Login | Register

Context and topography determine the role of basolateral amygdala metabotropic glutamate receptor 5 in appetitive Pavlovian responding


Context and topography determine the role of basolateral amygdala metabotropic glutamate receptor 5 in appetitive Pavlovian responding

Khoo, Shaun Yon-Seng ORCID: https://orcid.org/0000-0002-0972-3788, LeCocq, Mandy Rita, Deyab, Ghislaine E. and Chaudhri, Nadia ORCID: https://orcid.org/0000-0003-4217-4044 (2019) Context and topography determine the role of basolateral amygdala metabotropic glutamate receptor 5 in appetitive Pavlovian responding. Neuropsychopharmacology . ISSN 1740-634X

Text (Accepted manuscript) (application/pdf)
Khoo-etal-2019-NPP-Postprint.pdf - Accepted Version
Available under License Spectrum Terms of Access.


Preclinical data have shown that the excitatory metabotropic Gαq-coupled glutamate receptor, mGluR5, has a role in substance abuse and relapse. However, little is known about the contribution of mGluR5 to the expression of conditioned responding elicited by appetitive Pavlovian cues. We investigated this question in rats that were trained to associate a discrete, auditory conditioned stimulus (CS) with a fructose-glucose solution (5.5% fructose/4.5% glucose; ‘sugar’). In subsequent tests for the expression of conditioned responding without sugar delivery, CS-elicited fluid port entries were elevated in a context associated with sugar, relative to an equally familiar, neutral context. Inhibiting mGluR5 via systemic injections of a negative allosteric modulator (MTEP; 5 mg/kg) reduced CS port entries in both the sugar context and neutral context. Targeting MTEP microinjections (3 µg/side; 0.3 µl/min) to the nucleus accumbens (Acb) core had no effect on CS port entries at test, whereas the same manipulation in the basolateral amygdala (BLA) produced effects that were topographically dependent. Specifically, microinjecting MTEP in the posterior BLA had no effect on behavior, whereas inhibiting mGluR5 in the anterior BLA enhanced the contextual discrimination of CS port entries. These data are the first to show a role of mGluR5 in the context-dependent expression of appetitive Pavlovian conditioned responding, with a topographically defined arrangement of mGluR5 in the BLA being particularly important for context-based responding to a discrete, appetitive cue.

Divisions:Concordia University > Research Units > Centre for Studies in Behavioural Neurobiology
Item Type:Article
Authors:Khoo, Shaun Yon-Seng and LeCocq, Mandy Rita and Deyab, Ghislaine E. and Chaudhri, Nadia
Journal or Publication:Neuropsychopharmacology
Date:February 2019
  • Canadian Institutes of Health Research
  • Natural Sciences and Engineering Research Council
  • Fonds de la recherche du Québec
  • Concordia Horizon Postodoctoral Fellowship
  • Graduate Fellowship, Faculty of Arts and Science, Concordia University
Digital Object Identifier (DOI):10.1038/s41386-019-0335-6
Keywords:glutamate, mGlu5, GRM5, Pavlovian conditioning, sugar, addiction, context, cue, MK-801, NMDA, reinstatement, goal-tracking
ID Code:984953
Deposited On:12 Feb 2019 22:05
Last Modified:08 Aug 2019 00:00
Related URLs:
Additional Information:This is a post-peer-review, pre-copyedit version of an article published in Neuropsychopharmacology. The final authenticated version is available at: https://doi.org/10.1038/s41386-019-0335-6 Readers may also access the final version using the author's share link: https://rdcu.be/blQSk


