Abstract
Rationale
Reward-associated cues can trigger incentive motivation for reward and invigorate reward-seeking behaviour via Pavlovian-to-instrumental transfer (PIT). Glutamate signaling within the basolateral amygdala (BLA) modulates cue-triggered increases in incentive motivation. However, the role of BLA metabotropic group II glutamate (mGlu2/3) receptors is largely unknown.
Objectives
In Experiment 1, we characterized cue-triggered increases in incentive motivation for water reward using the PIT paradigm. In Experiment 2, we assessed the influence of intra-BLA microinjections of the mGlu2/3 receptor agonist LY379268 on this effect.
Methods
Water-restricted male Sprague–Dawley rats learned to press a lever for water. Separately, they learned to associate one of two auditory cues with free water. On test days, rats could lever press under extinction conditions (no water), with intermittent, non-contingent CS+ and CS- presentations. In Experiment 1, rats were tested under baseline conditions. In Experiment 2, rats received intra-BLA microinjections of LY379268 (0, 3 and 6 \({\mu }\)g/hemisphere) before testing.
Results
Across experiments, CS+, but not CS-, presentations increased water-associated lever pressing during testing, even though responding was reinforced neither by water nor the CS+. Intra-BLA LY379268 abolished both CS+ potentiated pressing on the water-associated lever and CS+ evoked conditioned approach to the site of water delivery. LY379268 did not influence locomotion or instrumental and Pavlovian response rates during intervals between CS presentations or during the CS-, indicating no motor effects.
Conclusions
mGlu2/3 receptor activity in the BLA mediates cue-triggered potentiation of incentive motivation for reward, suppressing both cue-induced increases in instrumental pursuit of the reward and anticipatory approach behaviour.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Change history
06 September 2021
A Correction to this paper has been published: https://doi.org/10.1007/s00213-021-05959-9
References
Backstrom P, Hyytia P (2005) Suppression of alcohol self-administration and cue-induced reinstatement of alcohol seeking by the mGlu2/3 receptor agonist LY379268 and the mGlu8 receptor agonist (S)-3,4-DCPG. Eur J Pharmacol 528(1–3):110–118. https://doi.org/10.1016/j.ejphar.2005.10.051
Baptista MAS, Martin-Fardon R, Weiss F (2004) Preferential effects of the metabotropic glutamate 2/3 receptor agonist LY379268 on conditioned reinstatement versus primary reinforcement: comparison between cocaine and a potent conventional reinforcer. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience 24(20):4723–4727. https://doi.org/10.1523/JNEUROSCI.0176-04.2004
Becker JB, Koob GF (2016) Sex differences in animal models: focus on addiction. Pharmacol Rev 68(2):242–263. https://doi.org/10.1124/pr.115.011163
Berridge KC, Robinson TE (2003) Parsing reward. Trends Neurosci 26(9):507–513. https://doi.org/10.1016/S0166-2236(03)00233-9
Bindra D (1978) How adaptive behavior is produced: a perceptual-motivational alternative to response-reinforcement. Behavioral and Brain Sciences 1(1):41–91. https://doi.org/10.1017/S0140525X00059380
Blundell P, Hall G, Killcross S (2001) Lesions of the basolateral amygdala disrupt selective aspects of reinforcer representation in rats. J Neurosci 21(22):9018–9026. https://doi.org/10.1523/JNEUROSCI.21-22-09018.2001
Bolles RC (1972) Reinforcement, expectancy, and learning. Psychol Rev 79(5):394–409. https://doi.org/10.1037/h0033120
Bossert JM, Poles GC, Sheffler-Collins SI, Ghitza UE (2006) The mGluR2/3 agonist LY379268 attenuates context- and discrete cue-induced reinstatement of sucrose seeking but not sucrose self-administration in rats. Behav Brain Res 173(1):148–152. https://doi.org/10.1016/j.bbr.2006.06.008
Cannady R, Grondin JJ, Fisher KR, Hodge CW, Besheer J (2011) Activation of group II metabotropic glutamate receptors inhibits the discriminative stimulus effects of alcohol via selective activity within the amygdala. Neuropsychopharmacology 36(11):2328–2338. https://doi.org/10.1038/npp.2011.121
