title: Receptor subtypes and signal transduction mechanisms contributing to the estrogenic attenuation of cannabinoid-induced changes in energy homeostasis.
abstract: We examined the receptor subtypes and signal transduction mechanisms contributing to the estrogenic modulation of cannabinoid-induced changes in energy balance. Food intake and, in some cases, O2 consumption, CO2 production and the respiratory exchange ratio were evaluated in ovariectomized female guinea pigs treated s.c. with the cannabinoid receptor agonist WIN 55,212-2 or its cremephor/ethanol/0.9% saline vehicle, and either with estradiol benzoate (EB), the estrogen receptor (ER) α agonist PPT, the ERβ agonist DPN, the Gq-coupled membrane ER agonist STX, the GPR30 agonist G-1 or their respective vehicles. Patch-clamp recordings were performed in hypothalamic slices. EB, STX, PPT and G-1 decreased daily food intake. Of these, EB, STX and PPT blocked the WIN 55,212-2-induced increase in food intake within 1-4 h. The estrogenic diminution of cannabinoid-induced hyperphagia correlated with a rapid (within 15 min) attenuation of cannabinoid-mediated decreases in glutamatergic synaptic input onto arcuate neurons, which was completely blocked by inhibition of protein kinase C (PKC) and attenuated by inhibition of protein kinase A (PKA). STX, but not PPT, mimicked this rapid estrogenic effect. However, PPT abolished the cannabinoid-induced inhibition of glutamatergic neurotransmission in cells from animals treated 24 h prior. The estrogenic antagonism of this presynaptic inhibition was observed in anorexigenic proopiomelanocortin neurons. These data reveal that estrogens negatively modulate cannabinoid-induced changes in energy balance via Gq-coupled membrane ER- and ERα-mediated mechanisms involving activation of PKC and PKA. As such, they further our understanding of the pathways through which estrogens act to temper cannabinoid sensitivity in regulating energy homeostasis in females.
authors.affiliation: Department of Basic Medical Sciences, Western University of Health Sciences, Pomona, CA 91766, USA.
authors.forename: Neal
authors.initials: N
authors.lastname: Washburn
authors.forename: Amanda
authors.initials: A
authors.lastname: Borgquist
authors.forename: Kate
authors.initials: K
authors.lastname: Wang
authors.forename: Garrett S
authors.initials: GS
authors.lastname: Jeffery
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Kelly
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Wagner
mesh_terms: D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology; D002186:Cannabinoids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004435:Eating / Q000187:drug effects / Q000502:physiology; D004734:Energy Metabolism / Q000187:drug effects* / Q000235:genetics; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D043882:Receptors, Cannabinoid / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology
chemical_list: D048588:Benzoxazines; D002186:Cannabinoids; D004967:Estrogens; D009025:Morpholines; D009281:Naphthalenes; 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