The endogenous opioid and cannabinoid systems are powerful neurophysiological modulators of excitability in the brain, and have been linked to numerous behaviors. They are also substrates for drugs of abuse. Yet despite their unique molecular and pharmacological identities, the systems often appear to be intertwined, and drugs targeted to one system can modify responses mediated by the other system. The cellular interface between opioids and cannabinoids is not generally understood: it probably varies depending on the brain structures and behaviors involved. The mammalian hippocampus has intricate endogenous opioid and cannabinoid systems which have been studied individually. However, there is virtually no information about the ways in which they overlap or how they might interact. A potentially crucial link may be provided by the neuropeptide, cholecystokinin (CCK), which potently controls actions mediated by a major opioid receptor, the f-receptor (MOR), at both cellular and behavioral levels. The endogenous cannabinoid system in hippocampus is targeted mainly to the particular set of GABAergic interneurons that also contain CCK. In hippocampus, the brain cannabinoid receptor, CB1, is almost exclusively expressed by CCK-containing interneurons. The f-opioid receptor is localized on the neurochemically-distinct, parvalbumin-containing interneurons, that express neither CCK nor CB1. The precise and complex convergence of these three systems onto interneurons that target pyramidal cells, which are the major hippocampal output neurons, cannot be a chance occurrence. The objective of this proposal is to test the Working Hypothesis that the endogenous opioid, cannabinoid and CCK systems mutually interact via hippocampal interneurons, and thereby jointly regulate the excitability and susceptibility to short- and long-term plasticity of the pyramidal cells. The prominent roles of these systems in drug abuse and major brain disorders such as epilepsy and schizophrenia underscore the significance of the inherent unresolved questions. We will use a variety of experimental approaches in in vitro brain slices, including electrophysiological, immunocytochemical, and optical techniques, to test the major hypothesis of this project.
The Specific Aims are to test the following hypotheses: 1. The interneurons that are sensitive to opioids and cannabinoids can be functionally classified by their pharmacological properties. 2. CCK affects both f-opioid and endocannabinoid-sensitive interneurons. 3. Short-term inhibitory response plasticities mediated via MORs and CB1 interact with each other and with CCK. 4. Long-term inhibitory response plasticities mediated via MORs and CB1 interact with each other and with CCK.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Neurobiology of Learning and Memory Study Section (LAM)
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Nadler, Laurie S
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University of Maryland Baltimore
Schools of Medicine
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Tang, Ai-Hui; Alger, Bradley E (2015) Homer protein-metabotropic glutamate receptor binding regulates endocannabinoid signaling and affects hyperexcitability in a mouse model of fragile X syndrome. J Neurosci 35:3938-45
Nagode, Daniel A; Tang, Ai-Hui; Yang, Kun et al. (2014) Optogenetic identification of an intrinsic cholinergically driven inhibitory oscillator sensitive to cannabinoids and opioids in hippocampal CA1. J Physiol 592:103-23
Mattison, Hayley A; Bagal, Ashish A; Mohammadi, Michael et al. (2014) Evidence of calcium-permeable AMPA receptors in dendritic spines of CA1 pyramidal neurons. J Neurophysiol 112:263-75
Alger, Bradley E; Tang, Ai-Hui (2012) Do cannabinoids reduce brain power? Nat Neurosci 15:499-501
Wang, Meina; Hill, Matthew N; Zhang, Longhua et al. (2012) Acute restraint stress enhances hippocampal endocannabinoid function via glucocorticoid receptor activation. J Psychopharmacol 26:56-70
Alger, Bradley E (2012) Endocannabinoids at the synapse a decade after the dies mirabilis (29 March 2001): what we still do not know. J Physiol 590:2203-12
Tang, Ai-Hui; Karson, Miranda A; Nagode, Daniel A et al. (2011) Nerve terminal nicotinic acetylcholine receptors initiate quantal GABA release from perisomatic interneurons by activating axonal T-type (Cav3) Ca²? channels and Ca²? release from stores. J Neurosci 31:13546-61
Zhang, Longhua; Wang, Meina; Bisogno, Tiziana et al. (2011) Endocannabinoids generated by Ca2+ or by metabotropic glutamate receptors appear to arise from different pools of diacylglycerol lipase. PLoS One 6:e16305
Nagode, Daniel A; Tang, Ai-Hui; Karson, Miranda A et al. (2011) Optogenetic release of ACh induces rhythmic bursts of perisomatic IPSCs in hippocampus. PLoS One 6:e27691
Alger, Bradley E; Kim, Jimok (2011) Supply and demand for endocannabinoids. Trends Neurosci 34:304-15

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