Cartoni E, Balleine B, Baldassarre G (2016) Appetitive Pavlovian-instrumental transfer: a review. Neurosci Biobehav Rev 71:829–848. https://doi.org/10.1016/j.neubiorev.2016.09.020
Collins AL, Aitken TJ, Huang IW, Shieh C, Greenfield VY, Monbouquette HG, ... Wassum KM (2019) Nucleus accumbens cholinergic interneurons oppose cue-motivated behavior. Biol Psychiat 86 5 388-396.https://doi.org/10.1016/j.biopsych.2019.02.014
Conn PJ, Pin JP (1997) Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol 37:205–237. https://doi.org/10.1146/annurev.pharmtox.37.1.205
Corbit LH, Balleine BW (2005) Double dissociation of basolateral and central amygdala lesions on the general and outcome-specific forms of pavlovian-instrumental transfer. J Neurosci 25(4):962–970. https://doi.org/10.1523/JNEUROSCI.4507-04.2005
De Tommaso M, Mastropasqua T, Turatto M (2018) Working for beverages without being thirsty: human Pavlovian-instrumental transfer despite outcome devaluation. Learn Motiv 63:37–48. https://doi.org/10.1016/j.lmot.2018.01.001
Delamater AR, Holland PC (2008) The influence of CS-US interval on several different indices of learning in appetitive conditioning. J Exp Psychol Anim Behav Process 34(2):202–222. https://doi.org/10.1037/0097-7403.34.2.202
Derman, R. C., Bass, C. E., & Ferrario, C. R. (2020). Effects of hM4Di activation in CamKII basolateral amygdala neurons and CNO treatment on sensory-specific vs. general PIT: refining PIT circuits and considerations for using CNO. Psychopharmacology (Berl), 237(5), 1249–1266. doi:https://doi.org/10.1007/s00213-020-05453-8
Derman RC, Ferrario CR (2018) Enhanced incentive motivation in obesity-prone rats is mediated by NAc core CP-AMPARs. Neuropharmacology 131:326–336. https://doi.org/10.1016/j.neuropharm.2017.12.039
Everitt BJ, Dickinson A, Robbins TW (2001) The neuropsychological basis of addictive behaviour. Brain Res Brain Res Rev 36(2–3):129–138. https://doi.org/10.1016/s0165-0173(01)00088-1
Feltenstein MW, See RE (2007) NMDA receptor blockade in the basolateral amygdala disrupts consolidation of stimulus-reward memory and extinction learning during reinstatement of cocaine-seeking in an animal model of relapse. Neurobiol Learn Mem 88(4):435–444. https://doi.org/10.1016/j.nlm.2007.05.006
Flagel SB, Clark JJ, Robinson TE, Mayo L, Czuj A, Willuhn I, ... Akil H2011)A selective role for dopamine in stimulus-reward learning. Nature 469 7328; 53-57.https://doi.org/10.1038/nature09588
Flagel SB, Watson SJ, Robinson TE, Akil H (2007) Individual differences in the propensity to approach signals vs goals promote different adaptations in the dopamine system of rats. Psychopharmacology 191(3):599–607. https://doi.org/10.1007/s00213-006-0535-8
Gabriele A, See RE (2010) Reversible inactivation of the basolateral amygdala, but not the dorsolateral caudate putamen, attenuates consolidation of cocaine-cue associative learning in a reinstatement model of drug-seeking. Eur J Neurosci 32(6):1024–1029. https://doi.org/10.1111/j.1460-9568.2010.07394.x
Garceau C, Samaha AN, Cordahi T, Servonnet A, Khoo SY-S (2021) Dataset: role of basolateral amygdala metabotropic group II glutamate receptors in the response to reward-associated cues. Figshare.https://doi.org/10.6084/m9.figshare.13251125
Gu G, Lorrain DS, Wei H, Cole RL, Zhang X, Daggett L P, ... Lechner SM (2008)Distribution of metabotropic glutamate 2 and 3 receptors in the rat forebrain: Implication in emotional responses and central disinhibition.Brain Res 1197; 47-62.https://doi.org/10.1016/j.brainres.2007.12.057
Hall J, Parkinson JA, Connor TM, Dickinson A, Everitt BJ (2001) Involvement of the central nucleus of the amygdala and nucleus accumbens core in mediating Pavlovian influences on instrumental behaviour. Eur J Neurosci 13(10):1984–1992. https://doi.org/10.1046/j.0953-816x.2001.01577.x
Holland PC (2004) Relations between Pavlovian-instrumental transfer and reinforcer devaluation. J Exp Psychol Anim Behav Process 30(2):104–117. https://doi.org/10.1037/0097-7403.30.2.104
Holmes NM, Marchand AR, Coutureau E (2010) Pavlovian to instrumental transfer: a neurobehavioural perspective. Neurosci Biobehav Rev 34(8):1277–1295. https://doi.org/10.1016/j.neubiorev.2010.03.007
