Abstract
Cathinones, such as mephedrone (Meph), are often co-abused with alcoholic drinks. In the present study, we investigated the combined effects of Meph plus ethanol (EtOH) on neurotransmitter release in the nucleus accumbens (NAc) and the medial prefrontal cortex (mPFC). A guide canula was stereotaxically implanted into either the NAc or the mPFC of male Sprague-Dawley rats. Seven days after surgery, a microdialysis probe was inserted and rats were administered saline, EtOH (1 g/kg, i.p.), Meph (25 mg/kg, s.c.), or their combination, and dialysates were collected. Serotonin (5-HT), dopamine (DA), and their metabolites (5-HIAA, DOPAC and HVA) were determined through high-pressure liquid chromatography coupled to mass spectrometry. 5-HT and DA peaked 40 min after Meph administration (with or without EtOH co-treatment) in both areas. EtOH combined with Meph increased the 5-HT release compared with the rats receiving Meph alone (85% in NAc, 65% in mPFC), although the overall change in the area under the curve only reached statistical significance in the NAc. In mPFC, the increased release of 5-HT lasted longer in the combination than that in the Meph group. Moreover, EtOH potentiated the psychostimulant effect of Meph measured as a locomotor activity. Given that both 5-HT and DA are also related with reward and impulsivity, the observed effects point to an increased risk of abuse liability when combining Meph with EtOH compared with consuming these drugs alone.
This is a preview of subscription content, log in via an institution to check access.
Abbreviations
- 5-HIAA:
-
5-Hydroxyindoleacetic acid
- 5-HT:
-
Serotonin
- DA:
-
Dopamine
- DOPAC:
-
3,4-Dihydroxyphenylacetic acid
- EtOH:
-
Alcohol/ethanol
- LC-MS:
-
Liquid chromatography-mass spectrometry
- MDMA:
-
3,4-Methylenedioxymethamphetamine
- Meph:
-
Mephedrone
- mPFC:
-
Medial prefrontal cortex
- NAc:
-
Nucleus accumbens
References
Baumann MH, Ayestas MA Jr, Partilla JS, Sink JR, Shulgin AT, Daley PF, Brandt SD, Rothman RB, Ruoho AE, Cozzi NV (2012) The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue. Neuropsychopharmacology 37(5):1192–1203. https://doi.org/10.1038/npp.2011.304
Ben-Hamida S, Tracqui A, de Vasconcelos AP, Szwarc E, Lazarus C, Kelche C, Jones BC, Cassel JC (2009) Ethanol increases the distribution of MDMA to the rat brain: possible implications in the ethanol-induced potentiation of the psychostimulant effects of MDMA. Int J Neuropsychopharmacol 12(3-4):749–759. https://doi.org/10.1159/000253554
Bloom F, Lad P, Pittman Q, Rogers J (1982) Blood alcohol levels in rats: non-uniform yields from intraperitoneal doses based on body weight. Br J Pharmacol 75(1):251–254. https://doi.org/10.1111/j.1476-5381.1982.tb08780.x
Brabant C, Guarnieri DJ, Quertemont E (2014) Stimulant and motivational effects of alcohol: lessons from rodent and primate models. Pharmacol Biochem Behav 122:37–52. https://doi.org/10.1016/j.pbb.2014.03.006
Brodie MS, Trifunović RD, Shefner SA (1995) Serotonin potentiates ethanol-induced excitation of ventral tegmental area neurons in brain slices from three different rat strains. J Pharmacol Exp Ther 273(3):1139–1146
Brunt TM, Koeter MW, Niesink RJ, van den Brink W (2012) Linking the pharmacological content of ecstasy tablets to the subjective experiences of drug users. Psychopharmacology 220(4):751–762. https://doi.org/10.1007/s00213-011-2529-4
Cassel JC, Jeltsch H, Koenig J, Jones BC (2004) Locomotor and pyretic effects of MDMA-ethanol associations in rats. Alcohol 34(2-3):285–289. https://doi.org/10.1016/j.alcohol.2004.09.003
Cassel JC, Riegert C, Rutz S, Koenig J, Rothmaier K, Cosquer B, Lazarus C, Birthelmer A, Jeltsch H, Jones BC, Jackisch R (2005) Ethanol, 3,4-methylenedioxymethamphetamine (ecstasy) and their combination: long-term behavioral, neurochemical and neuropharmacological effects in the rat. Neuropsychopharmacology 30(10):1870–1882. https://doi.org/10.1038/sj.npp.1300714
Ciudad-Roberts A, Camarasa J, Ciudad CJ, Pubill D, Escubedo E (2015) Alcohol enhances the psychostimulant and conditioning effects of mephedrone in adolescent mice; postulation of unique roles of D3 receptors and BDNF in place preference acquisition. Br J Pharmacol 172:4970–4984. https://doi.org/10.1111/bph.13266.
