The mGluR2 Positive Allosteric Modulator, AZD8529, and Cue-Induced Relapse to Alcohol Seeking in Rats
Open accessAbstract
Group II metabotropic glutamate receptors (mGluR2 and mGluR3) may control relapse of alcohol seeking, but previously available Group II agonists were unable to discriminate between mGluR2 and mGluR3. Here we use AZD8529, a novel positive allosteric mGluR2 modulator, to determine the role of this receptor for alcohol-related behaviors in rats. We assessed the effects of AZD8529 (20 and 40 mg/kg s.c.) on male Wistar rats trained to self-administer 20% alcohol and determined the effects of AZD8529 on self-administration, as well as stress-induced and cue-induced reinstatement of alcohol seeking. The on-target nature of findings was evaluated in Indiana P-rats, a line recently shown to carry a mutation that disrupts the gene encoding mGluR2. The behavioral specificity of AZD8529 was assessed using self-administration of 0.2% saccharin and locomotor activity tests. AZD8529 marginally decreased alcohol self-administration at doses that neither affected 0.2% saccharin self-administration nor locomotor activity. More importantly, cue- but not stress-induced alcohol seeking was blocked by the mGluR2 positive allosteric modulator. This effect of AZD8529 was completely absent in P rats lacking functional mGluR2s, demonstrating the receptor specificity of this effect. Our findings provide evidence for a causal role of mGluR2 in cue-induced relapse to alcohol seeking. They contribute support for the notion that positive allosteric modulators of mGluR2 block relapse-like behavior across different drug categories.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Several studies established a causal role for reduced prefrontal metabotropic glutamate receptor 2 function in craving and relapse responses in preclinical models of alcohol dependence.
“Several studies established a causal role for reduced prefrontal metabotropic glutamate receptor 2 (mGluR2) function in craving and relapse responses in preclinical models of alcohol dependence [48–52].”
From Psilocybin-assisted therapy for severe alcohol use disorder: protocol for a double-blind, randomized, placebo-controlled, 7-month parallel-group phase II superiority trial (2024) · cites this paper as [49]
The Results (page unavailable) report that the mGluR2 modulator AZD8529 blocked cue-induced reinstatement of alcohol seeking in rats. The Discussion (page unavailable) also describes a prefrontal mGluR2 deficit in postdependent rats whose targeted rescue restored control over seeking, but attributes that experiment to Meinhardt et al. (2013). This paper does not itself establish that reduced prefrontal mGluR2 function causes craving and relapse responses in alcohol-dependent rats; its AZD8529 experiment tested a systemic treatment. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
PHARMACOLOGY AND FUNCTIONS OF METABOTROPIC GLUTAMATE RECEPTORS
Conn, P. J., & Pin, J. (1997) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.37.1.205 · Cited by 3,083 · see citing works
The metabotropic glutamate receptors: Structure and functions
Pin, J., & Duvoisin, R. M. (1995) · Neuropharmacology · doi:10.1016/0028-3908(94)00129-g · Cited by 2,267 · see citing works
Glutamate as a neurotransmitter in the brain: review of physiology and pathology
Meldrum, B. S. (2000) · The Journal of Nutrition · doi:10.1093/jn/130.4.1007s · Cited by 1,667 · see citing works
The glutamate homeostasis hypothesis of addiction
Kalivas, P. W. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2515 · Cited by 1,350 · see citing works
Progressive Ratio as a Measure of Reward Strength
Hodos, W. (1961) · Science · doi:10.1126/science.134.3483.943 · Cited by 1,147 · see citing works
Pharmacological agents acting at subtypes of metabotropic glutamate receptors
Schoepp, D. D., Jane, D. E., & Monn, J. A. (1999) · Neuropharmacology · doi:10.1016/s0028-3908(99)00092-1 · Cited by 1,061 · see citing works
Animal Models of Alcoholism: Neurobiology of High Alcohol-Drinking Behavior in Rodents
McBride, W. J. H., & Li, T. (1998) · Critical Reviews in Neurobiology · doi:10.1615/critrevneurobiol.v12.i4.40 · Cited by 618 · see citing works