Imre G (2007) The preclinical properties of a novel group II metabotropic glutamate receptor agonist LY379268. CNS Drug Rev 13(4):444–464. https://doi.org/10.1111/j.1527-3458.2007.00024.x
Johnson AR, Thibeault KC, Lopez AJ, Peck EG, Sands LP, Sanders CM, ... Calipari ES2019)Cues play a critical role in estrous cycle-dependent enhancement of cocaine reinforcement.Neuropsychopharmacology 44 (7)1189-1197.https://doi.org/10.1038/s41386-019-0320-0
Khoo SY-S, LeCocq MR, Deyab GE, Chaudhri N (2019) Context and topography determine the role of basolateral amygdala metabotropic glutamate receptor 5 in appetitive Pavlovian responding. Neuropsychopharmacology 44(9):1524–1533. https://doi.org/10.1038/s41386-019-0335-6
Lichtenberg NT, Pennington ZT, Holley SM, Greenfield VY, Cepeda C, Levine MS, Wassum KM (2017) Basolateral amygdala to orbitofrontal cortex projections enable cue-triggered reward expectations. J Neurosci 37(35):8374–8384. https://doi.org/10.1523/JNEUROSCI.0486-17.2017
Lovibond PF (1983) Facilitation of instrumental behavior by a Pavlovian appetitive conditioned stimulus. J Exp Psychol Anim Behav Process 9(3):225–247. https://doi.org/10.1037/0097-7403.9.3.225
Lu L, Uejima JL, Gray SM, Bossert JM, Shaham Y (2007) Systemic and central amygdala injections of the mGluR(2/3) agonist LY379268 attenuate the expression of incubation of cocaine craving. Biol Psychiatry 61(5):591–598. https://doi.org/10.1016/j.biopsych.2006.04.011
Ludwig AM, Wikler A, Stark LH (1974) The first drink: psychobiological aspects of craving. Arch Gen Psychiatry 30(4):539–547. https://doi.org/10.1001/archpsyc.1974.01760100093015
Mahlberg J, Seabrooke T, Weidemann G, Hogarth L, Mitchell CJ, Moustafa AA (2019) Human appetitive Pavlovian-to-instrumental transfer: a goal-directed account. Psychol Res. https://doi.org/10.1007/s00426-019-01266-3
Malvaez M, Greenfield VY, Wang AS, Yorita AM, Feng L, Linker KE, ... Wassum KM(2015) Basolateral amygdala rapid glutamate release encodes an outcome-specific representation vital for reward-predictive cues to selectively invigorate reward-seeking actions. Sci Rep5; 12511. https://doi.org/10.1038/srep12511
Nasser HM, Lafferty DS, Lesser EN, Bacharach SZ, Calu DJ (2018) Disconnection of basolateral amygdala and insular cortex disrupts conditioned approach in Pavlovian lever autoshaping. Neurobiol Learn Mem 147:35–45. https://doi.org/10.1016/j.nlm.2017.11.010
Nicolas C, Russell TI, Pierce AF, Maldera S, Holley A, You ZB, ... Ikemoto S(2019) Incubation of cocaine craving after intermittent-access self-administration: sex differences and estrous cycle. Biol Psychiat 85 (11); 915-924.https://doi.org/10.1016/j.biopsych.2019.01.015
O’Brien CP, Childress AR, Ehrman R, Robbins SJ (1998) Conditioning factors in drug abuse: can they explain compulsion? J Psychopharmacol 12(1):15–22. https://doi.org/10.1177/026988119801200103
Ohishi H, Neki A, Mizuno N (1998) Distribution of a metabotropic glutamate receptor, mGluR2, in the central nervous system of the rat and mouse: an immunohistochemical study with a monoclonal antibody. Neurosci Res 30(1):65–82. https://doi.org/10.1016/s0168-0102(97)00120-x
Olney JJ, Warlow SM, Naffziger EE, Berridge KC (2018) Current perspectives on incentive salience and applications to clinical disorders. Curr Opin Behav Sci 22:59–69. https://doi.org/10.1016/j.cobeha.2018.01.007
Paxinos G, Watson C (2007) The rat brain in stereotaxic coordinates, 6th edn. Academic Press, London
Petralia RS, Wang YX, Niedzielski AS, Wenthold RJ (1996) The metabotropic glutamate receptors, mGluR2 and mGluR3, show unique postsynaptic, presynaptic and glial localizations. Neuroscience 71(4):949–976. https://doi.org/10.1016/0306-4522(95)00533-1
Prevost C, Liljeholm M, Tyszka JM, O’Doherty JP (2012) Neural correlates of specific and general Pavlovian-to-Instrumental Transfer within human amygdalar subregions: a high-resolution fMRI study. J Neurosci 32(24):8383–8390. https://doi.org/10.1523/JNEUROSCI.6237-11.2012
Puaud M, Higuera-Matas A, Brunault P, Everitt BJ, Belin D (2021) The basolateral amygdala to nucleus accumbens core circuit mediates the conditioned reinforcing effects of cocaine-paired cues on cocaine seeking. Biol Psychiat 89(4):356–365. https://doi.org/10.1016/j.biopsych.2020.07.022
