Activation of Group II Metabotropic Glutamate Receptors Attenuates Both Stress and Cue-Induced Ethanol-Seeking and Modulates c-fos Expression in the Hippocampus and Amygdala
Open accessAbstract
Major precipitating factors for relapse to drug use are stress and exposure to drug-related environmental stimuli. Group II (mGlu(2/3)) metabotropic glutamate receptors (mGluRs) are densely expressed within circuitries mediating the motivating effects of stress and drug cues and, therefore, may participate in regulating drug-seeking linked to both of these risk factors. Thus, we tested the hypothesis that pharmacological activation of group II mGluRs modifies both stress- and cue-induced ethanol-seeking, using reinstatement models of relapse. In parallel, brain c-fos expression was examined to identify neural substrates for the behavioral effects of group II mGluR activation. The selective mGlu(2/3) agonist LY379268 (1R,4R,5S,6R-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate) (0.3, 1.0, and 3.0 mg/kg, s.c.) dose dependently blocked the recovery of extinguished ethanol-seeking induced by either footshock stress or ethanol-associated discriminative stimuli. These effects were accompanied by modulation of c-fos expression in the hippocampus, central nucleus of the amygdala, bed nucleus of the stria terminalis, and medial parvocellular paraventricular nucleus of the hypothalamus. The results implicate group II mGluRs as a shared neuropharmacological substrate for ethanol-seeking elicited by both drug cues and stress and identify group II mGluRs as promising treatment targets for relapse prevention.
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Agonism of Group II receptors leads to an increase in activity in the predominantly inhibitory BNST (but also in the PVN) in response to stress, overall suggesting a reduction in HPA activity via suppression of excitatory signaling.
“Agonism of these receptors also leads to an increase in activity in the predominantly inhibitory BNST (but also in the PVN) in response to stress, overall suggesting a reduction in HPA activity via suppression of excitatory signaling.”
From Glutamate receptors in domestication and modern human evolution (2020) · cites this paper as Zhao et al., 2006
Activation of Group II receptors is downregulated in the hippocampus.
“At the same time, activation of Group II receptors is downregulated in the hippocampus (Zhao et al., 2006).”
From Glutamate receptors in domestication and modern human evolution (2020) · cites this paper as Zhao et al., 2006
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Cites
Gray, J. A. (1982) · Behavioral and Brain Sciences · doi:10.1017/s0140525x00013066 · Cited by 4,477 · see citing works
The reinstatement model of drug relapse: history, methodology and major findings
Shaham, Y., Shalev, U., Lu, L., de Wit, H., & Stewart, J. (2003) · Psychopharmacology · doi:10.1007/s00213-002-1224-x · Cited by 1,615 · see citing works
Pattern and time course of immediate early gene expression in rat brain following acute stress
Cullinan, W. E., Herman, J. P., Battaglia, D. F., Akil, H., & Watson, S. J. (1995) · Neuroscience · doi:10.1016/0306-4522(94)00355-9 · Cited by 1,056 · see citing works
Schoepp, D. D. (2001) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)29296-x · Cited by 693 · see citing works
Conditioning factors in drug abuse: can they explain compulsion?
O’Brien, C. P., Childress, A. R., Ehrman, R. N., & Robbins, S. J. (1998) · Journal of Psychopharmacology · doi:10.1177/026988119801200103 · Cited by 680 · see citing works
Metabotropic glutamate receptors as novel targets for anxiety and stress disorders
Swanson, C. J., Bures, M., Johnson, M. P., Linden, A.-M., Monn, J. A., & Schoepp, D. D. (2005) · Nature Reviews Drug Discovery · doi:10.1038/nrd1630 · Cited by 607 · see citing works
Ohishi, H., Shigemoto, R., Nakanishi, S., & Mizuno, N. (1993) · Neuroscience · doi:10.1016/0306-4522(93)90485-x · Cited by 560 · see citing works
Limbic and Motor Circuitry Underlying Footshock-Induced Reinstatement of Cocaine-Seeking Behavior
McFarland, K., Davidge, S. B., Lapish, C. C., & Kalivas, P. W. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.4177-03.2004 · Cited by 524 · see citing works
Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior
Boutrel, B., Kenny, P. J., Specio, S. E., Martin-Fardon, R., Markou, A., Koob, G. F., & de Lecea, L. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0507480102 · Cited by 520 · see citing works
Self-citationFuchs, R. A., Evans, K. A., Ledford, C. C., Parker, M. P., Case, J. M., Mehta, R. H., & See, R. E. (2004) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300579 · Cited by 517 · see citing works
Ohishi, H., Shigemoto, R., Nakanishi, S., & Mizuno, N. (1993) · The Journal of Comparative Neurology · doi:10.1002/cne.903350209 · Cited by 514 · see citing works