Glutamatergic substrates of drug addiction and alcoholism
Gass, J. T., & Olive, M. F. (2007) · Biochemical Pharmacology · doi:10.1016/j.bcp.2007.06.039 · Cited by 485 · see citing works
Pharmacological treatment of alcohol dependence: Target symptoms and target mechanisms
Heilig, M. A., & Egli, M. (2006) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2006.02.001 · Cited by 378 · see citing works
Self-citationConn, P. J., Lindsley, C. W., & Jones, C. K. (2008) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2008.10.006 · Cited by 330 · see citing works
Selective breeding for alcohol preference and associated responses
Li, T., Lumeng, L., & Doolittle, D. P. (1993) · Behavior Genetics · doi:10.1007/bf01067421 · Cited by 324 · 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
Ethanol withdrawal is associated with increased extracellular glutamate in the rat striatum
Rossetti, Z. L., & Carboni, S. (1995) · European Journal of Pharmacology · doi:10.1016/0014-2999(95)00344-k · Cited by 237 · 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
The 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
Hermann, D., Weber‐Fahr, W., Sartorius, A., Hoerst, M., Frischknecht, U., Tunc‐Skarka, N., Perreau‐Lenz, S., Hansson, A. C., Krumm, B., Kiefer, F., et al. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.07.034 · Cited by 197 · see citing works
Rendleman, R. L., & Walkup, J. T. (2012) · Elsevier eBooks · doi:10.1016/b978-1-4377-0435-8.00049-4 · Cited by 197 · see citing works
Liechti, M. E., Lhuillier, L., Kaupmann, K., & Markou, A. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.1766-07.2007 · Cited by 193 · see citing works
Zhao, Y., Dayas, C. V., Aujla, H., Baptista, M. A. S., Martin-Fardon, R., & Weiss, F. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.2384-06.2006 · Cited by 192 · see citing works
Lü, L., Uejima, J. L., Gray, S. M., Bossert, J. M., & Shaham, Y. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.04.011 · Cited by 192 · see citing works
Spooren, W. P. J. M., Ballard, T. M., Gasparini, F., Amalric, M., Mutel, V., & Schreiber, R. (2003) · Behavioural Pharmacology · doi:10.1097/01.fbp.0000081783.35927.8f · Cited by 177 · see citing works
Meinhardt, M. W., Hansson, A. C., Perreau‐Lenz, S., Bauder-Wenz, C., Stählin, O., Heilig, M. A., Harper, C. G., Drescher, K. U., Spanagel, R., & Sommer, W. H. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.4062-12.2013 · Cited by 170 · see citing works
Self-citationSchaffhauser, H., Rowe, B. A., Morales, S., Chavez-Noriega, L. E., Yin, R., Jachec, C., Rao, S. P., Bain, G., Pinkerton, A. B., Vernier, J., et al. (2003) · Molecular Pharmacology · doi:10.1124/mol.64.4.798 · Cited by 160 · see citing works
Caprioli, D., Venniro, M., Zeric, T., Li, X., Adhikary, S., Madangopal, R., Marchant, N. J., Lucantonio, F., Schoenbaum, G., Bossert, J. M., et al. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2015.02.018 · Cited by 145 · see citing works
Umhau, J. C., Momenan, R., Schwandt, M. L., Singley, E., Lifshitz, M., Doty, L., Adams, L. J., Vengeliene, V., Spanagel, R., Zhang, Y., et al. (2010) · Archives of General Psychiatry · doi:10.1001/archgenpsychiatry.2010.125 · Cited by 144 · see citing works
Self-citationBäckström, P., & Hyytiä, P. (2005) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2005.10.051 · Cited by 141 · see citing works
Loss of metabotropic glutamate receptor 2 escalates alcohol consumption
Zhou, Z., Karlsson, C., Liang, T., Xiong, W., Kimura, M., Tapocik, J. D., Yuan, Q., Barbier, E., Feng, A. Y., Flanigan, M. E., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1309839110 · Cited by 115 · see citing works
Self-citationSidhpura, N., Weiss, F., & Martin‐Fardon, R. (2010) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.01.005 · Cited by 114 · see citing works
Glutamate-based therapeutic approaches: allosteric modulators of metabotropic glutamate receptors
Marino, M. T., & Conn, P. J. (2005) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2005.09.006 · Cited by 111 · see citing works