Rescorla RA, Solomon RL (1967) Two-process learning theory: Relationships between Pavlovian conditioning and instrumental learning. Psychol Rev 74(3):151–182. https://doi.org/10.1037/h0024475
Robinson TE, Flagel SB (2009) Dissociating the predictive and incentive motivational properties of reward-related cues through the study of individual differences. Biol Psychiat 65(10):869–873. https://doi.org/10.1016/j.biopsych.2008.09.006
Schoepp DD (2001) Unveiling the functions of presynaptic metabotropic glutamate receptors in the central nervous system. J Pharmacol Exp Ther 299(1):12–20
Servonnet A, Hernandez G, El Hage C, Rompre PP, Samaha AN (2020) Optogenetic activation of the basolateral amygdala promotes both appetitive conditioning and the instrumental pursuit of reward cues. J Neurosci 40(8):1732–1743. https://doi.org/10.1523/JNEUROSCI.2196-19.2020
Shansky RM (2019) Are hormones a “female problem” for animal research? Science 364(6443):825–826. https://doi.org/10.1126/science.aaw7570
Shansky RM, Murphy AZ (2021) Considering sex as a biological variable will require a global shift in science culture. Nat Neurosci 24(4):457–464. https://doi.org/10.1038/s41593-021-00806-8
Shiflett MW, Balleine BW (2010) At the limbic-motor interface: disconnection of basolateral amygdala from nucleus accumbens core and shell reveals dissociable components of incentive motivation. Eur J Neurosci 32(10):1735–1743. https://doi.org/10.1111/j.1460-9568.2010.07439.x
Talmi D, Seymour B, Dayan P, Dolan RJ (2008) Human pavlovian-instrumental transfer. J Neurosci 28(2):360–368. https://doi.org/10.1523/JNEUROSCI.4028-07.2008
Uejima JL, Bossert JM, Poles GC, Lu L (2007) Systemic and central amygdala injections of the mGluR2/3 agonist LY379268 attenuate the expression of incubation of sucrose craving in rats. Behav Brain Res 181(2):292–296. https://doi.org/10.1016/j.bbr.2007.04.019
Walker KC (1942) The effect of a discriminative stimulus transferred to a previously unassociated response. J Exp Psychol 31(4):312–321. https://doi.org/10.1037/h0062929
Wyvell CL, Berridge KC (2000) Intra-accumbens amphetamine increases the conditioned incentive salience of sucrose reward: enhancement of reward “wanting” without enhanced “liking” or response reinforcement. J Neurosci 20(21):8122–8130. https://doi.org/10.1523/JNEUROSCI.20-21-08122.2000
Zhao Y, Dayas CV, Aujla H, Baptista MA, Martin-Fardon R, Weiss F (2006) 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. J Neurosci 26(39):9967–9974. https://doi.org/10.1523/JNEUROSCI.2384-06.2006
Zhou L, Pruitt C, Shin CB, Garcia AD, Zavala AR, See RE (2014) Fos expression induced by cocaine-conditioned cues in male and female rats. Brain Struct Funct 219(5):1831–1840. https://doi.org/10.1007/s00429-013-0605-8
Acknowledgements
The authors gratefully acknowledge Rifka (Rebecca) C. Derman, Carrie R. Ferrario and Cameron Nobile for generously sharing equipment, computer programs and advice in setting up the behavioural tasks used in this work.
Funding
This work was supported by the National Science and Engineering Research Council of Canada (grant 355923) and the Canada Foundation for Innovation to ANS (grant 24326). ANS holds a salary award from the Fonds de la Recherche du Québec-Santé (Grant #28988). SYK was supported by a postdoctoral fellowship from the Fonds de la Recherche du Québec – Santé (Grant #270051). CG was supported by a Master’s scholarship (B1X) from the Fonds de recherche du Québec—Nature et technologies (Grant #275340).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no competing interests.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The original version of this article was revised: The figures were incorrectly presented without panel titles.
Supplementary Information
ESM 1
(DOCX 111 kb)
Rights and permissions
About this article
Cite this article
Garceau, C., Samaha, AN., Cordahi, T. et al. Metabotropic group II glutamate receptors in the basolateral amygdala mediate cue-triggered increases in incentive motivation. Psychopharmacology 238, 2905–2917 (2021). https://doi.org/10.1007/s00213-021-05907-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-021-05907-7