1. Kalivas PW, Volkow ND. The neural basis of addiction: A pathology of motivation and choice. American Journal of Psychiatry. 2005;162(8):1403-13. doi:10.1176/appi.ajp.162.8.1403
2. Brown RM, Kupchik YM, Kalivas PW. The story of glutamate in drug addiction and of n-acetylcysteine as a potential pharmacotherapy. JAMA Psychiatry. 2013;70(9):895-7. doi:10.1001/jamapsychiatry.2013.2207
3. Brown RM, Kupchik YM, Spencer S, Garcia-Keller C, Spanswick DC, Lawrence AJ, et al. Addiction-like synaptic impairments in diet-induced obesity. Biological Psychiatry. 2015. doi:10.1016/j.biopsych.2015.11.019
4. Sengmany K, Gregory KJ. Metabotropic glutamate receptor subtype 5: molecular pharmacology, allosteric modulation and stimulus bias. British Journal of Pharmacology. 2016;173(20):3001-17. doi:10.1111/bph.13281
5. Haass-Koffler CL, Goodyear K, Long VM, Tran HH, Loche A, Cacciaglia R, et al. A Phase I randomized clinical trial testing the safety, tolerability and preliminary pharmacokinetics of the mGluR5 negative allosteric modulator GET 73 following single and repeated doses in healthy volunteers. European Journal of Pharmaceutical Sciences. 2017;109:78-85. doi:10.1016/j.ejps.2017.07.031
6. Caprioli D, Justinova Z, Venniro M, Shaham Y. Effect of novel allosteric modulators of metabotropic glutamate receptors on drug self-administration and relapse: A review of preclinical studies and their clinical implications. Biological Psychiatry. 2018;84(3):180-92. doi:10.1016/j.biopsych.2017.08.018
7. Sinclair CM, Cleva RM, Hood LE, Olive MF, Gass JT. mGluR5 receptors in the basolateral amygdala and nucleus accumbens regulate cue-induced reinstatement of ethanol-seeking behavior. Pharmacology Biochemistry and Behavior. 2012;101(3):329-35. doi:10.1016/j.pbb.2012.01.014
8. Bäckström P, Bachteler D, Koch S, Hyytiä P, Spanagel R. mGluR5 antagonist MPEP reduces ethanol-seeking and relapse behavior. Neuropsychopharmacology. 2004;29:921. doi:10.1038/sj.npp.1300381
9. Cowen MS, Djouma E, Lawrence AJ. The metabotropic glutamate 5 receptor antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine reduces ethanol self-administration in multiple strains of alcohol-preferring rats and regulates olfactory glutamatergic systems. Journal of Pharmacology and Experimental Therapeutics. 2005;315(2):590-600. doi:10.1124/jpet.105.090449
10. Tessari M, Pilla M, Andreoli M, Hutcheson DM, Heidbreder CA. Antagonism at metabotropic glutamate 5 receptors inhibits nicotine- and cocaine-taking behaviours and prevents nicotine-triggered relapse to nicotine-seeking. European Journal of Pharmacology. 2004;499(1):121-33. doi:10.1016/j.ejphar.2004.07.056
11. Chiamulera C, Epping-Jordan MP, Zocchi A, Marcon C, Cottiny C, Tacconi S, et al. Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice. Nature Neuroscience. 2001;4:873. doi:10.1038/nn0901-873
12. Chesworth R, Brown RM, Kim JH, Lawrence AJ. The metabotropic glutamate 5 receptor modulates extinction and reinstatement of methamphetamine-seeking in mice. PLoS ONE. 2013;8(7):e68371. doi:10.1371/journal.pone.0068371
13. Knackstedt LA, Trantham-Davidson HL, Schwendt M. The role of ventral and dorsal striatum mGluR5 in relapse to cocaine-seeking and extinction learning. Addiction Biology. 2014;19(1):87-101. doi:10.1111/adb.12061
14. Field M, Cox WM. Attentional bias in addictive behaviors: A review of its development, causes, and consequences. Drug and Alcohol Dependence. 2008;97(1):1-20. doi:10.1016/j.drugalcdep.2008.03.030
15. Handford CE, Tan S, Lawrence AJ, Kim JH. The effect of the mGlu5 negative allosteric modulator MTEP and NMDA receptor partial agonist D-cycloserine on Pavlovian conditioned fear. International Journal of Neuropsychopharmacology. 2014;17(9):1521-32. doi:10.1017/S1461145714000303
16. Gravius A, Barberi C, Schäfer D, Schmidt WJ, Danysz W. The role of group I metabotropic glutamate receptors in acquisition and expression of contextual and auditory fear conditioning in rats – a comparison. Neuropharmacology. 2006;51(7):1146-55. doi:10.1016/j.neuropharm.2006.07.008
17. Simonyi A, Serfozo P, Parker KE, Ramsey AK, Schachtman TR. Metabotropic glutamate receptor 5 in conditioned taste aversion learning. Neurobiology of Learning and Memory. 2009;92(3):460-3. doi:10.1016/j.nlm.2009.05.002
