Ritalin Use Modifies Alcohol Effects in Rats


Methylphenidate (MPD), known as Ritalin, is a common drug prescribed for those diagnosed with Attention Deficit Hyperactivity Disorder (ADHD).There are reports that many MPD users consume alcohol, resulting in toxic effects and hospitalization. The goal of this study was to investigate the effects of ethanol in rats concomitant with acute and repetitive MPD exposure. Rats were divided into four groups, control (saline), 0.6 mg/kg MPD, 2.5 mg/kg MPD, and 10.0 mg/kg MPD groups and lasted for 12 consecutive days. Ethanol was given after repeated MPD administration as follows. On experimental day 1 (ED 1), all animals were treated with saline to establish baseline, on ED 2 through ED 7 either saline or MPD (0.6, 2.5, or 10.0 mg/kg) was given. On ED 11, after three days without treatment (ED 8 - 10), rats were treated as they were on ED 2 - 7. At ED 12, 1 g/kg ethanol was administered, and one hour of locomotor activity was recorded after alcohol administration, using the open field assay. The data show a dose response characteristic of increased locomotor activity with increasing doses of MPD. Ethanol administration alone depresses locomotor activity. The depressive effect of alcohol was significantly attenuated in animals treated with MPD, in a dose dependent manner. The higher dose of MPD previously administered resulted in a larger attenuation of the ethanol’s suppressive effect. These trends demonstrate that chronic MPD exposure directly influences the effects of alcohol in rats. Under these circumstances, it is reasonable to assume that a subject will need to consume an increased amount of ethanol in order to attain the ethanol effect desired. This discrepancy between effects and exposure may be a liability for ethanol toxicity.

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Sonne, B. and Dafny, N. (2014) Ritalin Use Modifies Alcohol Effects in Rats. Journal of Behavioral and Brain Science, 4, 453-464. doi: 10.4236/jbbs.2014.410044.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Askenasy, E.P., Taber, K.H., Yang, P.B. and Dafny, N. (2007) Methylphenidate (Ritalin): Behavioral Studies in the Rat. International Journal of Neuroscience, 117, 757-794.
[2] Biederman, J., Faraone, S.V., Mick, E., Milberger, S., Spencer, T.J. and Wilens, T. (1995) Psychoactive Substance Use Disorders in Adults with Attention Deficit Hyperactivity Disorder (ADHD): Effects of ADHD and Psychiatric Comorbidity. American Journal of Psychiatry, 152, 1652-1658.
[3] Crutchley, A. and Temlett, J.A. (1999) Methylphenidate (Ritalin) Use and Abuse. South African Medical Journal, 89, 1076-1079.
[4] McCance-Katz, E.F., Kosten, T.R. and Jatlow, P. (1998) Concurrent Use of Cocaine and Alcohol Is More Potent and Potentially More Toxic than Use of Either Alone—A Multiple-Dose Study. Biological Psychiatry, 44, 250-259.
[5] Nakamura, M. and Jang, I.S. (2010) Presynaptic Nicotinic Acetylcholine Receptors Enhance GABAergic Synaptic Transmission in Rat Periaqueductal Gray Neurons. European Journal of Pharmacology, 640, 178-184.
[6] Teo, S.K. Stirling, D.I., Hoberman, A.M., Christian, M.S., Thomas, S.D. and Khetani, V.D. (2003) D-Methylphenidate and D,L-Methylphenidate Are Not Developmental Toxicants in Rats and Rabbits. Birth Defects Research and Brain Development Reproductive Toxicology, 68, 162-171.
[7] Wilens, T.E., Adler, L.A., Adams, J., Sgambati, S., Rotrosen, J., Sawtelle, R., Utzinger, L. and Fusillo, S. (2008) Misuse and Diversion of Stimulants Prescribed for ADHD: A Systematic Review of the Literature. Journal of the American Academy of Child and Adolescent Psychiatry, 47, 21-31.
[8] Darredeau, C., Barrett, S.P., et al. (2007) Patterns and Predictors of Medication Compliance, Diversion, and Misuse in Adult Prescribed Methylphenidate Users. Human Psychopharmacology, 22, 529-536.
[9] McCabe, S.E., Knight, J.R., Teter, C.J. and Wechsler, H. (2005) Non-Medical Use of Prescription Stimulants among US College Students: Prevalence and Correlates from a National Survey. Addiction, 100, 96-106.