Ciudad-Roberts A, Duart-Castells L, Camarasa J, Pubill D, Escubedo E (2016) The combination of ethanol with mephedrone increases the signs of neurotoxicity and impairs neurogenesis and learning in adolescent CD-1 mice. Toxicol Appl Pharmacol 293:10–20. https://doi.org/10.1016/j.taap.2015.12.019.
Clapp P, Bhave SV, Hoffman PL (2008) How adaptation of the brain to alcohol leads to dependence: a pharmacological perspective. Alcohol Res Health 31(4):310–339
Dalley JW, Theobald DE, Eagle DM, Passetti F, Robbins TW (2002) Deficits in impulse control associated with tonically-elevated serotonergic function in rat prefrontal cortex. Neuropsychopharmacology 26(6):716–728. https://doi.org/10.1016/S0893-133X(01)00412-2
Daws LC, Montañez S, Munn JL, Owens WA, Baganz NL, Boyce-Rustay JM, Millstein RA, Wiedholz LM, Murphy DL, Holmes A (2006) Ethanol inhibits clearance of brain serotonin by a serotonin transporter-independent mechanism. J Neurosci 26(24):6431–6438. https://doi.org/10.1523/JNEUROSCI.4050-05.2006
Elliott S, Evans J (2014) A 3-year review of new psychoactive substances in casework. Forensic Sci Int 243:55–60. https://doi.org/10.1016/j.forsciint.2014.04.017
Golembiowska K, Jurczak A, Kaminska K, Noworyta-Sokolowska K, Gorska A (2016) Effect of some psychoactive drugs used as “legal highs” on brain neurotransmitters. Neurotox Res 29:394–407. https://doi.org/10.1007/s12640-015-9569-1.
Hadlock GC, Webb KM, McFadden LM, Chu PW, Ellis JD, Allen SC, Andrenyak DM, Vieira-Brock PL, German CL, Conrad KM, Hoonakker AJ, Gibb JW, Wilkins DG, Hanson GR, Fleckenstein AE (2011) 4-Methylmethcathinone (mephedrone): neuropharmacological effects of a designer stimulant of abuse. J Pharmacol Exp Ther 339(2):530–536. https://doi.org/10.1124/jpet.111.184119
Hammerslag LR, Waldman AJ, Gulley JM (2014) Effects of amphetamine exposure in adolescence or young adulthood on inhibitory control in adult male and female rats. Behav Brain Res 263:22–33. https://doi.org/10.1016/j.bbr.2014.01.015
Imperato A, Di Chiara G (1986) Preferential stimulation of dopamine release in the nucleus accumbens of freely moving rats by ethanol. J Pharmacol Exp Ther 239(1):219–228
Jones BC, Ben-Hamida S, de Vasconcelos AP, Kelche C, Lazarus C, Jackisch R, Cassel JC (2010) Effects of ethanol and ecstasy on conditioned place preference in the rat. J Psychopharmacol 24(2):275–279. https://doi.org/10.1177/0269881109102775
Kehr J, Ichinose F, Yoshitake S, Goiny M, Sievertsson T, Nyberg F, Yoshitake T (2011) Mephedrone, compared with MDMA (ecstasy) and amphetamine, rapidly increases both dopamine and 5-HT levels in nucleus accumbens of awake rats. Br J Pharmacol 164(8):1949–1958. https://doi.org/10.1111/j.1476-5381.2011.01499.x
López-Arnau R, Martínez-Clemente J, Pubill D, Escubedo E, Camarasa J (2012) Comparative neuropharmacology of three psychostimulant cathinone derivatives: butylone, mephedrone and methylone. Br J Pharmacol 167:407–420. https://doi.org/10.1111/j.1476-5381.2012.01998.x.
