Skip to main content
SpringerLink
Log in

Role of ethanol-derived acetaldehyde in operant oral self-administration of ethanol in rats

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

The role of ethanol-derived acetaldehyde has not been examined yet on performance in a model of operant oral self-administration. However, previous studies reported that an acetaldehyde-sequestering agent, d-penicillamine (DP) and an inhibitor of catalase-mediated acetaldehyde production, 3-amino-1,2,4-triazole (3-AT) reduce voluntary ethanol consumption.

Objectives

The aim of our investigation was to evaluate the effects of DP and 3-AT on acquisition and maintenance of oral operant ethanol self-administration.

Methods

Using operant chambers, rats learned to nose poke in order to receive ethanol solution (5–10 % v/v) under an FR1 schedule of reinforcement in which discrete light and tone cues were presented during ethanol delivery.

Results

DP and 3-AT impair the acquisition of ethanol self-administration, whereas its maintenance is not affected neither by drug given alone for both 10 or 5 % ethanol nor by drugs association for 5 % ethanol. Moreover, when the concentration of ethanol was diminished from 10 to 5 %, rats increased the rate of self-administration behaviour.

Conclusions

These findings suggest that brain acetaldehyde plays a critical role during acquisition of operant self-administration in ethanol-naïve rats. In contrast, during the maintenance phase, acetaldehyde could contribute to ethanol self-administration by a combined mechanism: On one hand, its lack (by DP or 3-AT) might result in further ethanol-seeking and taking and, on the other, inhibition of ethanol metabolism (by 3-AT) might release an action of the un-metabolised fraction of ethanol that does not overall result in compromising maintenance of ethanol self-administration.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Aragon CM, Amit Z (1992) The effect of 3-amino-1,2,4-triazole on voluntary ethanol consumption: evidence for brain catalase involvement in the mechanism of action. Neuropharmacology 31:709–712

    Article  CAS  PubMed  Google Scholar 

  • Bienkowski P, Kostowski W, Koros E (1999) Ethanol-reinforced behaviour in the rat: effects of naltrexone. Eur J Pharmacol 374:321–327. doi:10.1016/S0014-2999(99)00245-9

    Article  CAS  PubMed  Google Scholar 

  • Correa M, Miquel M, Sanchis-Segura C, Aragon CM (1999) Acute lead acetate administration potentiates ethanol-induced locomotor activity in mice: the role of brain catalase. Alcohol Clin Exp Res 23:799–805

    CAS  PubMed  Google Scholar 

  • Correa M, Salamone JD, Segovia KN, Pardo M, Longoni R, Spina L, Peana AT, Vinci S, Acquas E (2012) Piecing together the puzzle of acetaldehyde as a neuroactive agent. Neurosci Biobehav Rev 36:404–430. doi:10.1016/j.neubiorev.2011.07.009

    Article  CAS  PubMed  Google Scholar 

  • Czachowski CL, Legg BH, Samson HH (2001) Effects of acamprosate on ethanol-seeking and self-administration in the rat. Alcohol Clin Exp Res 25:344–350. doi:10.1111/j.1530-0277.2001.tb02220.x

    Article  CAS  PubMed  Google Scholar 

  • Davies M (2003) The role of GABAA receptors in mediating the effects of alcohol in the central nervous system. J Psychiatry Neurosci 28:263–274

    PubMed Central  PubMed  Google Scholar 

  • Escarabajal D, Miquel M, Aragon CM (2000) A psychopharmacological study of the relationship between brain catalase activity and ethanol-induced locomotor activity in mice. J Stud Alcohol 61:493–498

    Article  CAS  PubMed  Google Scholar 

  • Font L, Miquel M, Aragon CM (2005) Prevention of ethanol-induced behavioral stimulation by D-penicillamine: a sequestration agent for acetaldehyde. Alcohol Clin Exp Res 29:1156–1164

    Article  CAS  PubMed  Google Scholar 

  • Font L, Aragon CM, Miquel M (2006a) Voluntary ethanol consumption decreases after the inactivation of central acetaldehyde by d-penicillamine. Behav Brain Res 171:78–86. doi:10.1016/j.bbr.2006.03.020

    Article  CAS  PubMed  Google Scholar 

  • Font L, Aragon CM, Miquel M (2006b) Ethanol-induced conditioned place preference, but not aversion, is blocked by treatment with D -penicillamine, an inactivation agent for acetaldehyde. Psychopharmacology (Berl) 184:56–64. doi:10.1007/s00213-005-0224-z

