Skip to main content

Advertisement

SpringerLink
Log in

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

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

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.

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

  • Barrett SP, Pihl RO (2002) Oral methylphenidate–alcohol co-abuse. J Clin Psychopharmacol 22(6):633–634

    Article  PubMed  CAS  Google Scholar 

  • Barrett SP, Darredeau C, Pihl RO (2006) Patterns of simultaneous polysubstance use in drug using university students. Hum Psychopharmacol 21(4):255–263

    Article  PubMed  Google Scholar 

  • 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):871–878

    Article  PubMed  CAS  Google Scholar 

  • 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):264–270

    Article  PubMed  CAS  Google Scholar 

  • 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):2966–2978

    Article  PubMed  CAS  Google Scholar 

  • 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):1111–1120

    Article  PubMed  CAS  Google Scholar 

  • Biederman J, Faraone SV (2005) Attention-deficit hyperactivity disorder. Lancet 366(9481):237–248

    Article  PubMed  Google Scholar 

  • Biederman J, Spencer T (2002) Methylphenidate in treatment of adults with Attention-Deficit/Hyperactivity Disorder. J Atten Disord 6(Suppl 1):S101–S107

    PubMed  Google Scholar 

  • 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):569–575

    Article  PubMed  CAS  Google Scholar 

  • Cunningham CL, Patel P (2007) Rapid induction of Pavlovian approach to an ethanol-paired visual cue in mice. Psychopharmacol 192(2):231–241

    Article  CAS  Google Scholar 

  • 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):1115–1132

    Article  PubMed  Google Scholar 

  • 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):529–536

    Article  PubMed  Google Scholar 

  • 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):31–39

    Article  Google Scholar 

  • 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):189–193

    Article  Google Scholar 

  • Godfrey J (2009) Safety of therapeutic methylphenidate in adults: a systematic review of the evidence. J Psychopharmacol 23(2):194–205

    Article  PubMed  CAS  Google Scholar 

  • 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):267–272

    Article  PubMed  CAS  Google Scholar 

  • 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):830–842

    Article  PubMed  Google Scholar 

  • Jerlhag E (2008) The antipsychotic aripiprazole antagonizes the ethanol- and amphetamine-induced locomotor stimulation in mice. Alcohol 42(2):123–127

    Article  PubMed  CAS  Google Scholar 

  • 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, MD

  • Kamens HM, Crabbe JC (2007) The parallel rod floor test: a measure of ataxia in mice. Nat Protoc 2(2):277–281

    Article  PubMed  Google Scholar 

  • 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):253–266

    PubMed  CAS  Google Scholar 

  • 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):135–143

    Article  PubMed  Google Scholar 

  • Kuczenski R, Segal DS (1997) Effects of methylphenidate on extracellular dopamine, serotonin, and norepinephrine: comparison with amphetamine. J Neurochem 68(5):2032–2037

    Article  PubMed  CAS  Google Scholar 

  • 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):876–883

    PubMed  CAS  Google Scholar 

  • Kuczenski R, Segal DS (2005) Stimulant actions in rodents: implications for attention-deficit/hyperactivity disorder treatment and potential substance abuse. Biol Psychiatry 57(11):1391–1396

    Article  PubMed  CAS  Google Scholar 

  • 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):140–149

    Article  CAS  Google Scholar 

  • Mallonee E, Calvin S (2005). Emergency Department Visits Involving Underage Drinking 2004. The New DAWN Report 1-4

  • 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):585–593

    Article  PubMed  CAS  Google Scholar 

  • Markowitz JS, Patrick KS (2008) Differential pharmacokinetics and pharmacodynamics of methylphenidate enantiomers: does chirality matter? J Clin Psychopharmacol 28(3 Suppl 2):S54–S61

    Article  PubMed  CAS  Google Scholar 

  • 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):362–366

    Article  PubMed  CAS  Google Scholar 

  • 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):620–624

    PubMed  CAS  Google Scholar 

  • Martin CS (2008) Timing of alcohol and other drug use. Alcohol Res Health 31(2):96–99

    Google Scholar 

  • 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):501–504

    Google Scholar 

  • 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):529–537

    PubMed  Google Scholar 

  • McGovern RW, Middaugh LD, Patrick KS, Griffin WC 3rd (2011) The discriminative stimulus properties of methylphenidate in C57BL/6J mice. Behav Pharmacol 22(1):14–22

