Abstract
Rationale
After a history of intermittent cocaine intake, rats develop patterns of drug use characteristic of substance use disorder. The dorsal striatum is involved in the increased pursuit of cocaine after intermittent drug self-administration experience. Within the dorsal striatum, chronic cocaine use changes metabotropic glutamate type II receptor (mGlu2/3) density and function.
Objectives
We examined the extent to which activity at Glu2/3 receptors mediates responding for cocaine after intermittent cocaine use.
Methods
Male (n = 11) and female (n = 10) Wistar rats self-administered 0.25 mg/kg/infusion cocaine during 10 daily intermittent access (IntA) sessions (5 min ON/25 min OFF, for 5 h/session). We then examined the effects of microinjections of the mGlu2/3 receptor agonist LY379268 (0, 1, and 3 µg/hemisphere) into the ventrolateral part of the dorsal striatum on cocaine self-administration under a progressive ratio schedule of reinforcement.
Results
Across 10 IntA sessions, the sexes showed similar levels of cocaine intake. In females only, locomotion significantly increased over sessions, suggesting that female rats developed psychomotor sensitization to self-administered cocaine. After 10 IntA sessions, intra-dorsal striatum LY379268 significantly reduced breakpoints achieved for cocaine, active lever presses, and cocaine infusions earned under progressive ratio. LY379268 had no effects on locomotion or inactive lever presses, indicating no motor effects.
Conclusions
These results suggest that mGlu2/3 receptor activation in the ventrolateral dorsal striatum suppresses incentive motivation for cocaine, and this holds promise for new treatments to manage substance use disorder.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
Data and Med-PC code are available on Figshare (Khoo and Samaha 2023).
References
aCSF (1×) (2011) Cold Spring Harbor Protocols. pdb.rec066845. https://doi.org/10.1101/pdb.rec066845
Adewale AS, Platt DM, Spealman RD (2006) Pharmacological stimulation of group II metabotropic glutamate receptors reduces cocaine self-administration and cocaine-induced reinstatement of drug seeking in squirrel monkeys. J Pharmacol Exp Ther 318(2):922–931. https://doi.org/10.1124/jpet.106.105387
Algallal H, Allain F, Ndiaye NA, Samaha A-N (2020) Sex differences in cocaine self-administration behaviour under long access versus intermittent access conditions. Addict Biol 25(5):e12809. https://doi.org/10.1111/adb.12809
Allain F, Bouayad-Gervais K, Samaha A-N (2018) High and escalating levels of cocaine intake are dissociable from subsequent incentive motivation for the drug in rats. Psychopharmacology 235(1):317–328. https://doi.org/10.1007/s00213-017-4773-8
Allain F, Minogianis EA, Roberts DCS, Samaha AN (2015) How fast and how often: the pharmacokinetics of drug use are decisive in addiction. Neurosci Biobehav Rev 56:166–179. https://doi.org/10.1016/j.neubiorev.2015.06.012
Allain F, Roberts DCS, Lévesque D, Samaha AN (2017) Intermittent intake of rapid cocaine injections promotes robust psychomotor sensitization, increased incentive motivation for the drug and mGlu2/3 receptor dysregulation. Neuropharmacology 117:227–237. https://doi.org/10.1016/j.neuropharm.2017.01.026
Allain F, Samaha A-N (2019) Revisiting long-access versus short-access cocaine self-administration in rats: intermittent intake promotes addiction symptoms independent of session length. Addict Biol 24(4):641–651. https://doi.org/10.1111/adb.12629
Anton RF, O’Malley SS, Ciraulo DA, Cisler RA, Couper D, Donovan DM, Gastfriend DR, Hosking JD, Johnson BA, LoCastro JS, Longabaugh R, Mason BJ, Mattson ME, Miller WR, Pettinati HM, Randall CL, Swift R, Weiss RD, Williams LD, Combine Study Research Group, f. t (2006) Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA 295(17):2003-2017.https://doi.org/10.1001/jama.295.17.2003
