Psychopharmacology

, Volume 225, Issue 3, pp 613–625

Interactive effects of methylphenidate and alcohol on discrimination, conditioned place preference and motor coordination in C57BL/6J mice

  • William C. GriffinIII
  • Robin W. McGovern
  • Guinevere H. Bell
  • Patrick K. Randall
  • Lawrence D. Middaugh
  • Kennerly S. Patrick
Original Investigation

Abstract

Introduction

Prior research indicates methylphenidate (MPH) and alcohol (ethanol, EtOH) interact to significantly affect responses humans and mice. The present studies tested the hypothesis that MPH and EtOH interact to potentiate ethanol-related behaviors in mice.

Methods

We used several behavioral tasks including: drug discrimination in MPH-trained and EtOH-trained mice, conditioned place preference (CPP), rota-rod and the parallel rod apparatus. We also used gas chromatographic methods to measure brain tissue levels of EtOH and the d- and l-isomers of MPH and the metabolite, ethylphenidate (EPH).

Results

In discrimination, EtOH (1 g/kg) produced a significant leftward shift in the MPH generalization curve (1–2 mg/kg) for MPH-trained mice, but no effects of MPH (0.625–1.25 mg/kg) on EtOH discrimination in EtOH-trained mice (0–2.5 g/kg) were observed. In CPP, the MPH (1.25 mg/kg) and EtOH (1.75 g/kg) combination significantly increased time on the drug paired side compared to vehicle (30.7 %), but this was similar to MPH (28.8 %) and EtOH (33.6 %). Footslip errors measured in a parallel rod apparatus indicated that the drug combination was very ataxic, with footslips increasing 29.5 % compared to EtOH. Finally, brain EtOH concentrations were not altered by 1.75 g/kg EtOH combined with 1.25 mg/kg MPH. However, EtOH significantly increased d-MPH and l-EPH without changing l-MPH brain concentrations.

Conclusions

The enhanced behavioral effects when EtOH is combined with MPH are likely due to the selective increase in brain d-MPH concentrations. These studies are consistent with observations in humans of increased interoceptive awareness of the drug combination and provide new clinical perspectives regarding enhanced ataxic effects of this drug combination.

Keywords

Psychostimulant Methylphenidate Ethanol Interoceptive Reinforcement Ataxia Mouse Drug–drug interaction 

