title: Repeated cannabinoid administration increases indices of noradrenergic activity in rats.
abstract: The present study examined the impact of repeated administration of a synthetic cannabinoid agonist, WIN 55,212-2 on the coeruleo-cortical pathway, a circuit implicated in anxiety. Male Sprague-Dawley rats received repeated systemic injections of WIN 55,212-2 (3.0 mg/kg). A separate group of rats received repeated WIN 55,212-2 injections followed by a period of abstinence. Control animals received vehicle injections. Ninety minutes following the last injection on day 8, anxiety-related behavior was assessed using the elevated plus maze. The abstinent group was tested after another 8 days. Following behavioral testing, brain tissue was extracted from the locus coeruleus (LC) and probed for tyrosine hydroxylase (TH) expression. In a separate group of animals, in vivo microdialysis was used to monitor extracellular norepinephrine efflux in the frontal cortex following repeated WIN 55,212-2 administration and following a period of abstinence. Repeated administration of WIN 55,212-2 evoked an anxiogenic-like response that was accompanied by an increase in TH protein expression in the LC. A similar neurochemical profile was observed using in vivo microdialysis where an augmented increase in cortical norepinephrine efflux was identified in response to a systemic injection of WIN 55,212-2 on day 8. Anxiety-like behavior, catecholamine synthesizing enzyme levels and NE efflux returned to control values after 8 days of abstinence. The present findings indicate that repeated administration of a synthetic cannabinoid receptor agonist induces transient anxiety-like behaviors that correlate with increases in catecholamine synthesizing enzyme expression in the LC and augmented norepinephrine efflux in response to a challenge injection of WIN 55,212-2.
authors.affiliation: Thomas Jefferson University, Department of Neurosurgery, Farber Institute for Neurosciences, Philadelphia, PA 19107, United States. michelle.page@jefferson.edu
authors.forename: M E
authors.initials: ME
authors.lastname: Page
authors.forename: V C
authors.initials: VC
authors.lastname: Oropeza
authors.forename: S E
authors.initials: SE
authors.lastname: Sparks
authors.forename: Y
authors.initials: Y
authors.lastname: Qian
authors.forename: A S
authors.initials: AS
authors.lastname: Menko
authors.forename: E J
authors.initials: EJ
authors.lastname: Van Bockstaele
mesh_terms: D000818:Animals; D001007:Anxiety / Q000139:chemically induced / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects; D048588:Benzoxazines / Q000494:pharmacology; D015153:Blotting, Western; D002186:Cannabinoids / Q000008:administration & dosage / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism / Q000502:physiology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists; D013268:Stimulation, Chemical; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D048588:Benzoxazines; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D014446:Tyrosine 3-Monooxygenase; D009638:Norepinephrine