title: Endocannabinoid CB1 receptor-mediated rises in Ca(2+) and depolarization-induced suppression of inhibition within the laterodorsal tegmental nucleus.
abstract: Cannabinoid type 1 receptors (CB1Rs) are functionally active within the laterodorsal tegmental nucleus (LDT), which is critically involved in control of rapid eye movement sleep, cortical arousal, and motivated states. To further characterize the cellular consequences of activation of CB1Rs in this nucleus, we examined whether CB1R activation led to rises in intracellular Ca(2+) ([Ca(2+)]i) and whether processes shown in other regions to involve endocannabinoid (eCB) transmission were present in the LDT. Using a combination of Ca(2+) imaging in multiple cells loaded with Ca(2+) imaging dye via 'bulk-loading' or in single cells loaded with dye via a patch-clamp electrode, we found that WIN 55212-2 (WIN-2), a potent CB1R agonist, induced increases in [Ca(2+)]i which were sensitive to AM251, a CB1R antagonist. A proportion of rises persisted in TTX and/or low-extracellular Ca(2+) conditions. Attenuation of these increases by a reversible inhibitor of sarcoplasmic reticulum Ca(2+)-ATPases, suggests these rises occurred following release of Ca(2+) from intracellular stores. Under voltage clamp conditions, brief, direct depolarization of LDT neurons resulted in a decrease in the frequency and amplitude of AM251-sensitive, inhibitory postsynaptic currents (IPSCs), which was an action sensitive to presence of a Ca(2+) chelator. Finally, actions of DHPG, a mGlu1R agonist, on IPSC activity were examined and found to result in an AM251- and BAPTA-sensitive inhibition of both the frequency and amplitude of sIPSCs. Taken together, our data further characterize CB1R and eCB actions in the LDT and indicate that eCB transmission could play a role in the processes governed by this nucleus.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Soni
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark. kak1@sund.ku.dk.
authors.forename: Kristi A
authors.initials: KA
authors.lastname: Kohlmeier
mesh_terms: D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D063388:Endocannabinoids / Q000502:physiology*; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000502:physiology; D013681:Tegmentum Mesencephali / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*
chemical_list: D048588:Benzoxazines; D063388:Endocannabinoids; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; C103505:AM 251; D008734:Methoxyhydroxyphenylglycol; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D002118:Calcium; C010117:3,4-dihydroxyphenylglycol
keywords: Ca2+ imaging; DSI; LDT; Marijuana; Synaptic transmission; mGluR