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. J Neurosci 24(20):4723–4727. https://doi.org/10.1523/jneurosci.0176-04.2004
Berendse HW, Graaf YG-D, Groenewegen HJ (1992) Topographical organization and relationship with ventral striatal compartments of prefrontal corticostriatal projections in the rat. J Comp Neurol 316(3):314–347. https://doi.org/10.1002/cne.903160305
Beveridge T, Wray P, Brewer A, Shapiro B, Mahoney J, Newton T, Haile C, De La Garza I (2012) Analyzing human cocaine use patterns to inform animal addiction model development. College on Problems of Drug Dependence Annual Meeting, Palm Springs, CA
Beveridge TJR, Smith HR, Nader MA, Porrino LJ (2011) Group II metabotropic glutamate receptors in the striatum of non-human primates: dysregulation following chronic cocaine self-administration. Neurosci Lett 496(1):15–19. https://doi.org/10.1016/j.neulet.2011.03.077
Bossert JM, Gray SM, Lu L, Shaham Y (2006) Activation of group II metabotropic glutamate receptors in the nucleus accumbens shell attenuates context-induced relapse to heroin seeking. Neuropsychopharmacology 31(10):2197–2209. https://doi.org/10.1038/sj.npp.1300977
Brandt L, Chao T, Comer SD, Levin FR (2021) Pharmacotherapeutic strategies for treating cocaine use disorder—what do we have to offer? Addiction 116(4):694–710. https://doi.org/10.1111/add.15242
Calipari ES, Ferris MJ, Siciliano CA, Zimmer BA, Jones SR (2014) Intermittent cocaine self-administration produces sensitization of stimulant effects at the dopamine transporter. J Pharmacol Exp Ther 349(2):192–198. https://doi.org/10.1124/jpet.114.212993
Carr CC, Ferrario CR, Robinson TE (2020) Intermittent access cocaine self-administration produces psychomotor sensitization: effects of withdrawal, sex and cross-sensitization. Psychopharmacology 237(6):1795–1812. https://doi.org/10.1007/s00213-020-05500-4
Carroll KM (1997) Integrating psychotherapy and pharmacotherapy to improve drug abuse outcomes. Addict Behav 22(2):233–245. https://doi.org/10.1016/S0306-4603(96)00038-X
Cetin T, Freudenberg F, Füchtemeier M, Koch M (2004) Dopamine in the orbitofrontal cortex regulates operant responding under a progressive ratio of reinforcement in rats. Neurosci Lett 370(2):114–117. https://doi.org/10.1016/j.neulet.2004.08.002
Cohen P, Sas A (1994) Cocaine use in Amsterdam in non Deviant Subcultures. Addict Res 2(1):71–94. https://doi.org/10.3109/16066359409005547
Conn PJ, Pin J-P (1997) Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol 37(1):205–237. https://doi.org/10.1146/annurev.pharmtox.37.1.205
Dohovics R, Janáky R, Varga V, Saransaari P, Oja SS (2003) Cyclic AMP-mediated regulation of striatal glutamate release: interactions of presynaptic ligand- and voltage-gated ion channels and G-protein-coupled receptors. Neurochem Int 43(4):425–430. https://doi.org/10.1016/S0197-0186(03)00031-7
Gueye AB, Allain F, Samaha A-N (2018) Intermittent intake of rapid cocaine injections promotes the risk of relapse and increases mesocorticolimbic BDNF levels during abstinence. Neuropsychopharmacology. https://doi.org/10.1038/s41386-018-0249-8
Hao Y, Martin-Fardon R, Weiss F (2010) Behavioral and functional evidence of metabotropic glutamate receptor 2/3 and metabotropic glutamate receptor 5 dysregulation in cocaine-escalated rats: factor in the transition to dependence. Biol Psychiat 68(3):240–248. https://doi.org/10.1016/j.biopsych.2010.02.011
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
