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Endocannabinoid CB1 receptor-mediated rises in Ca2+ and depolarization-induced suppression of inhibition within the laterodorsal tegmental nucleus

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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 Ca2+ ([Ca2+]i) and whether processes shown in other regions to involve endocannabinoid (eCB) transmission were present in the LDT. Using a combination of Ca2+ imaging in multiple cells loaded with Ca2+ 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 [Ca2+]i which were sensitive to AM251, a CB1R antagonist. A proportion of rises persisted in TTX and/or low-extracellular Ca2+ conditions. Attenuation of these increases by a reversible inhibitor of sarcoplasmic reticulum Ca2+-ATPases, suggests these rises occurred following release of Ca2+ 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 Ca2+ 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.

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Acknowledgments

We acknowledge Mr. Jason Allen Teem for his excellent laboratory skills and assistance in the preparation of brain slices and conducting portions of the immunohistochemistry presented in this report. We would also like to express our thanks to the reviewers who suggested experiments that improved the MS. Funding for this work has been provided in part by a stipend to NS and equipment grants from the Drug Research Academy, funds from the University of Copenhagen and, in part, by a grant to KAK from the Philip Morris External Research Program.

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The authors disclose that they have no conflicts of interest with respect to this manuscript.

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  1. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark

    Neeraj Soni & Kristi A. Kohlmeier

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  1. Neeraj Soni
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Correspondence to Kristi A. Kohlmeier.

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Soni, N., Kohlmeier, K.A. Endocannabinoid CB1 receptor-mediated rises in Ca2+ and depolarization-induced suppression of inhibition within the laterodorsal tegmental nucleus. Brain Struct Funct 221, 1255–1277 (2016). https://doi.org/10.1007/s00429-014-0969-4

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