    Article  CAS  Google Scholar 

  • Font L, Miquel M, Aragon CM (2008) Involvement of brain catalase activity in the acquisition of ethanol-induced conditioned place preference. Physiol Behav 93:733–741. doi:10.1016/j.physbeh.2007.11.026

    Article  CAS  PubMed  Google Scholar 

  • Graham DL, Self DW (2010) Integrating behavioral and molecular approaches in mouse self-administration studies. In: Kuhn CM, Koob GF (eds) Advances in the neuroscience of addiction, vol Chapter 5, 2nd edn. CRC Press, Boca Raton, pp pp. 164–pp. 165

    Google Scholar 

  • Grant KA, Samson HH (1986) The induction of oral ethanol self-administration by contingent ethanol delivery. Drug Alcohol Depend 16:361–368

    Article  CAS  PubMed  Google Scholar 

  • Ingjaldsson JT, Thayer JF, Laberg JC (2003) Preattentive processing of alcohol stimuli. Scand J Psychol 44:161–165. doi:10.1111/1467-9450.00334

    Article  PubMed  Google Scholar 

  • Israel Y, Quintanilla ME, Karahanian E, Rivera-Meza M, Herrera-Marschitz M (2015) The “first hit” toward alcohol reinforcement: role of ethanol metabolites. Alcohol Clin Exp Res 39:776–786. doi:10.1111/acer.12709

    Article  CAS  PubMed  Google Scholar 

  • Kaminski BJ, Van Linn ML, Cook JM, Yin W, Weerts EM (2013) Effects of the benzodiazepine GABAA α1-preferring ligand, 3-propoxy-β-carboline hydrochloride (3-PBC), on alcohol seeking and self-administration in baboons. Psychopharmacology 227:127–136. doi:10.1007/s00213-012-2946-z

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Karahanian E, Quintanilla ME, Tampier L, Rivera-Meza M, Bustamante D, Gonzalez-Lira V, Morales P, Herrera-Marschitz M, Israel Y (2011) Ethanol as a prodrug: brain metabolism of ethanol mediates its reinforcing effects. Alcohol Clin Exp Res 35:606–612. doi:10.1111/j.1530-0277.2011.01439.x

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Karahanian E, Rivera-Meza M, Tampier L, Quintanilla ME, Herrera-Marschitz M, Israel Y (2015) Long-term inhibition of ethanol intake by the administration of an aldehyde dehydrogenase-2 (ALDH2)-coding lentiviral vector into the ventral tegmental area of rats. Addict Biol 20:336–344. doi:10.1111/adb.12130

    Article  CAS  PubMed  Google Scholar 

  • Koechling UM, Amit Z (1994) Effects of 3-amino-1,2,4-triazole on brain catalase in the mediation of ethanol consumption in mice. Alcohol 11:235–239. doi:10.1016/0741-8329(94)90036-1

    Article  CAS  PubMed  Google Scholar 

  • Kumar S, Porcu P, Werner DF, Matthews DB, Diaz-Granados JL, Helfand RS, Morrow AL (2009) The role of GABA(A) receptors in the acute and chronic effects of ethanol: a decade of progress. Psychopharmacology (Berl) 205:529–564. doi:10.1007/s00213-009-1562-z

    Article  CAS  Google Scholar 

  • Ledesma JC, Font L, Baliño P, Aragon CM (2013) Modulation of ethanol-induced conditioned place preference in mice by 3-amino-1,2,4-triazole and D-penicillamine depends on ethanol dose and number of conditioning trials. Psychopharmacology 230:557–568. doi:10.1007/s00213-013-3177-7

    Article  CAS  PubMed  Google Scholar 

  • Ledesma JC, Baliño P, Aragon CM (2014) Reduction in central H2O2 levels prevents voluntary ethanol intake in mice: a role for the brain catalase-H2O2 system in alcohol binge drinking. Alcohol Clin Exp Res 38:60–67. doi:10.1111/acer.12253

    Article  CAS  PubMed  Google Scholar 

  • Martí-Prats L, Sánchez-Catalán MJ, Orrico A, Zornoza T, Polache A, Granero L (2013) Opposite motor responses elicited by ethanol in the posterior VTA: the role of acetaldehyde and the non-metabolized fraction of ethanol. Neuropharmacology 72:204–214. doi:10.1016/j.neuropharm.2013.04.047

    Article  PubMed  Google Scholar 

  • Nagasawa HT, Goon DJ, DeMaster EG (1978) 2,5,5-Trimethylthiazolidine-4-carboxylic acid, a D(-)-penicillamine-directed pseudometabolite of ethanol. Detoxication mechanism for acetaldehyde. J Med Chem 21:1274–1279. doi:10.1021/jm00210 a019