References

  1. Barrett SP, Pihl RO (2002) Oral methylphenidate–alcohol co-abuse. J Clin Psychopharmacol 22(6):633–634PubMedCrossRefGoogle Scholar
  2. Barrett SP, Darredeau C, Pihl RO (2006) Patterns of simultaneous polysubstance use in drug using university students. Hum Psychopharmacol 21(4):255–263PubMedCrossRefGoogle Scholar
  3. Becker HC, Baros AM (2006) Effect of duration and pattern of chronic ethanol exposure on tolerance to the discriminative stimulus effects of ethanol in C57BL/6J mice. J Pharmacol Exp Ther 319(2):871–878PubMedCrossRefGoogle Scholar
  4. Bell GH, Griffin WC 3rd, Patrick KS (2011a) Oral and transdermal dl-methylphenidate–ethanol interactions in C57BL/6J mice: potentiation of locomotor activity with oral delivery. Pharmacol Biochem Behav 100(2):264–270PubMedCrossRefGoogle Scholar
  5. Bell GH, Novak AJ, Griffin WC 3rd, Patrick KS (2011b) Transdermal and oral dl-methylphenidate–ethanol interactions in C57BL/6J mice: transesterification to ethylphenidate and elevation of d-methylphenidate concentrations. J Pharm Sci 100(7):2966–2978PubMedCrossRefGoogle Scholar
  6. Berridge CW, Devilbiss DM, Andrzejewski ME, Arnsten AF, Kelley AE, Schmeichel B et al (2006) Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex at low doses that enhance cognitive function. Biol Psychiatry 60(10):1111–1120PubMedCrossRefGoogle Scholar
  7. Biederman J, Faraone SV (2005) Attention-deficit hyperactivity disorder. Lancet 366(9481):237–248PubMedCrossRefGoogle Scholar
  8. Biederman J, Spencer T (2002) Methylphenidate in treatment of adults with Attention-Deficit/Hyperactivity Disorder. J Atten Disord 6(Suppl 1):S101–S107PubMedGoogle Scholar
  9. Crissman AM, Studders SL, Becker HC (2004) Tolerance to the discriminative stimulus effects of ethanol following chronic inhalation exposure to ethanol in C57BL/6J mice. Behav Pharmacol 15(8):569–575PubMedCrossRefGoogle Scholar
  10. Cunningham CL, Patel P (2007) Rapid induction of Pavlovian approach to an ethanol-paired visual cue in mice. Psychopharmacol 192(2):231–241CrossRefGoogle Scholar
  11. Cunningham CL, Patel P, Milner L (2006) Spatial location is critical for conditioning place preference with visual but not tactile stimuli. Behav Neurosci 120(5):1115–1132PubMedCrossRefGoogle Scholar
  12. Darredeau C, Barrett SP, Jardin B, Pihl RO (2007) Patterns and predictors of medication compliance, diversion, and misuse in adult prescribed methylphenidate users. Hum Psychopharmacol 22(8):529–536PubMedCrossRefGoogle Scholar
  13. dela Peńa IC, Ahn HS, Choi JY, Shin CY, Ryu JH, Cheong JH (2011) Methylphenidate self-administration and conditioned place preference in an animal model of attention-deficit hyperactivity disorder: the spontaneously hypertensive rat. Behav Pharmacol 22(1):31–39CrossRefGoogle Scholar
  14. dela Peña I, Lee JC, Lee HL, Woo TS, Lee HC, Sohn AR et al (2012) Differential behavioral responses of the spontaneously hypertensive rat to methylphenidate and methamphetamine: lack of a rewarding effect of repeated methylphenidate treatment. Neurosci Lett 514(2):189–193CrossRefGoogle Scholar
  15. Godfrey J (2009) Safety of therapeutic methylphenidate in adults: a systematic review of the evidence. J Psychopharmacol 23(2):194–205PubMedCrossRefGoogle Scholar
  16. Griffin WC 3rd, Novak AJ, Middaugh LD, Patrick KS (2010) The interactive effects of methylphenidate and ethanol on ethanol consumption and locomotor activity in mice. Pharmacol Biochem Behav 95(3):267–272PubMedCrossRefGoogle Scholar
  17. Hasin DS, Stinson FS, Ogburn E, Grant BF (2007) Prevalence, correlates, disability, and comorbidity of DSM-IV alcohol abuse and dependence in the United States: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Arch Gen Psychiatry 64(7):830–842PubMedCrossRefGoogle Scholar
  18. Jerlhag E (2008) The antipsychotic aripiprazole antagonizes the ethanol- and amphetamine-induced locomotor stimulation in mice. Alcohol 42(2):123–127PubMedCrossRefGoogle Scholar
  19. Johnston LD, O'Malley PM, Bachman JG, Schulenberg JE (2008). Monitoring the future national results on adolescent drug use: overview of key findings, 2007. edn, vol. NIH Publication No. 08-6418. National Institute on Drug Abuse, Bethesda, MDGoogle Scholar
