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      Estrogen Differentially Modulates the Cannabinoid- Induced Presynaptic Inhibition of Amino Acid Neurotransmission in Proopiomelanocortin Neurons of the Arcuate Nucleus

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          Abstract

          The present study sought to determine whether cannabinoids inhibit glutamatergic and GABAergic synaptic input onto neurons of the hypothalamic arcuate nucleus (ARC), and whether estrogen modulates this process. Whole-cell patch clamp recordings were performed in hypothalamic slices prepared from ovariectomized female guinea pigs. CB1 receptor activation reduced the amplitude of excitatory postsynaptic currents (EPSCs) evoked by electrical stimulation that were sensitive to ionotropic glutamate receptor antagonists. The CB1 receptor antagonist AM251 increased evoked EPSC (eEPSC) amplitude, and reversed the agonist-induced decrease. CB1 receptor activation similarly decreased the amplitude of evoked inhibitory postsynaptic currents (eIPSCs). The cannabinoid-induced reduction in eEPSC and eIPSC amplitude correlated with a decrease in the frequency of miniature EPSCs (mEPSCs) and IPSCs (mIPSCs) that were abolished by ionotropic glutamate and GABA<sub>A</sub> receptor antagonists, respectively. AM251 increased mEPSC frequency, and antagonized the agonist-induced decrease. Compared to neurons obtained from vehicle-treated controls, estradiol benzoate (25 µg; s.c.) given 24 h prior to experimentation increased mEPSC frequency, and markedly decreased the potency of CB1 receptor agonists to decrease mEPSC frequency. Conversely, the steroid potentiated the cannabinoid-induced decrease in mIPSC frequency. These effects were observed in neurons subsequently identified as proopiomelanocortin (POMC) neurons. These data reveal that ARC neurons, including POMC neurons, receive glutamatergic and GABAergic synaptic inputs that are presynaptically inhibited by cannabinoids, and differentially modulated by estrogen. These opposing effects of estrogen on the cannabinoid regulation of amino acid neurotransmission excite POMC neurons, and lend additional insight into the mechanisms underlying estrogen-induced anorexia and negative feedback of the reproductive axis.

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          Most cited references 30

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          Cannabis: pharmacology and toxicology in animals and humans.

          Cannabis is one of the most widely used drugs throughout the world. The psychoactive constituent of cannabis, delta 9-tetrahydrocannabinol (delta 9-THC), produces a myriad of pharmacological effects in animals and humans. For many decades, the mechanism of action of cannabinoids, compounds which are structurally similar to delta 9-THC, was unknown. Tremendous progress has been made recently in characterizing cannabinoid receptors both centrally and peripherally and in studying the role of second messenger systems at the cellular level. Furthermore, an endogenous ligand, anandamide, for the cannabinoid receptor has been identified. Anandamide is a fatty-acid derived compound that possesses pharmacological properties similar to delta 9-THC. The production of complex behavioral events by cannabinoids is probably mediated by specific cannabinoid receptors and interactions with other neurochemical systems. Cannabis also has great therapeutic potential and has been used for centuries for medicinal purposes. However, cannabinoid-derived drugs on the market today lack specificity and produce many unpleasant side effects, thus limiting therapeutic usefulness. The advent of highly potent analogs and a specific antagonist may make possible the development of compounds that lack undesirable side effects. The advancements in the field of cannabinoid pharmacology should facilitate our understanding of the physiological role of endogenous cannabinoids.
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            Regulation of GABAA receptor function by protein kinase C phosphorylation.

            GABAA receptors possess consensus sequences for phosphorylation by PKC that are located on the presumed intracellular domains of beta and gamma 2 subunits. PKC phosphorylation sites were analyzed using purified receptor subunits and were located on up to 3 serine residues in beta 1 and gamma 2 subunits. The role of phosphorylation in receptor function was studied using recombinant receptors expressed in kidney cells and Xenopus oocytes and was compared with native neuronal GABAA receptors. For recombinant and native GABAA receptors, PKC phosphorylation caused a reduction in the amplitudes of GABA-activated currents without affecting the time constants for current decay. Selective site-directed mutagenesis of the serine residues reduced the effects of phorbol esters and revealed that serine 343 in the gamma 2 subunit exerted the largest effect on the GABA-activated response. These results indicate that PKC phosphorylation can differentially modulate GABAA receptor function.
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              GABA release from proopiomelanocortin neurons.

              Neural networks controlling food intake and energy homeostasis clearly involve proopiomelanocortin (POMC) neurons and their peptide transmitters. alpha-melanocyte-stimulating hormone from arcuate POMC neurons potently reduces food intake, whereas arcuate neuropeptide Y (NPY) neurons act in opposition to stimulate food intake. In addition to orexigenic peptides, NPY neurons also release the inhibitory neurotransmitter GABA, which can act in a local circuit to inhibit POMC neuron activity. Whether or not reciprocal inhibition could occur has not yet been determined, because the presence of a rapid neurotransmitter in POMC neurons has not been demonstrated previously. Here, we used primary cultures of fluorescently labeled POMC neurons that had formed recurrent synapses (autapses) to detect the release of neurotransmitter. When an action potential was evoked in the axon of a POMC neuron with autapses, a short-latency synaptic current was recorded in the same cell. The autaptic current was abolished by GABA(A) receptor antagonists and substantially inhibited by opioids. Double-label in situ RNA hybridization for POMC and glutamic acid decarboxylase, the GABA synthetic enzyme, revealed colocalization of mRNAs in approximately one-third of POMC neurons in vivo. Our results suggest that these neurons can exert rapid inhibitory effects via the release of GABA, in addition to the more sustained actions provided by POMC peptides. However, this rapid inhibition may not play a major role within local hypothalamic circuits, but rather is likely to be important in more distant projection areas as indicated by the colocalization of vesicular GABA transporter immunoreactivity predominantly in extrahypothalamic POMC terminals.
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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                2006
                January 2007
                09 November 2006
                : 84
                : 2
                : 123-137
                Affiliations
                Department of Basic Medical Sciences, Western University of Health Sciences, Pomona, Calif., USA
                Article
                96996 Neuroendocrinology 2006;84:123–137
                10.1159/000096996
                17106183
                © 2006 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 9, Tables: 1, References: 62, Pages: 15
                Categories
                GnRH, Gonadotropins, Gonadal Steroids and Reproduction

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