    Article  CAS  PubMed  Google Scholar 

  • National Research Council (1996) Guide for the Care and Use of Laboratory Animals. National Academies Press, Washington, DC

    Google Scholar 

  • Orrico A, Hipólito L, Sánchez-Catalán MJ, Martí-Prats L, Zornoza T, Granero L, Polache A (2013) Efficacy of D-penicillamine, a sequestering acetaldehyde agent, in the prevention of alcohol relapse-like drinking in rats. Psychopharmacology (Berl) 228:563–575. doi:10.1007/s00213-013-3065-1

    Article  CAS  Google Scholar 

  • Peana AT, Acquas E (2013) Behavioral and biochemical evidence of the role of acetaldehyde in the motivational effects of ethanol Front. Behav Neurosci 7:86. doi:10.3389/fnbeh.2013.00086

    CAS  Google Scholar 

  • Peana AT, Enrico P, Assaretti AR, Pulighe E, Muggironi G, Nieddu M, Diana M (2008) Key role of ethanol-derived acetaldehyde in the motivational properties induced by intragastric ethanol: a conditioned place preference study in the rat. Alcohol Clin Exp Res 32:249–258. doi:10.1111/j.1530-0277.2007.00574.x

    Article  CAS  PubMed  Google Scholar 

  • Peana AT, Muggironi G, Diana M (2010) Acetaldehyde- motivational effects; a study on oral self-administration behavior. Front Psychiatry 1:23. doi:10.3389/fpsyt.2010.00023

    PubMed Central  PubMed  Google Scholar 

  • Peana AT, Muggironi G, Fois GR, Zinellu M, Sirca D, Diana M (2012) Effect of (L)-cysteine on acetaldehyde self-administration. Alcohol 46:489–497. doi:10.1016/j.alcohol.2011.10.004

    Article  CAS  PubMed  Google Scholar 

  • Peana AT, Muggironi G, Fois G, Diana M (2013) Alpha- lipoic acid reduces ethanol self- administration in rats. Alcohol Clin Exp Res 37:1816–1822. doi:10.1111/acer.12169

    Article  CAS  PubMed  Google Scholar 

  • Pelloux Y, Costentin J, Duterte-Boucher D (2015) Differential involvement of anxiety and novelty preference levels on oral ethanol consumption in rats. Psychopharmacology (Berl) Mar 13. [Epub ahead of print]

  • Samson HH, Pfeffer AO, Tolliver GA (1988) Oral ethanol self-administration in rats: models of alcohol-seeking behavior. Alcohol Clin Exp Res 12:591–598

    Article  CAS  PubMed  Google Scholar 

  • Tomie A, Grimes KL, Pohorecky LA (2008) Behavioral characteristics and neurobiological substrates shared by Pavlovian sign tracking and drug abuse. Brain Res Rev 58:121–135. doi:10.1016/j.brainresrev.2007.12.003

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • U.S. Pharmacopeia National Formulary (1995) Alcoholmetric Table Based on Data in the National Bureau of Standard Bulletin, Vol. 9. Rand McNally, Taunton, MA, pp 424-425

Download references

Acknowledgments

This work was supported through grants from Fondazione Banco di Sardegna (Sassari, Italy) to ATP (2013).

This study was carried out in accordance with the Italian legislation (D.L. 116, 1992), which allowed experimentation on laboratory animals only after submission and approval of a research project to welfare and health organisation on animal’s experimentation of the University of Sassari (Sassari, Italy) and to the Ministry of Health (Rome, Italy), and in accordance with European Council directives on the matter (n. 2007/526/CE) and the “Guide for the care and use of laboratory animals” as approved by the Society for Neuroscience (National Research Council 1996).

Conflict of interest

None declared.

Author information

Authors and Affiliations

  1. Department of Chemistry and Pharmacy, University of Sassari, Via Muroni, 23, 07100, Sassari, Italy

    Alessandra T. Peana, Valeria Porcheddu, Federico Bennardini & Antonio Carta

  2. Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy

    Michela Rosas & Elio Acquas

  3. Centre of Excellence on Neurobiology of Addiction, University of Cagliari, Cagliari, Italy

    Elio Acquas

Authors
  1. Alessandra T. Peana
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Valeria Porcheddu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Federico Bennardini
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Antonio Carta
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michela Rosas
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Elio Acquas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alessandra T. Peana.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Peana, A.T., Porcheddu, V., Bennardini, F. et al. Role of ethanol-derived acetaldehyde in operant oral self-administration of ethanol in rats. Psychopharmacology 232, 4269–4276 (2015). https://doi.org/10.1007/s00213-015-4049-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-015-4049-0

Keywords

Search

Navigation