18. O'Connor EC, Crombag HS, Mead AN, Stephens DN. The mGluR5 antagonist MTEP dissociates the acquisition of predictive and incentive motivational properties of reward-paired stimuli in mice. Neuropsychopharmacology. 2010;35:1807. doi:10.1038/npp.2010.48
19. Meyers AM, Mourra D, Beeler JA. High fructose corn syrup induces metabolic dysregulation and altered dopamine signaling in the absence of obesity. PLOS ONE. 2017;12(12):e0190206. doi:10.1371/journal.pone.0190206
20. Hoebel BG, Avena NM, Bocarsly ME, Rada P. Natural addiction: A behavioral and circuit model based on sugar addiction in rats. Journal of Addiction Medicine. 2009;3(1):33-41. doi:10.1097/ADM.0b013e31819aa621
21. Sciascia JM, Reese RM, Janak PH, Chaudhri N. Alcohol-seeking triggered by discrete pavlovian cues is invigorated by alcohol contexts and mediated by glutamate signaling in the basolateral amygdala. Neuropsychopharmacology. 2015;40(12):2801-12. doi:10.1038/npp.2015.130
22. Millan EZ, Reese RM, Grossman CD, Chaudhri N, Janak PH. Nucleus accumbens and posterior amygdala mediate cue-triggered alcohol seeking and suppress behavior during the omission of alcohol-predictive cues. Neuropsychopharmacology. 2015;40(11):2555-65. doi:10.1038/npp.2015.102
23. Valyear MD, Glovaci I, Zaari A, Lahlou S, Trujillo-Pisanty I, Chapman CA, et al. Divergent mesolimbic dopamine circuits support alcohol-seeking triggered by discrete cues and contexts. bioRxiv. 2018:475343. doi:10.1101/475343
24. Mihov Y, Hasler G. Negative allosteric modulators of metabotropic glutamate receptors subtype 5 in addiction: A therapeutic window. International Journal of Neuropsychopharmacology. 2016;19(7):pyw002-pyw. doi:10.1093/ijnp/pyw002
25. Parkes SL, Westbrook RF. The basolateral amygdala is critical for the acquisition and extinction of associations between a neutral stimulus and a learned danger signal but not between two neutral stimuli. The Journal of Neuroscience. 2010;30(38):12608-18. doi:10.1523/jneurosci.2949-10.2010
26. Homayoun H, Moghaddam B. Bursting of prefrontal cortex neurons in awake rats is regulated by metabotropic glutamate 5 (mGlu5) receptors: Rate-dependent influence and interaction with NMDA receptors. Cerebral Cortex. 2006;16(1):93-105. doi:10.1093/cercor/bhi087
27. Homayoun H, Stefani MR, Adams BW, Tamagan GD, Moghaddam B. Functional interaction between NMDA and mGlu5 receptors: Effects on working memory, instrumental learning, motor behaviors, and dopamine release. Neuropsychopharmacology. 2004;29:1259. doi:10.1038/sj.npp.1300417
28. Fowler SW, Ramsey AK, Walker JM, Serfozo P, Olive MF, Schachtman TR, et al. Functional interaction of mGlu5 and NMDA receptors in aversive learning in rats. Neurobiology of Learning and Memory. 2011;95(1):73-9. doi:10.1016/j.nlm.2010.11.009
29. Khoo SY-S, Uhrig A, Chaudhri N. Context does not invigorate responding to a neutral stimulus. Figshare. 2019. doi:10.6084/m9.figshare.7483478
30. Chaudhri N, Woods CA, Sahuque LL, Gill TM, Janak PH. Unilateral inactivation of the basolateral amygdala attenuates context-induced renewal of pavlovian-conditioned alcohol-seeking. European Journal of Neuroscience. 2013;38(5):2751-61. doi:10.1111/ejn.12278
31. Panayi MC, Killcross S. Functional heterogeneity within the rodent lateral orbitofrontal cortex dissociates outcome devaluation and reversal learning deficits. eLife. 2018;7:e37357. doi:10.7554/eLife.37357
32. Khoo SY-S, LeCocq MR, Deyab GE, Chaudhri N. Context and topography determine the role of basolateral amygdala metabotropic glutamate receptor 5 in appetitive Pavlovian responding. Figshare. 2019. doi:10.6084/m9.figshare.7045493
33. Gass JT, Osborne MPH, Watson NL, Brown JL, Olive MF. mGluR5 antagonism attenuates methamphetamine reinforcement and prevents reinstatement of methamphetamine-seeking behavior in rats. Neuropsychopharmacology. 2009;34:820. doi:10.1038/npp.2008.140
34. Knackstedt LA, Schwendt M. mGlu5 receptors and relapse to cocaine-seeking: The role of receptor trafficking in postrelapse extinction learning deficits. Neural Plasticity. 2016;2016:9312508. doi:10.1155/2016/9312508
35. Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 6th ed. London: Academic Press; 2007.
36. Swanson LW. Brain maps 4.0—Structure of the rat brain: An open access atlas with global nervous system nomenclature ontology and flatmaps. Journal of Comparative Neurology. 2018;526(6):935-43. doi:10.1002/cne.24381