Psychological stress, drug-related cues and cocaine craving
Sinha, R., Fuse, T., Aubin, L.-R., & O'Malley, S. S. (2000) · Psychopharmacology · doi:10.1007/s002130000499 · Cited by 463 · see citing works
Neisewander, J. L., Baker, D. L., Fuchs, R. A., Tran-Nguyen, L. T. L., Palmer, A., & Marshall, J. F. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-02-00798.2000 · Cited by 438 · see citing works
Neurobiology of craving, conditioned reward and relapse
Weiss, F. (2005) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2004.11.001 · Cited by 411 · see citing works
Self-citationHippocampus and context in classical conditioning
Holland, P. C., & Bouton, M. E. (1999) · Current Opinion in Neurobiology · doi:10.1016/s0959-4388(99)80027-0 · Cited by 377 · see citing works
Sinha, R., Talih, M., Malison, R. T., Cooney, N. L., Anderson, G. M., & Kreek, M. J. (2003) · Psychopharmacology · doi:10.1007/s00213-003-1525-8 · Cited by 366 · see citing works
Dayas, C. V., Buller, K. M., & Day, T. A. (1999) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.1999.00645.x · Cited by 303 · see citing works
Self-citationCartmell, J., Monn, J. A., & Schoepp, D. D. (1999) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)35084-0 · Cited by 270 · see citing works
Neural substrates of conditioned-cued relapse to drug-seeking behavior
See, R. E. (2002) · Pharmacology Biochemistry and Behavior · doi:10.1016/s0091-3057(01)00682-7 · Cited by 257 · see citing works
A Role of Ventral Tegmental Area Glutamate in Contextual Cue-Induced Relapse to Heroin Seeking
Bossert, J. M., Liu, S. Y., Lu, L., & Shaham, Y. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.3207-04.2004 · Cited by 241 · see citing works
Baptista, M. A. S., Martin‐Fardon, R., & Weiss, F. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.0176-04.2004 · Cited by 235 · see citing works
Self-citationThe ups and downs of addiction: role of metabotropic glutamate receptors
Kenny, P. J., & Markou, A. (2004) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2004.03.009 · Cited by 223 · see citing works
Fox, H. C., Talih, M., Malison, R. T., Anderson, G. M., Kreek, M. J., & Sinha, R. (2005) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2005.05.002 · Cited by 164 · see citing works
Bäckström, P., & Hyytiä, P. (2005) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2005.10.051 · Cited by 141 · see citing works
Funk, D. R., Li, Z., & Lê, A. D. (2005) · Neuroscience · doi:10.1016/j.neuroscience.2005.10.062 · Cited by 138 · see citing works
Franklin, T. R., & Druhan, J. P. (2000) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2000.00071.x · Cited by 126 · see citing works
Cartmell, J., Monn, J. A., & Schoepp, D. D. (2000) · Psychopharmacology · doi:10.1007/s002130050072 · Cited by 117 · see citing works
Linden, A.-M., Greene, S. J., Bergeron, M., & Schoepp, D. D. (2003) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300321 · Cited by 106 · see citing works
Alcohol selectively attenuates stress-induced c-fos expression in rat hippocampus
Ryabinin, A. E., Melia, K. R., Cole, M., Bloom, F. E., & Wilson, M. (1995) · Journal of Neuroscience · doi:10.1523/jneurosci.15-01-00721.1995 · Cited by 99 · see citing works
Kilbride, J., Huang, L., Rowan, M. J., & Anwyl, R. (1998) · European Journal of Pharmacology · doi:10.1016/s0014-2999(98)00526-3 · Cited by 96 · see citing works
Tatarczynska, E., Kłodzińska, A., Kroczka, B., Chojnacka-Wójcik, E., & Pilc, A. (2001) · Psychopharmacology · doi:10.1007/s002130100798 · Cited by 92 · see citing works
The novel mGluR2/3 agonist LY379268 attenuates cue-induced reinstatement of heroin seeking
Bossert, J. M., Busch, R. F., & Gray, S. M. (2005) · Neuroreport · doi:10.1097/00001756-200506210-00026 · Cited by 90 · see citing works
Possible neural substrates of beer-craving in rats
Topple, A. N., Hunt, G. E., & McGregor, I. S. (1998) · Neuroscience Letters · doi:10.1016/s0304-3940(98)00574-6 · Cited by 88 · see citing works
Buller, K. M., Xu, & Day (1998) · Journal of Neuroendocrinology · doi:10.1046/j.1365-2826.1998.00231.x · Cited by 75 · see citing works
Expression of fos protein in various rat brain areas following acute nicotine and diazepam
Salminen, O., Lahtinen, S., & Ahtee, L. (1996) · Pharmacology Biochemistry and Behavior · doi:10.1016/0091-3057(95)02132-9 · Cited by 69 · see citing works
Mecamylamine and Ethanol Preference in Healthy Volunteers
Young, E. M., Mahler, S. V., Chi, H., & de Wit, H. (2005) · Alcoholism Clinical and Experimental Research · doi:10.1097/01.alc.0000150007.34702.16 · Cited by 65 · see citing works
Kew, J. N. C., Pflimlin, M., Kemp, J. A., & Mutel, V. (2002) · Neuropharmacology · doi:10.1016/s0028-3908(02)00084-9 · Cited by 57 · see citing works
Walker, D. L., Rattiner, L. M., & Davis, M. (2002) · Behavioral Neuroscience · doi:10.1037//0735-7044.116.6.1075 · Cited by 53 · see citing works
