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.
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Kalivas PW, Volkow ND. The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry. 2005;162:1403–13. https://doi.org/10.1176/appi.ajp.162.8.1403
Brown RM, Kupchik YM, Kalivas PW. The story of glutamate in drug addiction and of n-acetylcysteine as a potential pharmacotherapy. JAMA Psychiatry. 2013;70:895–7. https://doi.org/10.1001/jamapsychiatry.2013.2207
Brown RM, Kupchik YM, Spencer S, Garcia-Keller C, Spanswick DC, Lawrence AJ. et al. Addiction-like synaptic impairments in diet-induced obesity. Biol Psychiatry. 2017;81:797–806.
Sengmany K, Gregory KJ. Metabotropic glutamate receptor subtype 5: molecular pharmacology, allosteric modulation and stimulus bias. Br J Pharmacol. 2016;173:3001–17. https://doi.org/10.1111/bph.13281
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. Eur J Pharm Sci. 2017;109:78–85. https://doi.org/10.1016/j.ejps.2017.07.031
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. Biol Psychiatry. 2018;84:180–92. https://doi.org/10.1016/j.biopsych.2017.08.018
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. Pharmacol Biochem Behav. 2012;101:329–35. https://doi.org/10.1016/j.pbb.2012.01.014
Bäckström P, Bachteler D, Koch S, Hyytiä P, Spanagel R. mGluR5 antagonist MPEP reduces ethanol-seeking and relapse behavior. Neuropsychopharmacology. 2004;29:921 https://doi.org/10.1038/sj.npp.1300381
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. J Pharmacol Exp Ther. 2005;315:590–600. https://doi.org/10.1124/jpet.105.090449
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. Eur J Pharmacol. 2004;499:121–33. https://doi.org/10.1016/j.ejphar.2004.07.056
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. Nat Neurosci. 2001;4:873. https://doi.org/10.1038/nn0901-873
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:e68371. https://doi.org/10.1371/journal.pone.0068371
Knackstedt LA, Trantham-Davidson HL, Schwendt M. The role of ventral and dorsal striatum mGluR5 in relapse to cocaine-seeking and extinction learning. Addict Biol. 2014;19:87–101. https://doi.org/10.1111/adb.12061
Field M, Cox WM. Attentional bias in addictive behaviors: a review of its development, causes, and consequences. Drug Alcohol Depend. 2008;97:1–20. https://doi.org/10.1016/j.drugalcdep.2008.03.030
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. Int J Neuropsychopharmacol. 2014;17:1521–32. https://doi.org/10.1017/S1461145714000303
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;51:1146–55. https://doi.org/10.1016/j.neuropharm.2006.07.008
Simonyi A, Serfozo P, Parker KE, Ramsey AK, Schachtman TR. Metabotropic glutamate receptor 5 in conditioned taste aversion learning. Neurobiol Learn Mem. 2009;92:460–3. https://doi.org/10.1016/j.nlm.2009.05.002
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 https://doi.org/10.1038/npp.2010.48
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:e0190206 https://doi.org/10.1371/journal.pone.0190206
Hoebel BG, Avena NM, Bocarsly ME, Rada P. Natural addiction: a behavioral and circuit model based on sugar addiction in rats. J Addict Med. 2009;3:33–41. https://doi.org/10.1097/ADM.0b013e31819aa621
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;40:2801–12. https://doi.org/10.1038/npp.2015.130
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;40:2555–65. https://doi.org/10.1038/npp.2015.102
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. https://doi.org/10.1101/475343
Mihov Y, Hasler G. Negative allosteric modulators of metabotropic glutamate receptors subtype 5 in addiction: a therapeutic window. Int J Neuropsychopharmacol. 2016;19:pyw002-pyw. https://doi.org/10.1093/ijnp/pyw002
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. J Neurosci. 2010;30:12608–18. https://doi.org/10.1523/jneurosci.2949-10.2010
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. Cereb Cortex. 2006;16:93–105. https://doi.org/10.1093/cercor/bhi087
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. https://doi.org/10.1038/sj.npp.1300417
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. Neurobiol Learn Mem. 2011;95:73–9. https://doi.org/10.1016/j.nlm.2010.11.009
Khoo SY-S, Uhrig A, Chaudhri N. Context does not invigorate responding to a neutral stimulus. Figshare. 2019. https://doi.org/10.6084/m9.figshare.7483478
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. Eur J Neurosci. 2013;38:2751–61. https://doi.org/10.1111/ejn.12278
Panayi MC, Killcross S. Functional heterogeneity within the rodent lateral orbitofrontal cortex dissociates outcome devaluation and reversal learning deficits. eLife . 2018;7:e37357. https://doi.org/10.7554/eLife.37357
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. https://doi.org/10.6084/m9.figshare.7045493
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. https://doi.org/10.1038/npp.2008.140
Knackstedt LA, Schwendt M. mGlu5 receptors and relapse to cocaine-seeking: the role of receptor trafficking in postrelapse extinction learning deficits. Neural Plast. 2016;2016:9312508. https://doi.org/10.1155/2016/9312508
Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 6th ed. London: Academic Press; 2007.