37. McLaughlin RJ, Floresco SB. The role of different subregions of the basolateral amygdala in cue-induced reinstatement and extinction of food-seeking behavior. Neuroscience. 2007;146(4):1484-94. doi:10.1016/j.neuroscience.2007.03.025
38. Keefer SE, Petrovich GD. Distinct recruitment of basolateral amygdala-medial prefrontal cortex pathways across Pavlovian appetitive conditioning. Neurobiology of Learning and Memory. 2017;141:27-32. doi:10.1016/j.nlm.2017.03.006
39. Kantak KM, Black Y, Valencia E, Green-Jordan K, Eichenbaum HB. Dissociable effects of lidocaine inactivation of the rostral and caudal basolateral amygdala on the maintenance and reinstatement of cocaine-seeking behavior in rats. The Journal of Neuroscience. 2002;22(3):1126-36. doi:10.1523/jneurosci.22-03-01126.2002
40. Gass JT, Olive MF. Positive allosteric modulation of mGluR5 receptors facilitates extinction of a cocaine contextual memory. Biological Psychiatry. 2009;65(8):717-20. doi:10.1016/j.biopsych.2008.11.001
41. Perry CJ, Reed F, Zbukvic IC, Kim JH, Lawrence AJ. The metabotropic glutamate 5 receptor is necessary for extinction of cocaine-associated cues. British Journal of Pharmacology. 2016;173(6):1085-94. doi:10.1111/bph.13437
42. Kumaresan V, Yuan M, Yee J, Famous KR, Anderson SM, Schmidt HD, et al. Metabotropic glutamate receptor 5 (mGluR5) antagonists attenuate cocaine priming- and cue-induced reinstatement of cocaine seeking. Behavioural Brain Research. 2009;202(2):238-44. doi:10.1016/j.bbr.2009.03.039
43. Georgiou P, Zanos P, Ehteramyan M, Hourani S, Kitchen I, Maldonado R, et al. Differential regulation of mGlu5R and ΜOPr by priming- and cue-induced reinstatement of cocaine-seeking behaviour in mice. Addiction Biology. 2015;20(5):902-12. doi:10.1111/adb.12208
44. Besheer J, Grondin JJM, Salling MC, Spanos M, Stevenson RA, Hodge CW. Interoceptive effects of alcohol require mGlu5 receptor activity in the nucleus accumbens. The Journal of Neuroscience. 2009;29(30):9582-91. doi:10.1523/jneurosci.2366-09.2009
45. Gass JT, Olive MF. Role of protein kinase C epsilon (PKCɛ) in the reduction of ethanol reinforcement due to mGluR5 antagonism in the nucleus accumbens shell. Psychopharmacology. 2009;204(4):587-97. doi:10.1007/s00213-009-1490-y
46. Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, Bernard A, et al. Genome-wide atlas of gene expression in the adult mouse brain. Nature. 2007;445(7124):168-76. doi:10.1038/nature05453
47. Kim J, Pignatelli M, Xu S, Itohara S, Tonegawa S. Antagonistic negative and positive neurons of the basolateral amygdala. Nature Neuroscience. 2016;19:1636. doi:10.1038/nn.4414
48. Mashhoon Y, Wells AM, Kantak KM. Interaction of the rostral basolateral amygdala and prelimbic prefrontal cortex in regulating reinstatement of cocaine-seeking behavior. Pharmacology Biochemistry and Behavior. 2010;96(3):347-53. doi:10.1016/j.pbb.2010.06.005
49. Szalay JJ, Morin ND, Kantak KM. Involvement of the dorsal subiculum and rostral basolateral amygdala in cocaine cue extinction learning in rats. European Journal of Neuroscience. 2011;33(7):1299-307. doi:10.1111/j.1460-9568.2010.07581.x
50. Wright CI, Groenewegen HJ. Patterns of overlap and segregation between insular cortical, intermediodorsal thalamic and basal amygdaloid afferents in the nucleus accumbens of the rat. Neuroscience. 1996;73(2):359-73. doi:10.1016/0306-4522(95)00592-7
51. Wright CI, Groenewegen HJ. Patterns of convergence and segregation in the medial nucleus accumbens of the rat: Relationships of prefrontal cortical, midline thalamic, and basal amygdaloid afferents. The Journal of Comparative Neurology. 1995;361(3):383-403. doi:10.1002/cne.903610304
52. Beyeler A, Chang C-J, Silvestre M, Lévêque C, Namburi P, Wildes CP, et al. Organization of valence-encoding and projection-defined neurons in the basolateral amygdala. Cell Reports. 2018;22(4):905-18. doi:10.1016/j.celrep.2017.12.097
53. Janak PH, Tye KM. From circuits to behaviour in the amygdala. Nature. 2015;517(7534):284-92. doi:10.1038/nature14188
All items in Spectrum are protected by copyright, with all rights reserved. The use of items is governed by Spectrum's terms of access.

Repository Staff Only: item control page

Downloads per month over past year

Research related to the current document (at the CORE website)
- Research related to the current document (at the CORE website)
Back to top Back to top