Walker, D. L., Rattiner, L. M., & Davis, M. (2002) · Behavioral Neuroscience · doi:10.1037/0735-7044.116.6.1075 · Cited by 53 · see citing works
Schroeder, B. E., Schiltz, C. A., & Kelley, A. E. (2002) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300007 · Cited by 43 · see citing works
Thompson, B. L., & Rosen, J. B. (2005) · Neuropharmacology · doi:10.1016/j.neuropharm.2005.07.024 · Cited by 23 · see citing works
Conditioned Taste Aversion Induced by Ethanol in Alcohol-Preferring Rats
Ciccocioppo, R., Angeletti, S., Chhada, M., et al. (1999) · Pharmacology Biochemistry and Behavior · doi:10.1016/s0091-3057(99)00104-5 · Cited by 21 · see citing works
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Sinha, R. (2008) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1441.030 · Cited by 1,904 · see citing works
Scofield, M. D., Heinsbroek, J. A., Gipson, C. D., Kupchik, Y. M., Spencer, S., Smith, A. C. W., Roberts-Wolfe, D., & Kalivas, P. W. (2016) · Pharmacological Reviews · doi:10.1124/pr.116.012484 · Cited by 598 · see citing works
Stress-induced reinstatement of drug seeking: 20 years of progress
Mantsch, J. R., Baker, D. A., Funk, D., Lê, A. D., & Shaham, Y. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2015.142 · Cited by 438 · see citing works
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Holmes, A., Spanagel, R., & Krystal, J. H. (2013) · Psychopharmacology · doi:10.1007/s00213-013-3226-2 · Cited by 197 · see citing works
Development of pharmacotherapies for drug addiction: a Rosetta stone approach
Koob, G. F., Kenneth Lloyd, G., & Mason, B. J. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2828 · Cited by 154 · see citing works
Pfarr, S., Meinhardt, M. W., Klee, M. L., Hansson, A. C., Vengeliene, V., Schonig, K., Bartsch, D., Hope, B. T., Spanagel, R., & Sommer, W. H. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.0684-15.2015 · Cited by 143 · see citing works
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Roberto, M., Kirson, D., & Khom, S. (2021) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a039339 · Cited by 112 · see citing works
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Alasmari, F., Goodwani, S., McCullumsmith, R. E., & Sari, Y. (2018) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2018.10.001 · Cited by 85 · see citing works
Kufahl, P. R., Martin-Fardon, R., & Weiss, F. (2011) · Neuropsychopharmacology · doi:10.1038/npp.2011.174 · Cited by 72 · see citing works
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O’Rourke, T., & Boeckx, C. (2020) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.10.004 · Cited by 50 · see citing works
Augier, E., Dulman, R. S., Rauffenbart, C., Augier, G., Cross, A. J., & Heilig, M. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2016.107 · Cited by 44 · see citing works
Flores‐Ramirez, F. J., Varodayan, F. P., Patel, R. R., Illenberger, J. M., Di Ottavio, F., Roberto, M., & Martin‐Fardon, R. (2023) · British Journal of Pharmacology · doi:10.1111/bph.16015 · Cited by 19 · see citing works
Self-citation
- Authors
- Zhao, Y., Dayas, C. V., Aujla, H., Baptista, M. A. S., Martin-Fardon, R., & Weiss, F.
- Affiliations
- Scripps Research Institute (US)
- Corresponding author
- Dayas, Christopher V.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2006-09-27
- Volume
- 26
- Issue
- 39
- Pages
- 9967-9974
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6674480
- OpenAlex
- W1997540962
- Cited by
- 192
- References
- 42
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 1 · 2023: 4 · 2022: 7 · 2021: 13 · 2020: 5 · 2019: 13 · 2018: 12 · 2017: 9 · 2016: 11 · 2015: 8 · 2014: 13 · 2013: 12 · 2012: 14
- FWCI
- 4.42
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eli Lilly and Company
- National Institutes of Health (AA06420)
- Medical Research Council
- National Health and Medical Research Council
- National Institute on Alcohol Abuse and Alcoholism (AA 10531, R01AA010531, AA-06420, P50AA006420)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Keywords
- group II metabotropic glutamate receptors, mGlu2/3 receptors, LY379268, ethanol seeking, relapse, stress, drug cues, reinstatement, Fos expression, hippocampus, amygdala, bed nucleus of the stria terminalis, paraventricular nucleus, alcoholism, relapse prevention
- MeSH terms
- Alcohol Drinking, Ethanol, Alcoholism, Amino Acids, Amygdala, Animals, Anxiety, Cues, Electroshock, Extinction, Psychological, Hippocampus, Limbic System, Male, Motivation, Nerve Tissue Proteins, Synaptic Transmission, Paraventricular Hypothalamic Nucleus, Reward, Self Administration, Septal Nuclei, Stress, Physiological, Proto-Oncogene Proteins c-fos, Genes, fos, Rats, Wistar, Receptors, Metabotropic Glutamate, Excitatory Amino Acid Agonists, Bridged Bicyclo Compounds, Heterocyclic, Rats, Secondary Prevention
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