title: Control of cannabinoid CB1 receptor function on glutamate axon terminals by endogenous adenosine acting at A1 receptors.
abstract: Marijuana is a widely used drug that impairs memory through interaction between its psychoactive constituent, Delta-9-tetrahydrocannabinol (Delta(9)-THC), and CB(1) receptors (CB1Rs) in the hippocampus. CB1Rs are located on Schaffer collateral (Sc) axon terminals in the hippocampus, where they inhibit glutamate release onto CA1 pyramidal neurons. This action is shared by adenosine A(1) receptors (A1Rs), which are also located on Sc terminals. Furthermore, A1Rs are tonically activated by endogenous adenosine (eADO), leading to suppressed glutamate release under basal conditions. Colocalization of A1Rs and CB1Rs, and their coupling to shared components of signal transduction, suggest that these receptors may interact. We examined the roles of A1Rs and eADO in regulating CB1R inhibition of glutamatergic synaptic transmission in the rodent hippocampus. We found that A1R activation by basal or experimentally increased levels of eADO reduced or eliminated CB1R inhibition of glutamate release, and that blockade of A1Rs with caffeine or other antagonists reversed this effect. The CB1R-A1R interaction was observed with the agonists WIN55,212-2 and Delta(9)-THC and during endocannabinoid-mediated depolarization-induced suppression of excitation. A1R control of CB1Rs was stronger in the C57BL/6J mouse hippocampus, in which eADO levels were higher than in Sprague Dawley rats, and the eADO modulation of CB1R effects was absent in A1R knock-out mice. Since eADO levels and A1R activation are regulated by homeostatic, metabolic, and pathological factors, these data identify a mechanism in which CB1R function can be controlled by the brain adenosine system. Additionally, our data imply that caffeine may potentiate the effects of marijuana on hippocampal function.
authors.affiliation: Electrophysiology Research Section, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224, USA.
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Hoffman
authors.forename: Nora
authors.initials: N
authors.lastname: Laaris
authors.forename: Masahito
authors.initials: M
authors.lastname: Kawamura
authors.forename: Susan A
authors.initials: SA
authors.lastname: Masino
authors.forename: Carl R
authors.initials: CR
authors.lastname: Lupica
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology; D001703:Biophysics; D056547:CA1 Region, Hippocampal / Q000166:cytology; D002110:Caffeine / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D013759:Dronabinol / Q000494:pharmacology; D004558:Electric Stimulation / Q000379:methods; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D018756:GABA Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D066298:In Vitro Techniques; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000166:cytology*; D018408:Patch-Clamp Techniques / Q000379:methods; D010721:Phosphinic Acids / Q000494:pharmacology; D010852:Picrotoxin / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism*; D011412:Propanolamines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D043682:Receptor, Adenosine A1 / Q000502:physiology*; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D014970:Xanthines / Q000494:pharmacology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
chemical_list: D000241:Adenosine; D048588:Benzoxazines; D002110:Caffeine; D002121:Calcium Channel Blockers; D013759:Dronabinol; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D018698:Glutamic Acid; D008734:Methoxyhydroxyphenylglycol; D009025:Morpholines; D009281:Naphthalenes; D010721:Phosphinic Acids; D010852:Picrotoxin; D010880:Piperidines; D011412:Propanolamines; D011720:Pyrazoles; D011810:Quinoxalines; D043682:Receptor, Adenosine A1; D043884:Receptor, Cannabinoid, CB1; D014970:Xanthines; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C085075:CGP 55845A; C103505:AM 251; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C056723:FG 9041; C051360:1,3-dipropyl-8-cyclopentylxanthine; C010117:3,4-dihydroxyphenylglycol