Viktoria
authors.initials: V
authors.lastname: Klippenstein
authors.forename: F Markus
authors.initials: FM
authors.lastname: Leweke
authors.forename: Rainer
authors.initials: R
authors.lastname: Spanagel
authors.forename: Miriam
authors.initials: M
authors.lastname: Schneider
mesh_terms: D000367:Age Factors; D000428:Alcohol Drinking / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D048588:Benzoxazines / Q000494:pharmacology*; D002186:Cannabinoids / Q000819:agonists / Q000378:metabolism / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism; D004644:Emotions / Q000187:drug effects; D000431:Ethanol / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D000072233:Homer Scaffolding Proteins; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012741:Sexual Maturation
chemical_list: D048588:Benzoxazines; D002186:Cannabinoids; D002352:Carrier Proteins; D000072233:Homer Scaffolding Proteins; D009025:Morpholines; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; D016194:Receptors, N-Methyl-D-Aspartate; D000431:Ethanol; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone