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Efficacy and side effects of baclofen and the novel GABAB receptor positive allosteric modulator CMPPE in animal models for alcohol and cocaine addiction

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Abstract

Rationale

Preclinical studies suggest that the GABAB receptor is a potential target for treatment of substance use disorders. However, recent clinical trials report adverse effects in patients treated with the GABAB receptor agonist baclofen and even question efficacy. How can the discrepancy between preclinical and clinical findings be explained?

Objective

To test efficacy and adverse effects of baclofen and the novel GABAB positive allosteric modulator (PAM) CMPPE in rat addiction models, which were developed in accordance with DSM.

Methods

We used a well-characterized rat model of long-term alcohol consumption with repeated deprivation phases that result in compulsive alcohol drinking in a relapse situation, and a rat model of long-term intravenous cocaine self-administration resulting in key symptoms of addictive behavior. We tested repeated baclofen (0, 1, and 3 mg/kg; i.p.) and CMPPE doses (0, 10, and 30 mg/kg; i.p.) in relapse-like situations, in either alcohol or cocaine addicted-like rats.

Results

Baclofen produced a weak anti-relapse effect at the highest dose in alcohol addicted-like rats, and this effect was mainly due to the treatment-induced sedation. CMPPE had a better profile, with a dose-dependent reduction of relapse-like alcohol drinking and without any signs of sedation. The cue-induced cocaine-seeking response was completely abolished by both compounds.

Conclusion

Positive allosteric modulation of the GABAB receptor provides efficacy, and no observable side effects in relapse behavior whereas baclofen may cause, not only sedation, but also considerable impairment of food intake or metabolism. However, targeting GABAB receptors may be effective in reducing certain aspects of addictive-like behavior, such as cue-reactivity.

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References

  • Agabio R, Colombo G (2014) GABAB receptor ligands for the treatment of alcohol use disorder: preclinical and clinical evidence. Front Neurosci 8:140

    Article  PubMed  PubMed Central  Google Scholar 

  • ANSM (2017) Le Baclofène en vie réelle en France entre 2009 et 2015. Usages, persistance et sécurité, et comparaison aux traitements des problèmes d’alcool ayant une autorisation de mise sur le marché. Rapport – 25th of July, 2017 - www.ansm.sante.fr

  • Beraha EM, Salemink E, Goudriaan AE, Bakker A, de Jong D, Smits N, Zwart JW, Geest DV, Bodewits P, Schiphof T, Defourny H, van Tricht M, van den Brink W, Wiers RW (2016) Efficacy and safety of high-dose baclofen for the treatment of alcohol dependence: a multicentre, randomised, double-blind controlled trial. Eur Neuropsychopharmacol 26:1950–1959

    Article  PubMed  CAS  Google Scholar 

  • Besheer J, Lepoutre V, Hodge CW (2004) GABA(B) receptor agonists reduce operant ethanol self-administration and enhance ethanol sedation in C57BL/6J mice. Psychopharmacology 174:358–366

    Article  PubMed  CAS  Google Scholar 

  • Beveridge TJ, Smith HR, Porrino LJ (2013) Differential development of tolerance to the functional and behavioral effects of repeated baclofen treatment in rats. Pharmacol Biochem Behav 106:27–32

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Braillon A, Naudet F (2017) Baclofen and alcohol use disorders: from miracle to mirage. Eur Neuropsychopharmacol 27:691–692

    Article  PubMed  CAS  Google Scholar 

  • Brebner K, Froestl W, Andrews M, Phelan R, Roberts DC (1999) The GABA(B) agonist CGP 44532 decreases cocaine self-administration in rats: demonstration using a progressive ratio and a discrete trials procedure. Neuropharmacology 38:1797–1804

    Article  PubMed  CAS  Google Scholar 

  • Brebner K, Ahn S, Phillips AG (2005) Attenuation of d-amphetamine self-administration by baclofen in the rat: behavioral and neurochemical correlates. Psychopharmacology 177:409–417

    Article  PubMed  CAS  Google Scholar 

  • Brown JW, Moeller A, Schmidt M, Turner SC, Nimmrich V, Ma J, Rueter LE, van der Kam E, Zhang M (2016) Anticonvulsant effects of structurally diverse GABA(B) positive allosteric modulators in the DBA/2J audiogenic seizure test: comparison to baclofen and utility as a pharmacodynamic screening model. Neuropharmacology 101:358–369

    Article  PubMed  CAS  Google Scholar 

  • Cannella N, Halbout B, Uhrig S, Evrard L, Corsi M, Corti C, Deroche-Gamonet V, Hansson AC, Spanagel R (2013) The mGluR2/3 agonist LY379268 induced anti-reinstatement effects in rats exhibiting addiction-like behavior. Neuropsychopharmacology 38:2048–2056

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Cannella N, Cosa-Linan A, Büchler E, Falfan-Melgoza C, Weber-Fahr W, Spanagel R (2018) In vivo structural imaging in rats reveals neuroanatomical correlates of behavioral sub-dimensions of cocaine addiction. Addict Biol 23:182–195

    Article  PubMed  CAS  Google Scholar 

  • Colombo G, Serra S, Brunetti G, Atzori G, Pani M, Vacca G, Addolorato G, Froestl W, Carai MA, Gessa GL (2002) The GABA(B) receptor agonists baclofen and CGP 44532 prevent acquisition of alcohol drinking behaviour in alcohol-preferring rats. Alcohol Alcohol 37:499–503

    Article  PubMed  CAS  Google Scholar 

  • Colombo G, Serra S, Brunetti G, Vacca G, Carai MA, Gessa GL (2003) Suppression by baclofen of alcohol deprivation effect in Sardinian alcohol-preferring (sP) rats. Drug Alcohol Depend 70(1):105–108

    Article  PubMed  CAS  Google Scholar 

  • Colombo G, Serra S, Vacca G, Carai MA, Gessa GL (2006) Baclofen-induced suppression of alcohol deprivation effect in Sardinian alcohol-preferring (sP) rats exposed to different alcohol concentrations. Eur J Pharmacol 550:123–126

    Article  PubMed  CAS  Google Scholar 

  • Deroche-Gamonet V, Belin D, Piazza PV (2004) Evidence for addiction-like behavior in the rat. Science 305:1014–1017

    Article  PubMed  CAS  Google Scholar 

  • Di Ciano P, Everitt BJ (2003) The GABA(B) receptor agonist baclofen attenuates cocaine- and heroin-seeking behavior by rats. Neuropsychopharmacology 28:510–518

    Article  PubMed  CAS  Google Scholar 

  • Filip M, Frankowska M (2007) Effects of GABA(B) receptor agents on cocaine priming, discrete contextual cue and food induced relapses. Eur J Pharmacol 571:166–173

    Article  PubMed  CAS  Google Scholar 

  • Filip M, Frankowska M, Sadakierska-Chudy A, Suder A, Szumiec L, Mierzejewski P, Bienkowski P, Przegaliński E, Cryan JF (2015) GABAB receptors as a therapeutic strategy in substance use disorders: focus on positive allosteric modulators. Neuropharmacology 88:36–47

    Article  PubMed  CAS  Google Scholar 

  • Froger-Colléaux C, Castagné V (2016) Effects of baclofen and raclopride on reinstatement of cocaine self-administration in the rat. Eur J Pharmacol 777:147–155

    Article  PubMed  CAS  Google Scholar 

  • Gjoni T, Urwyler S (2008) Receptor activation involving positive allosteric modulation, unlike full agonism, does not result in GABA B receptor desensitization. Neuropharmacology 55:1293–1299

    Article  PubMed  CAS  Google Scholar 

  • Kasanetz F, Deroche-Gamonet V, Berson N, Balado E, Lafourcade M, Manzoni O, Piazza PV (2010) Transition to addiction is associated with a persistent impairment in synaptic plasticity. Science 328:1709–1712

    Article  PubMed  CAS  Google Scholar 

  • Kiel LB, Hoegberg LC, Jansen T, Petersen JA, Dalhoff KP (2015) A nationwide register-based survey of baclofen toxicity. Basic Clin Pharmacol Toxicol 116:452–456

    Article  PubMed  CAS  Google Scholar 

  • Lehmann A, Mattsson JP, Edlund A, Johansson T, Ekstrand AJ (2003) Effects of repeated administration of baclofen to rats on GABA B receptor binding sites and subunit expression in the brain. Neurochem Res 28:387–393

    Article  PubMed  CAS  Google Scholar 

  • Maccioni P, Zaru A, Loi B, Lobina C, Carai MA, Gessa GL, Capra A, Mugnaini C, Pasquini S, Corelli F, Hyytiä P, Lumeng L, Colombo G (2012) Comparison of the effect of the GABAΒ receptor agonist, baclofen, and the positive allosteric modulator of the GABAB receptor, GS39783, on alcohol self-administration in 3 different lines of alcohol-preferring rats. Alcohol Clin Exp Res 36:1748–1766

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Munzar P, Kutkat SW, Miller CR, Goldberg SR (2000) Failure of baclofen to modulate discriminative-stimulus effects of cocaine or methamphetamine in rats. Eur J Pharmacol 408:169–174

    Article  PubMed  CAS  Google Scholar 

  • Paterson NE, Froestl W, Markou A (2004) The GABAB receptor agonists baclofen and CGP44532 decreased nicotine self-administration in the rat. Psychopharmacology 172:179–186

    Article  PubMed  CAS  Google Scholar 

  • Pelissier F, de Haro L, Cardona F, Picot C, Puskarczyk E, Sapori JM, Tournoud C, Franchitto N (2017) Self-poisoning with baclofen in alcohol-dependent patients: national reports to French poison control centers, 2008-2013. Clin Toxicol 55:275–284

    Article  CAS  Google Scholar 

  • Perdona' E, Costantini VJ, Tessari M, Martinelli P, Carignani C, Valerio E, Mok MH, Zonzini L, Visentini F, Gianotti M, Gordon L, Rocheville M, Corsi M, Capelli AM (2011) In vitro and in vivo characterization of the novel GABAB receptor positive allosteric modulator, 2-{1-[2-(4-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]-2-piperidinyl}ethanol (CMPPE). Neuropharmacology 61:957–966

    Article  PubMed  CAS  Google Scholar 

  • Reynaud M, Aubin HJ, Trinquet F, Zakine B, Dano C, Dematteis M, Trojak B, Paille F, Detilleux M (2017) A randomized, placebo-controlled study of high-dose baclofen in alcohol-dependent patients-the ALPADIR study. Alcohol Alcohol 52:439–446

    Article  PubMed  Google Scholar 

  • Roberts DC, Andrews MM, Vickers GJ (1996) Baclofen attenuates the reinforcing effects of cocaine in rats. Neuropsychopharmacology 15:417–423

    Article  PubMed  CAS  Google Scholar 

  • Slattery DA, Markou A, Froestl W, Cryan JF (2005) The GABAB receptor-positive modulator GS39783 and the GABAB receptor agonist baclofen attenuate the reward-facilitating effects of cocaine: intracranial self-stimulation studies in the rat. Neuropsychopharmacology 30:2065–2072

    Article  PubMed  CAS  Google Scholar 

  • Spanagel R (2009) Alcoholism: a systems approach from molecular physiology to addictive behavior. Physiol Rev 89:649–705

    Article  PubMed  CAS  Google Scholar 

  • Spanagel R (2017) Animal models of addiction. Dialogues Clin Neurosci 19(2)

  • Spanagel R, Hölter SM (1999) Long-term alcohol self-administration with repeated alcohol deprivation phases: an animal model of alcoholism? Alcohol Alcohol 34:231–243

    Article  PubMed  CAS  Google Scholar 

  • Spanagel R, Durstewitz D, Hansson A, Heinz A, Kiefer F, Köhr G, Matthäus F, Nöthen MM, Noori HR, Obermayer K, Rietschel M, Schloss P, Scholz H, Schumann G, Smolka M, Sommer W, Vengeliene V, Walter H, Wurst W, Zimmermann US, Addiction GWAS Resource Group., Stringer S, Smits Y, Derks EM (2013) A systems medicine research approach for studying alcohol addiction. Addict Biol 18:883–896

    Article  PubMed  Google Scholar 

  • Takahashi TT, Vengeliene V, Spanagel R (2017) Melatonin reduces motivation for cocaine self-administration and prevents relapse-like behavior in rats. Psychopharmacology 234:1741–1748