Swanson LW. Brain maps 4.0—Structure of the rat brain: an open access atlas with global nervous system nomenclature ontology and flatmaps. J Comp Neurol. 2018;526:935–43. https://doi.org/10.1002/cne.24381
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;146:1484–94. https://doi.org/10.1016/j.neuroscience.2007.03.025
Keefer SE, Petrovich GD. Distinct recruitment of basolateral amygdala-medial prefrontal cortex pathways across Pavlovian appetitive conditioning. Neurobiol Learn Mem. 2017;141:27–32. https://doi.org/10.1016/j.nlm.2017.03.006
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. J Neurosci. 2002;22:1126–36. https://doi.org/10.1523/jneurosci.22-03-01126.2002
Gass JT, Olive MF. Positive allosteric modulation of mGluR5 receptors facilitates extinction of a cocaine contextual memory. Biol Psychiatry. 2009;65:717–20. https://doi.org/10.1016/j.biopsych.2008.11.001
Perry CJ, Reed F, Zbukvic IC, Kim JH, Lawrence AJ. The metabotropic glutamate 5 receptor is necessary for extinction of cocaine-associated cues. Br J Pharmacol. 2016;173:1085–94. https://doi.org/10.1111/bph.13437
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. Behav Brain Res. 2009;202:238–44. https://doi.org/10.1016/j.bbr.2009.03.039
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. Addict Biol. 2015;20:902–12. https://doi.org/10.1111/adb.12208
Besheer J, Grondin JJM, Salling MC, Spanos M, Stevenson RA, Hodge CW. Interoceptive effects of alcohol require mGlu5 receptor activity in the nucleus accumbens. J Neurosci. 2009;29:9582–91. https://doi.org/10.1523/jneurosci.2366-09.2009
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;204:587–97. https://doi.org/10.1007/s00213-009-1490-y
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;445:168–76. https://doi.org/10.1038/nature05453
Kim J, Pignatelli M, Xu S, Itohara S, Tonegawa S. Antagonistic negative and positive neurons of the basolateral amygdala. Nat Neurosci. 2016;19:1636. https://doi.org/10.1038/nn.4414
Mashhoon Y, Wells AM, Kantak KM. Interaction of the rostral basolateral amygdala and prelimbic prefrontal cortex in regulating reinstatement of cocaine-seeking behavior. Pharmacol Biochem Behav. 2010;96:347–53. https://doi.org/10.1016/j.pbb.2010.06.005
Szalay JJ, Morin ND, Kantak KM. Involvement of the dorsal subiculum and rostral basolateral amygdala in cocaine cue extinction learning in rats. Eur J Neurosci. 2011;33:1299–307. https://doi.org/10.1111/j.1460-9568.2010.07581.x
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;73:359–73. https://doi.org/10.1016/0306-4522(95)00592-7
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. J Comp Neurol. 1995;361:383–403. https://doi.org/10.1002/cne.903610304
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 Rep. 2018;22:905–18. https://doi.org/10.1016/j.celrep.2017.12.097
Janak PH, Tye KM. From circuits to behaviour in the amygdala. Nature. 2015;517:284–92. https://doi.org/10.1038/nature14188
The authors gratefully acknowledge Belinda P. P. Lay for experiment suggestions, Franz Villaruel and Milan Valyear for assistance with blind histology, and Uri Shalev for access to locomotor testing equipment.
The authors declare no competing interests.
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Metabotropic glutamate receptor 5 signaling and appetitive Pavlovian behavior: implications for the treatment of addiction