  20. Kamens HM, Crabbe JC (2007) The parallel rod floor test: a measure of ataxia in mice. Nat Protoc 2(2):277–281PubMedCrossRefGoogle Scholar
  21. Kamens HM, Phillips TJ, Holstein SE, Crabbe JC (2005) Characterization of the parallel rod floor apparatus to test motor incoordination in mice. Genes Brain Behav 4(4):253–266PubMedGoogle Scholar
  22. Kroutil LA, Van Brunt DL, Herman-Stahl MA, Heller DC, Bray RM, Penne MA (2006) Nonmedical use of prescription stimulants in the United States. Drug Alcohol Depend 84(2):135–143PubMedCrossRefGoogle Scholar
  23. Kuczenski R, Segal DS (1997) Effects of methylphenidate on extracellular dopamine, serotonin, and norepinephrine: comparison with amphetamine. J Neurochem 68(5):2032–2037PubMedCrossRefGoogle Scholar
  24. Kuczenski R, Segal DS (2001) Locomotor effects of acute and repeated threshold doses of amphetamine and methylphenidate: relative roles of dopamine and norepinephrine. J Pharmacol Exp Ther 296(3):876–883PubMedGoogle Scholar
  25. Kuczenski R, Segal DS (2005) Stimulant actions in rodents: implications for attention-deficit/hyperactivity disorder treatment and potential substance abuse. Biol Psychiatry 57(11):1391–1396PubMedCrossRefGoogle Scholar
  26. LeVasseur NL, Zhu HJ, Markowitz JS, DeVane CL, Patrick KS (2008) Enantiospecific gas chromatographic-mass spectrometric analysis of urinary methylphenidate: implications for phenotyping. J Chromatogr B Anal Technol Biomed Life Sci 862(1–2):140–149CrossRefGoogle Scholar
  27. Mallonee E, Calvin S (2005). Emergency Department Visits Involving Underage Drinking 2004. The New DAWN Report 1-4Google Scholar
  28. Manjanatha MG, Shelton SD, Dobrovolsky VN, Shaddock JG, McGarrity LG, Doerge DR et al (2008) Pharmacokinetics, dose-range, and mutagenicity studies of methylphenidate hydrochloride in B6C3F1 mice. Environ Mol Mutagen 49(8):585–593PubMedCrossRefGoogle Scholar
  29. Markowitz JS, Patrick KS (2008) Differential pharmacokinetics and pharmacodynamics of methylphenidate enantiomers: does chirality matter? J Clin Psychopharmacol 28(3 Suppl 2):S54–S61PubMedCrossRefGoogle Scholar
  30. Markowitz JS, Logan BK, Diamond F, Patrick KS (1999) Detection of the novel metabolite ethylphenidate after methylphenidate overdose with alcohol coingestion. J Clin Psychopharmacol 19(4):362–366PubMedCrossRefGoogle Scholar
  31. Markowitz JS, DeVane CL, Boulton DW, Nahas Z, Risch SC, Diamond F et al (2000) Ethylphenidate formation in human subjects after the administration of a single dose of methylphenidate and ethanol. Drug Metab Dispos 28(6):620–624PubMedGoogle Scholar
  32. Martin CS (2008) Timing of alcohol and other drug use. Alcohol Res Health 31(2):96–99Google Scholar
  33. McCabe SE, Teter CJ, Boyd CJ, Guthrie SK (2004) Prevalence and correlates of illicit methylphenidate use among 8th, 10th, and 12th grade students in the United States, 2001. J Adol Health 35(6):501–504Google Scholar
  34. McCabe SE, Cranford JA, Morales M, Young A (2006) Simultaneous and concurrent polydrug use of alcohol and prescription drugs: prevalence, correlates, and consequences. J Stud Alcohol 67(4):529–537PubMedGoogle Scholar
  35. McGovern RW, Middaugh LD, Patrick KS, Griffin WC 3rd (2011) The discriminative stimulus properties of methylphenidate in C57BL/6J mice. Behav Pharmacol 22(1):14–22PubMedCrossRefGoogle Scholar
  36. Middaugh LD, Boggan WO, Randall CL (1987) Stimulatory effects of ethanol in C57BL/6 mice. Pharmacol Biochem Behav 27(3):421–424PubMedCrossRefGoogle Scholar
  37. Middaugh LD, Bao K, Shepherd CL (1992) Comparative effects of ethanol on motor activity and operant behavior. Pharmacol Biochem Behav 43(2):625–629PubMedCrossRefGoogle Scholar
  38. Nocjar C, Middaugh LD, Tavernetti M (1999) Ethanol consumption and place-preference conditioning in the alcohol-preferring C57BL/6 mouse: relationship with motor activity patterns. Alcohol Clin Exp Res 23(4):683–692PubMedGoogle Scholar
  39. Okie S (2006) ADHD in adults. N Engl J Med 354(25):2637–2641PubMedCrossRefGoogle Scholar