López-Arnau R, Martínez-Clemente J, Rodrigo T, Pubill D, Camarasa J, Escubedo E (2015) Neuronal changes and oxidative stress in adolescent rats after repeated exposure to mephedrone. Toxicol Appl Pharmacol 286(1):27–35. https://doi.org/10.1016/j.taap.2015.03.015
Martínez-Clemente J, López-Arnau R, Carbó M, Pubill D, Camarasa J, Escubedo E (2013) Mephedrone pharmacokinetics after intravenous and oral administration in rats: relation to pharmacodynamics. Psychopharmacology 230(2):295–306. https://doi.org/10.1007/s00213-013-3108-7
Mitchell JM, O'Neil JP, Janabi M, Marks SM, Jagust WJ, Fields HL (2012) Alcohol consumption induces endogenous opioid release in the human orbitofrontal cortex and nucleus accumbens. Sci Transl Med 4(116):116ra6. https://doi.org/10.1126/scitranslmed.3002902
Mohamed WM, Ben Hamida S, de Vasconcelos AP, Cassel JC, Jones BC (2009) Interactions between 3,4-methylenedioxymethamphetamine and ethanol in humans and rodents. Neuropsychobiology 60(3-4):188–194. https://doi.org/10.1159/000253554
Nestler EJ (2001) Molecular basis of long-term plasticity underlying addiction. Nat Rev Neurosci 2(2):119–128. https://doi.org/10.1038/35053570
O’Neill C, McElrath K (2012) Simultaneous use of mephedrone and alcohol: a qualitative study of users’ experiences. J Addict Res Ther S9-001(02):1–5. https://doi.org/10.4172/2155-6105.S9-001
Riegert C, Wedekind F, Ben Hamida S, Rutz S, Rothmaier AK, Jones BC, Cassel JC, Jackisch R (2008) Effects of ethanol and 3,4-methylenedioxymethamphetamine (MDMA) alone or in combination on spontaneous and evoked overflow of dopamine, serotonin and acetylcholine in striatal slices of the rat brain. Int J Neuropsychopharmacol 11(06):743–763. https://doi.org/10.1017/S1461145708008481
Siggins GR, Roberto M, Nie Z (2005) The tipsy terminal: presynaptic effects of ethanol. Pharmacol Ther 107:80–98
Wright MJ Jr, Angrish D, Aarde SM, Barlow DJ, Buczynski MW, Creehan KM, Vandewater SA, Parsons LH, Houseknecht KL, Dickerson TJ, Taffe MA (2012) Effect of ambient temperature on the thermoregulatory and locomotor stimulant effects of 4-methylmethcathinone in Wistar and Sprague-Dawley rats. PLoS One 7(8):e44652. https://doi.org/10.1371/journal.pone.0044652
Funding
This work was supported by grants from “Plan Nacional sobre Drogas” (2012I102) and from “Plan Nacional de Investigación Científica” (SAF2013-46135-P). Our group holds the quality mention from the “Generalitat de Catalunya” (2014SGR1081). None of the funding sources had further role in study design, collection, analysis, and interpretation of data, in the writing of the report and in the decision to submit the paper for publication. R. López-Arnau position was funded by an institutional program of the Universitat de Barcelona in collaboration with Obra Social de la Fundació Bancària La Caixa.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
All animal care and experimental protocols in this study complied with the guidelines of the European Community Council (86/609/ECC) and were approved by the Animal Ethics Committee of the University of Barcelona. All efforts were made to minimize animal suffering and to reduce the number of animals used.
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
López-Arnau, R., Buenrostro-Jáuregui, M., Camarasa, J. et al. Effect of the combination of mephedrone plus ethanol on serotonin and dopamine release in the nucleus accumbens and medial prefrontal cortex of awake rats. Naunyn-Schmiedeberg's Arch Pharmacol 391, 247–254 (2018). https://doi.org/10.1007/s00210-018-1464-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00210-018-1464-x