Ritzén, A., Mathiesen, J. M., & Thomsen, C. (2005) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/j.1742-7843.2005.pto_156.x · Cited by 104 · see citing works
Dahchour, A. (2003) · European Journal of Pharmacology · doi:10.1016/s0014-2999(02)02851-0 · Cited by 101 · 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
Rodd, Z. A., McKinzie, D. L., Bell, R. L., McQueen, V. K., MURPHY, J., Schoepp, D. D., & McBride, W. J. (2006) · Behavioural Brain Research · doi:10.1016/j.bbr.2006.03.032 · Cited by 86 · see citing works
Jin, X., Semenova, S., Yang, L., Ardecky, R., Sheffler, D. J., Dahl, R. S., Conn, P. J., Cosford, N. D. P., & Markou, A. (2010) · Neuropsychopharmacology · doi:10.1038/npp.2010.82 · Cited by 78 · see citing works
Justinová, Z., Panlilio, L. V., Secci, M. E., Redhi, G. H., Schindler, C. W., Cross, A. J., Mrzljak, L., Medd, A. M., Shaham, Y., & Goldberg, S. R. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2015.01.014 · Cited by 63 · see citing works
Self-citationDahchour, A., & Witte, P. D. (2000) · Pharmacology Biochemistry and Behavior · doi:10.1016/s0091-3057(99)00197-5 · Cited by 58 · see citing works
Kufahl, P. R., Watterson, L. R., Nemirovsky, N. E., Hood, L. E., Villa, A., Halstengard, C., Zautra, N., & Olive, M. F. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.05.037 · Cited by 50 · see citing works
Augier, E., Flanigan, M. E., Dulman, R. S., Pincus, A. B., Schank, J. R., Rice, K. C., Kejun, C., Heilig, M. A., & Tapocik, J. D. (2014) · Psychopharmacology · doi:10.1007/s00213-014-3605-3 · Cited by 44 · see citing works
Self-citationEffects of naltrexone on the intake of ethanol and flavored solutions in rats
Goodwin, F. L. W., Campisi, M., Babinska, I., et al. (2001) · Alcohol · doi:10.1016/s0741-8329(01)00163-x · Cited by 35 · see citing works
Augier, E., Dulman, R. S., Singley, E., & Heilig, M. A. (2017) · Journal of Visualized Experiments · doi:10.3791/53305 · Cited by 22 · see citing works
Self-citationStudies on an animal model of alcoholism.
Li, T., Lumeng, L., McBride, W. J., Waller, M. B., & Murphy, J. M. (1986) · PubMed · Cited by 21 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Meinhardt, M. W., Pfarr, S., Fouquet, G., Rohleder, C., Meinhardt, M. L., Barroso-Flores, J., Hoffmann, R., Jeanblanc, J., Paul, E., Wagner, K., et al. (2021) · Science Advances · doi:10.1126/sciadv.abh2399 · Cited by 89 · see citing works
Caprioli, D., Justinova, Z., Venniro, M., & Shaham, Y. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.08.018 · Cited by 55 · see citing works
Vanderijst, L., Hever, F., Buot, A., Dauré, C., Benoit, J., Hanak, C., Veeser, J., Morgiève, M., Campanella, S., Kornreich, C., et al. (2024) · BMC Psychiatry · doi:10.1186/s12888-024-05502-y · Cited by 13 · see citing works
- Authors
- Augier, E., Dulman, R. S., Rauffenbart, C., Augier, G., Cross, A. J., & Heilig, M.
- Affiliations
- Linköping University (SE)
- National Institutes of Health (US)
- AstraZeneca (United States) (US)
- Corresponding author
- Augier, Eric
- Venue
- Neuropsychopharmacology
- Published
- 2016-06-24
- Volume
- 41
- Issue
- 12
- Pages
- 2932-2940
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC5061885
- OpenAlex
- W2473950764
- Cited by
- 44
- References
- 41
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 5 · 2023: 7 · 2022: 3 · 2021: 5 · 2020: 5 · 2019: 2 · 2018: 2 · 2017: 6 · 2016: 4
- FWCI
- 2.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- AstraZeneca
- Vetenskapsrådet
- National Institute on Alcohol Abuse and Alcoholism
- National Institute on Drug Abuse
- 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
- mGluR2, group II metabotropic glutamate receptors, positive allosteric modulators, alcohol relapse, cue-induced reinstatement, alcohol self-administration, stress-induced reinstatement
- MeSH terms
- Alcohol Drinking, Ethanol, Animals, Conditioning, Operant, Cues, Disease Models, Animal, Dose-Response Relationship, Drug, Extinction, Psychological, Indoles, Male, Oxadiazoles, Recurrence, Reinforcement, Psychology, Saccharin, Self Administration, Rats, Wistar, Receptors, Metabotropic Glutamate, Rats, Drug-Seeking Behavior
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