James MH, Charnley JL, Flynn JR, Smith DW, Dayas CV (2011) Propensity to ‘relapse’ following exposure to cocaine cues is associated with the recruitment of specific thalamic and epithalamic nuclei. Neuroscience 199:235–242. https://doi.org/10.1016/j.neuroscience.2011.09.047
James MH, Stopper CM, Zimmer BA, Koll NE, Bowrey HE, Aston-Jones G (2019) Increased number and activity of a lateral subpopulation of hypothalamic orexin/hypocretin neurons underlies the expression of an addicted state in rats. Biol Psychiat 85(11):925–935. https://doi.org/10.1016/j.biopsych.2018.07.022
Jonkman S, Pelloux Y, Everitt BJ (2012) Differential roles of the dorsolateral and midlateral striatum in punished cocaine seeking. J Neurosci 32(13):4645–4650. https://doi.org/10.1523/jneurosci.0348-12.2012
Kalivas PW (2009) The glutamate homeostasis hypothesis of addiction. Nat Rev Neurosci 10(8):561–572. https://doi.org/10.1038/nrn2515
Kalivas PW, Volkow ND (2011) New medications for drug addiction hiding in glutamatergic neuroplasticity. Mol Psychiatry 16(10):974–986. https://doi.org/10.1038/mp.2011.46
Kampman K, Jarvis M (2015) American Society of Addiction Medicine (ASAM) national practice guideline for the use of medications in the treatment of addiction involving opioid use. J Addict Med 9(5):358–367. https://doi.org/10.1097/ADM.0000000000000166
Karkhanis AN, Beveridge TJR, Blough BE, Jones SR, Ferris MJ (2016) The individual and combined effects of phenmetrazine and mgluR2/3 agonist LY379268 on the motivation to self-administer cocaine. Drug Alcohol Depend 166:51–60. https://doi.org/10.1016/j.drugalcdep.2016.06.020
Kawa AB, Bentzley BS, Robinson TE (2016) Less is more: prolonged intermittent access cocaine self-administration produces incentive-sensitization and addiction-like behavior. Psychopharmacology 233(19):3587–3602. https://doi.org/10.1007/s00213-016-4393-8
Kawa AB, Robinson TE (2019) Sex differences in incentive-sensitization produced by intermittent access cocaine self-administration. Psychopharmacology 236(2):625–639. https://doi.org/10.1007/s00213-018-5091-5
Kawa AB, Valenta AC, Kennedy RT, Robinson TE (2019) Incentive and dopamine sensitization produced by intermittent but not long access cocaine self-administration. Eur J Neurosci 50(4):2663–2682. https://doi.org/10.1111/ejn.14418
Khoo SY-S, Samaha A-N (2023) Dataset: metabotropic glutamate group II receptor activation in the ventrolateral dorsal striatum suppresses the motivation for cocaine in rats. Figshare. https://doi.org/10.6084/m9.figshare.22574065
Khoo SY-S, Uhrig A, Samaha A-N, Chaudhri N (2022) Does vendor breeding colony influence sign- and goal-tracking in Pavlovian conditioned approach? A preregistered empirical replication. Neuroanat Behav 4:e46. https://doi.org/10.35430/nab.2022.e46
Kilbride J, Huang L, Rowan MJ, Anwyl R (1998) Presynaptic inhibitory action of the group II metabotropic glutamate receptor agonists, LY354740 and DCG-IV. Eur J Pharmacol 356(2):149–157. https://doi.org/10.1016/S0014-2999(98)00526-3
Leri F, Stewart J, Tremblay A, Bruneau J (2004) Heroin and cocaine co-use in a group of injection drug users in Montréal. J Psychiatry Neurosci 29(1):40–47
Linden AM, Bergeron M, Schoepp DD (2005) Comparison of c-Fos induction in the brain by the mGlu2/3 receptor antagonist LY341495 and agonist LY354740: evidence for widespread endogenous tone at brain mGlu2/3 receptors in vivo. Neuropharmacology 49:120–134. https://doi.org/10.1016/j.neuropharm.2005.05.006
Lucantonio F, Stalnaker TA, Shaham Y, Niv Y, Schoenbaum G (2012) The impact of orbitofrontal dysfunction on cocaine addiction. Nat Neurosci 15(3):358–366. https://doi.org/10.1038/nn.3014
Maney DL (2016) Perils and pitfalls of reporting sex differences. Philos Trans R Soc B: Biol Sci 371(1688):20150119. https://doi.org/10.1098/rstb.2015.0119