    Article  PubMed  CAS  Google Scholar 

  • Vengeliene V, Bilbao A, Molander A, Spanagel R (2008) Neuropharmacology of alcohol addiction. Br J Pharmacol 154:299–315

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Vengeliene V, Celerier E, Chaskiel L, Penzo F, Spanagel R (2009) Compulsive alcohol drinking in rodents. Addict Biol 14:384–396

    Article  PubMed  CAS  Google Scholar 

  • Vengeliene V, Leonardi-Essmann F, Sommer WH, Marston HM, Spanagel R (2010) Glycine transporter-1 blockade leads to persistently reduced relapse-like alcohol drinking in rats. Biol Psychiatry 68:704–711

    Article  PubMed  CAS  Google Scholar 

  • Vengeliene V, Noori HR, Spanagel R (2013) The use of a novel drinkometer system for assessing pharmacological treatment effects on ethanol consumption in rats. Alcohol Clin Exp Res 37:E322–E328

    Article  PubMed  CAS  Google Scholar 

  • Vengeliene V, Bilbao A, Spanagel R (2014) The alcohol deprivation effect model for studying relapse behavior: a comparison between rats and mice. Alcohol 48:313–320

    Article  PubMed  Google Scholar 

  • Vengeliene V, Moeller A, Meinhardt MW, Beardsley PM, Sommer WH, Spanagel R, Bespalov A (2016) The Calpain inhibitor A-705253 attenuates alcohol-seeking and relapse with low side-effect profile. Neuropsychopharmacology 41:979–988

    Article  PubMed  CAS  Google Scholar 

  • Walker BM, Koob GF (2007) The gamma-aminobutyric acid-B receptor agonist baclofen attenuates responding for ethanol in ethanol-dependent rats. Alcohol Clin Exp Res 31:11–18

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Xi ZX, Stein EA (1999) Baclofen inhibits heroin self-administration behavior and mesolimbic dopamine release. J Pharmacol Exp Ther 290:1369–1374

    PubMed  CAS  Google Scholar 

  • Young KA, Franklin TR, Roberts DC, Jagannathan K, Suh JJ, Wetherill RR, Wang Z, Kampman KM, O'Brien CP, Childress AR (2014) Nipping cue reactivity in the bud: baclofen prevents limbic activation elicited by subliminal drug cues. J Neurosci 34:5038–5043

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

We would like to thank Sabrina Koch and Elena Büchler for the excellent technical assistance.

Funding

Financial support for this work was provided by the Bundesministerium für Bildung und Forschung (e:Med program, FKZ: 01ZX1311A (Spanagel et al. 2013)). TTT was funded by CAPES Foundation, Ministry of Education of Brazil, Brasília – DF 70040-020, Brazil.

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Author notes

  1. Valentina Vengeliene and Tatiane T. Takahashi contributed equally to this work

Authors and Affiliations

  1. Institute of Psychopharmacology, Central Institute of Mental Health (CIMH), Medical Faculty Mannheim, Heidelberg University, J5, 68159, Mannheim, Germany

    Valentina Vengeliene, Tatiane T. Takahashi & Rainer Spanagel

  2. Valdman Institute of Pharmacology, Pavlov First State Medical University, St. Petersburg, Russia

    Olga A. Dravolina, Irina Belozertseva, Edwin Zvartau & Anton Y. Bespalov

  3. Exciva, Heidelberg, Germany

    Anton Y. Bespalov

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  1. Valentina Vengeliene
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  2. Tatiane T. Takahashi
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  3. Olga A. Dravolina
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  4. Irina Belozertseva
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  5. Edwin Zvartau
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  6. Anton Y. Bespalov
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  7. Rainer Spanagel
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Correspondence to Valentina Vengeliene.

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Vengeliene, V., Takahashi, T.T., Dravolina, O.A. et al. Efficacy and side effects of baclofen and the novel GABAB receptor positive allosteric modulator CMPPE in animal models for alcohol and cocaine addiction. Psychopharmacology 235, 1955–1965 (2018). https://doi.org/10.1007/s00213-018-4893-9

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  • DOI: https://doi.org/10.1007/s00213-018-4893-9

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