  40. Patrick KS, Kilts CD, Breese GR (1981) Synthesis and pharmacology of hydroxylated metabolites of methylphenidate. J Med Chem 24(10):1237–1240PubMedCrossRefGoogle Scholar
  41. Patrick KS, Caldwell RW, Ferris RM, Breese GR (1987) Pharmacology of the enantiomers of threo-methylphenidate. J Pharmacol Exp Ther 241(1):152–158PubMedGoogle Scholar
  42. Patrick KS, Williard RL, VanWert AL, Dowd JJ, Oatis JE Jr, Middaugh LD (2005) Synthesis and pharmacology of ethylphenidate enantiomers: the human transesterification metabolite of methylphenidate and ethanol. J Med Chem 48(8):2876–2881PubMedCrossRefGoogle Scholar
  43. Patrick KS, Straughn AB, Minhinnett RR, Yeatts SD, Herrin AE, DeVane CL et al (2007) Influence of ethanol and gender on methylphenidate pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 81(3):346–353PubMedCrossRefGoogle Scholar
  44. Schechter MD (1988) Advantages and disadvantages of a rapid method to train drug discrimination. Pharmacol Biochem Behav 31(1):239–242PubMedCrossRefGoogle Scholar
  45. Stolerman IP, Childs E, Ford MM, Grant KA (2011) Role of training dose in drug discrimination: a review. Behav Pharmacol 22(5–6):415–429PubMedCrossRefGoogle Scholar
  46. Szumlinski KK, Price KL, Frys KA, Middaugh LD (2002) Unconditioned and conditioned factors contribute to the 'reinstatement' of cocaine place conditioning following extinction in C57BL/6 mice. Behav Brain Res 136(1):151–160PubMedCrossRefGoogle Scholar
  47. Teter CJ, McCabe SE, LaGrange K, Cranford JA, Boyd CJ (2006) Illicit use of specific prescription stimulants among college students: prevalence, motives, and routes of administration. Pharmacotherapy 26(10):1501–1510PubMedCrossRefGoogle Scholar
  48. Trezza V, Damsteegt R, Vanderschuren LJMJ (2009) Conditioned place preference induced by social play behavior: parametrics, extinction, reinstatement and disruption by methylphenidate. Eur Neuropsychopharmacol 19(9):659–669PubMedCrossRefGoogle Scholar
  49. Williard RL, Middaugh LD, Zhu HJ, Patrick KS (2007) Methylphenidate and its ethanol transesterification metabolite ethylphenidate: brain disposition, monoamine transporters and motor activity. Behav Pharmacol 18(1):39–51PubMedCrossRefGoogle Scholar
  50. Wooters TE, Walton MT, Bardo MT (2011) Oral methylphenidate establishes a conditioned place preference in rats. Neurosci Lett 487(3):293–296PubMedCrossRefGoogle Scholar
  51. Zhu HJ, Patrick KS, Yuan HJ, Wang JS, Donovan JL, DeVane CL et al (2008) Two CES1 gene mutations lead to dysfunctional carboxylesterase 1 activity in man: clinical significance and molecular basis. Am J Hum Genet 82(6):1241–1248PubMedCrossRefGoogle Scholar
  52. Zhu HJ, Patrick KS, Markowitz JS (2011a) Enantiospecific determination of dl-methylphenidate and dl-ethylphenidate in plasma by liquid chromatography-tandem mass spectrometry: application to human ethanol interactions. J Chromatogr B Anal Technol Biomed Life Sci 879(11–12):783–788CrossRefGoogle Scholar
  53. Zhu J, Spencer TJ, Liu-Chen L-Y, Biederman J, Bhide PG (2011b) Methylphenidate and μ opioid receptor interactions: a pharmacological target for prevention of stimulant abuse. Neuropharmacology 61(1–2):283–292PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • William C. GriffinIII
    • 1
    • 5
  • Robin W. McGovern
    • 2
  • Guinevere H. Bell
    • 3
  • Patrick K. Randall
    • 1
  • Lawrence D. Middaugh
    • 4
  • Kennerly S. Patrick
    • 3
  1. 1.Department of Psychiatry and Behavioral ScienceCharleston Alcohol Research Center, Center for Drug and Alcohol ProgramsCharlestonUSA
  2. 2.Department of PsychologyWestminster CollegeNew WilmingtonUSA
  3. 3.Department of Pharmaceutical and Biomedical SciencesMedical University of South CarolinaCharlestonUSA
  4. 4.Department of Psychiatry and Behavioral Science and NeurosciencesCharleston Alcohol Research Center, Center for Drug and Alcohol Programs and Medical University of South CarolinaCharlestonUSA
  5. 5.Charleston Alcohol Research Center, Center for Drug and Alcohol Programs, MSC 861Medical University of South CarolinaCharlestonUSA

Personalised recommendations