title: Systemic administration of WIN 55,212-2 increases norepinephrine release in the rat frontal cortex.
abstract: Cannabinoid agonists modulate a variety of behavioral functions by activating cannabinoid receptors that are widely distributed throughout the central nervous system. In the present study, norepinephrine efflux was assessed in the frontal cortex of rats that received a systemic administration of the cannabinoid agonist, WIN 55,212-2. The synthetic cannabinoid agonist dose-dependently increased the release of norepinephrine in this brain region. Pretreatment with the cannabinoid receptor antagonist, SR 141716A, blocked the increase in norepinephrine release. To identify sites of cellular activation, immunocytochemical detection of c-Fos was combined with detection of the catecholamine synthesizing enzyme, tyrosine hydroxylase (TH), in the brainstem nucleus locus coeruleus (LC), a region that is the sole source of norepinephrine to the frontal cortex. Systemic administration of WIN 55,212-2 significantly increased the number of c-Fos immunoreactive cells within TH-containing neurons in the LC compared to vehicle-treated rats. Pretreatment with SR 141716A inhibited the WIN 55,212-2 induced c-Fos expression, while the antagonist alone did not affect c-Fos expression. Taken together, these data indicate that systemically administered cannabinoid agonists stimulate norepinephrine release in the frontal cortex by activating noradrenergic neurons in the coeruleo-frontal cortex pathway. These effects may partially underlie changes in attention, arousal and anxiety observed following exposure to cannabis-based drugs.
authors.affiliation: Department of Neurosurgery, Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, PA 19107, USA. veronica.oropeza@jefferson.edu
authors.forename: V C
authors.initials: VC
authors.lastname: Oropeza
authors.forename: M E
authors.initials: ME
authors.lastname: Page
authors.forename: E J
authors.initials: EJ
authors.lastname: Van Bockstaele
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005625:Frontal Lobe / Q000737:chemistry / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008125:Locus Coeruleus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D009025:Morpholines / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology*; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009638:Norepinephrine / Q000032:analysis / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; D016760:Proto-Oncogene Proteins c-fos; D043882:Receptors, Cannabinoid; 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