Martin B, Ji S, Maudsley S, Mattson MP (2010) “Control” laboratory rodents are metabolically morbid: Why it matters. Proc Natl Acad Sci 107(14):6127–6133. https://doi.org/10.1073/pnas.0912955107
Minogianis E-A, Samaha A-N (2020) Taking rapid and intermittent cocaine infusions enhances both incentive motivation for the drug and cocaine-induced gene regulation in corticostriatal regions. Neuroscience 442:314–328. https://doi.org/10.1016/j.neuroscience.2020.05.058
Minogianis E-A, Servonnet A, Filion M-P, Samaha A-N (2019) Role of the orbitofrontal cortex and the dorsal striatum in incentive motivation for cocaine. Behav Brain Res 372:112026. https://doi.org/10.1016/j.bbr.2019.112026
Minozzi S, Saulle R, De Crescenzo F, Amato L (2016) Psychosocial interventions for psychostimulant misuse. Cochrane Database Syst Rev (9):CD011866. https://doi.org/10.1002/14651858.CD011866.pub2
Moorman DE (2018) The role of the orbitofrontal cortex in alcohol use, abuse, and dependence. Prog Neuropsychopharmacol Biol Psychiatry 87:85–107. https://doi.org/10.1016/j.pnpbp.2018.01.010
Nicolas C, Russell TI, Pierce AF, Maldera S, Holley A, You Z-B, McCarthy MM, Shaham Y, Ikemoto S (2019) Incubation of cocaine craving after intermittent-access self-administration: sex differences and estrous cycle. Biol Psychiatry 85(11):915–924. https://doi.org/10.1016/j.biopsych.2019.01.015
Niedzielska-Andres E, Pomierny-Chamioło L, Andres M, Walczak M, Knackstedt LA, Filip M, Przegaliński E (2021) Cocaine use disorder: A look at metabotropic glutamate receptors and glutamate transporters. Pharmacol Ther 221:107797. https://doi.org/10.1016/j.pharmthera.2020.107797
Niswender CM, Conn PJ (2010) Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annu Rev Pharmacol Toxicol 50(1):295–322. https://doi.org/10.1146/annurev.pharmtox.011008.145533
Pacchioni AM, Gabriele A, See RE (2011) Dorsal striatum mediation of cocaine-seeking after withdrawal from short or long daily access cocaine self-administration in rats. Behav Brain Res 218(2):296–300. https://doi.org/10.1016/j.bbr.2010.12.014
Paxinos G, Watson C (2007) The rat brain in stereotaxic coordinates, 6th ed. Academic Press
Peacock A, Leung J, Larney S, Colledge S, Hickman M, Rehm J, Giovino GA, West R, Hall W, Griffiths P, Ali R, Gowing L, Marsden J, Ferrari AJ, Grebely J, Farrell M, Degenhardt L (2018) Global statistics on alcohol, tobacco and illicit drug use: 2017 status report. Addiction 113(10):1905–1926. https://doi.org/10.1111/add.14234
Peters J, Kalivas PW (2006) The group II metabotropic glutamate receptor agonist, LY379268, inhibits both cocaine- and food-seeking behavior in rats. Psychopharmacology 186(2):143–149. https://doi.org/10.1007/s00213-006-0372-9
Pomierny-Chamiolo L, Miszkiel J, Frankowska M, Mizera J, Filip M (2017) Neuroadaptive changes in metabotropic glutamate mGlu2/3R expression during different phases of cocaine addiction in rats. Pharmacol Rep 69(5):1073–1081. https://doi.org/10.1016/j.pharep.2017.04.016
Ray LA, Meredith LR, Kiluk BD, Walthers J, Carroll KM, Magill M (2020) Combined pharmacotherapy and cognitive behavioral therapy for adults with alcohol or substance use disorders: a systematic review and meta-analysis. JAMA Netw Open 3(6):e208279–e208279. https://doi.org/10.1001/jamanetworkopen.2020.8279
Richardson NR, Roberts DCS (1996) Progressive ratio schedules in drug self-administration studies in rats: a method to evaluate reinforcing efficacy. J Neurosci Methods 66(1):1–11. https://doi.org/10.1016/0165-0270(95)00153-0
Rowland NE (2007) Food or fluid restriction in common laboratory animals: balancing welfare considerations with scientific inquiry. Comp Med 57(2):149–160