    Article  PubMed  CAS  Google Scholar 

  • Middaugh LD, Boggan WO, Randall CL (1987) Stimulatory effects of ethanol in C57BL/6 mice. Pharmacol Biochem Behav 27(3):421–424

    Article  PubMed  CAS  Google Scholar 

  • Middaugh LD, Bao K, Shepherd CL (1992) Comparative effects of ethanol on motor activity and operant behavior. Pharmacol Biochem Behav 43(2):625–629

    Article  PubMed  CAS  Google Scholar 

  • 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):683–692

    PubMed  CAS  Google Scholar 

  • Okie S (2006) ADHD in adults. N Engl J Med 354(25):2637–2641

    Article  PubMed  CAS  Google Scholar 

  • Patrick KS, Kilts CD, Breese GR (1981) Synthesis and pharmacology of hydroxylated metabolites of methylphenidate. J Med Chem 24(10):1237–1240

    Article  PubMed  CAS  Google Scholar 

  • Patrick KS, Caldwell RW, Ferris RM, Breese GR (1987) Pharmacology of the enantiomers of threo-methylphenidate. J Pharmacol Exp Ther 241(1):152–158

    PubMed  CAS  Google Scholar 

  • 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):2876–2881

    Article  PubMed  CAS  Google Scholar 

  • 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):346–353

    Article  PubMed  CAS  Google Scholar 

  • Schechter MD (1988) Advantages and disadvantages of a rapid method to train drug discrimination. Pharmacol Biochem Behav 31(1):239–242

    Article  PubMed  CAS  Google Scholar 

  • Stolerman IP, Childs E, Ford MM, Grant KA (2011) Role of training dose in drug discrimination: a review. Behav Pharmacol 22(5–6):415–429

    Article  PubMed  Google Scholar 

  • 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):151–160

    Article  PubMed  CAS  Google Scholar 

  • 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):1501–1510

    Article  PubMed  Google Scholar 

  • 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):659–669

    Article  PubMed  CAS  Google Scholar 

  • 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):39–51

    Article  PubMed  CAS  Google Scholar 

  • Wooters TE, Walton MT, Bardo MT (2011) Oral methylphenidate establishes a conditioned place preference in rats. Neurosci Lett 487(3):293–296

    Article  PubMed  CAS  Google Scholar 

  • 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):1241–1248

    Article  PubMed  CAS  Google Scholar 

  • 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):783–788

    Article  CAS  Google Scholar 

  • 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):283–292

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank J. Reid Spears, Kathyrn Balcewicz, and Andrew Novak for expert technical assistance. Funding was provided by NIGMS Postdoctoral Scholarship K12 GM081265 to RWM and NIAAA RO1 AA016707 to KSP.

Conflict of interest

The authors have no conflicts of interest to disclose.

Author information

Authors and Affiliations

  1. Department of Psychiatry and Behavioral Science, Charleston Alcohol Research Center, Center for Drug and Alcohol Programs, Charleston, SC, USA

    William C. Griffin III & Patrick K. Randall

  2. Department of Psychology, Westminster College, New Wilmington, PA, USA

    Robin W. McGovern

  3. Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, Charleston, SC, 29425-0742, USA

    Guinevere H. Bell & Kennerly S. Patrick

  4. Department of Psychiatry and Behavioral Science and Neurosciences, Charleston Alcohol Research Center, Center for Drug and Alcohol Programs and Medical University of South Carolina, Charleston, SC, 29425-0742, USA

    Lawrence D. Middaugh

  5. Charleston Alcohol Research Center, Center for Drug and Alcohol Programs, MSC 861, Medical University of South Carolina, Charleston, SC, 29425-0742, USA

    William C. Griffin III

Authors
  1. William C. Griffin III
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robin W. McGovern
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guinevere H. Bell
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Patrick K. Randall
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lawrence D. Middaugh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kennerly S. Patrick
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to William C. Griffin III.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Griffin, W.C., McGovern, R.W., Bell, G.H. et al. Interactive effects of methylphenidate and alcohol on discrimination, conditioned place preference and motor coordination in C57BL/6J mice. Psychopharmacology 225, 613–625 (2013). https://doi.org/10.1007/s00213-012-2849-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-012-2849-z

Keywords

Search

Navigation