Samaha A-N, Khoo SYS, Ferrario CR, Robinson TE (2021) Dopamine “ups and downs” in addiction revisited. Trends Neurosci 44(7):516–526. https://doi.org/10.1016/j.tins.2021.03.003
Samaha AN, Minogianis EA, Nachar W (2011) Cues paired with either rapid or slower self-administered cocaine injections acquire similar conditioned rewarding properties. PLoS ONE 6(10):e26481. https://doi.org/10.1371/journal.pone.0026481
Schilman EA, Uylings HBM, Graaf YG-D, Joel D, Groenewegen HJ (2008) The orbital cortex in rats topographically projects to central parts of the caudate–putamen complex. Neurosci Lett 432(1):40–45. https://doi.org/10.1016/j.neulet.2007.12.024
Schoepp DD (2001) Unveiling the functions of presynaptic metabotropic glutamate receptors in the central nervous system. J Pharmacol Exp Ther 299(1):12–20. https://jpet.aspetjournals.org/content/jpet/299/1/12.full.pdf. Accessed 16 Apr 2022
Shin CB, Templeton TJ, Chiu AS, Kim J, Gable ES, Vieira PA, Kippin TE, Szumlinski KK (2018) Endogenous glutamate within the prelimbic and infralimbic cortices regulates the incubation of cocaine-seeking in rats. Neuropharmacology 128:293–300. https://doi.org/10.1016/j.neuropharm.2017.10.024
Singer BF, Fadanelli M, Kawa AB, Robinson TE (2018) Are cocaine-seeking “habits” necessary for the development of addiction-like behavior in rats? J Neurosci 38(1):60–73. https://doi.org/10.1523/jneurosci.2458-17.2017
Sparber SB, Fossom LH (1984) Amphetamine cumulation and tolerance development: concurrent and opposing phenomena. Pharmacol Biochem Behav 20(3):415–424. https://doi.org/10.1016/0091-3057(84)90280-6
Sparks LM, Sciascia JM, Ayorech Z, Chaudhri N (2014) Vendor differences in alcohol consumption and the contribution of dopamine receptors to Pavlovian-conditioned alcohol-seeking in Long-Evans rats. Psychopharmacology 231(4):753–764. https://doi.org/10.1007/s00213-013-3292-5
Spencer S, Kalivas PW (2017) Glutamate transport: a new bench to bedside mechanism for treating drug abuse. Int J Neuropsychopharmacol 20(10):797–812. https://doi.org/10.1093/ijnp/pyx050
Stalnaker TA, Cooch NK, Schoenbaum G (2015) What the orbitofrontal cortex does not do. Nat Neurosci 18(5):620–627. https://doi.org/10.1038/nn.3982
Warr O, Takahashi M, Attwell D (1999) Modulation of extracellular glutamate concentration in rat brain slices by cystine-glutamate exchange. J Physiol 514(3):783–793. https://doi.org/10.1111/j.1469-7793.1999.783ad.x
Weissenborn R, Whitelaw RB, Robbins TW, Everitt BJ (1998) Excitotoxic lesions of the mediodorsal thalamic nucleus attenuate intravenous cocaine self-administration. Psychopharmacology 140(2):225–232. https://doi.org/10.1007/s002130050761
Yager LM, Garcia AF, Donckels EA, Ferguson SM (2019) Chemogenetic inhibition of direct pathway striatal neurons normalizes pathological, cue-induced reinstatement of drug-seeking in rats. Addict Biol 24(2):251–264. https://doi.org/10.1111/adb.12594
Zimmer BA, Oleson EB, Roberts DCS (2012) The motivation to self-administer is increased after a history of spiking brain levels of cocaine. Neuropsychopharmacology 37(8):1901–1910. https://doi.org/10.1038/npp.2012.37
Funding
This work was supported by the Canadian Institutes of Health Research (Grant #168971) 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 Recherche du Québec—Santé (Awards #270051 and #306413).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no conflicts of interest.
Additional information
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Khoo, S.YS., Samaha, AN. Metabotropic glutamate group II receptor activation in the ventrolateral dorsal striatum suppresses incentive motivation for cocaine in rats. Psychopharmacology 240, 1247–1260 (2023). https://doi.org/10.1007/s00213-023-06363-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-023-06363-1