[10] Boyd, C.J., Morales, S.E. and McCabe, M. (2012) College Students’ Alcohol Use: A Critical Review. Annual Review of Nursing Research, 23, 179-211.
[11] O’Brien, M.S. and Anthony, J.C. (2009) Extra-Medical Stimulant Dependence among Recent Initiates. Drug and Alcohol Dependence, 104, 147-155.
[12] Barrett, S.P. and Pihl, R.O. (2002) Oral Methylpheni-date-Alcohol Co-Abuse. Journal of Clinical Psychopharmacology, 22, 633-634.
[13] Patrick, K.S., Straughn, A.B., Minhinnett, R.R., Yeatts, S.D., Herrin, A.E., DeVane, C.L., Malcolm, R., Janis, G.C. and Markowitz, J.S. (2007) Influence of Ethanol and Gender on Methylphenidate Pharmacokinetics and Pharmacodynamics. Clinical Pharmacology and Therapeutics, 81, 346-353.
[14] Gaytan, O., Ghelani, D., Martin, S., Swann, A. and Dafny, N. (1996) Dose Response Characteristics of Methylphenidate on Different Indices of Rats’ Locomotor Activity at the Beginning of the Dark Cycle. Brain Research, 727, 13-21.
[15] Gaytan, O., Ghelani, D., Martin, S., Swann, A. and Dafny, N. (1997) Methylphenidate: Diurnal Effects on Locomotor and Stereotypic Behavior in the Rat. Brain Research, 777, 1-12.
[16] Gaytan, O., Al-Rahim, S., Swann, A. and Dafny, N. (1997) Sensitization to Locomotor Effects of Methylphenidate in the Rat. Life Sciences, 61, 101-107.
[17] Gaytan, O., Swann, A., Yang, P. and Dafny, N. (2000) Diurnal Differences in Sensitization to Methylphenidate. Brain Research, 864, 24-39.
[18] Yang, P.B., Amini, B., Swann, A.C. and Dafny, N. (2003) Strain Differences in the Behavioral Responses of Male Rats to Chronically Administered Methylphenidate. Brain Research, 971, 139-152.
[19] Yang, P.B., Swann, A.C. and Dafny, N. (2006) Acute and Chronic Methylphenidate Dose-Response Assessment on Three Adolescent Male Rat Strains. Brain Research Bulletin, 71, 301-310.
[20] Yang, P.B., Swann, A.C. and Dafny, N. (2007) Chronic Administration of Methylphenidate Produces Neurophysiological and Behavioral Sensitization. Brain Research, 1145, 66-80.
[21] Yang, P.B., Swann, A.C. and Dafny, N. (2006) Dose-Response Characteristics of Methylphenidate on Locomotor Behavior and on Sensory Evoked Potentials Recorded from the VTA, NAc, and PFC in Freely Behaving Rats. Behavioral and Brain Function, 2, 3.
[22] Hoshaw, B.A. and Lewis, M.J. (2001) Behavioral Sensitization to Ethanol in Rats: Evidence from the Sprague-Dawley Strain. Pharmacology Biochemistry and Behavior, 68, 685-690.
[23] Algahim, M.F., Burau, K.D., Dafny, N., Swann, A.C., Wilcox, V.T., and Yang, P.B. (2009) Prolonged Methylphenidate Treatment Alters the Behavioral Diurnal Activity Pattern of Adult Male Sprague-Dawley Rats. Pharmacology Biochemistry Behavior, 92, 93-99.
[24] Gaytan, O., Lewis, C., Swann, A. and Dafny, N. (1999) Diurnal Differences in Amphetamine Sensitization. European Journal of Pharmacology, 374, 1-9.
[25] Yang, P., Beasley, A., Eckermann, K., Swann, A. and Dafny, N. (2000) Valproate Prevents the Induction of Sensitization to Methylphenidate (Ritalin) in Rats. Brain Research, 887, 276-284.
[26] Gaytan, O., Swann, A. and Dafny, N. (1998) Diurnal Differences in Rat’s Motor Response to Amphetamine. European Journal of Pharmacology, 345, 119-128.
[27] Zhang, C.L., Feng, Z.J., Liu, Y., Ji, X.H., Peng, J.Y., Zhang, X.H., Zhen, X.C. and Li, B.M. (2012) Methylphenidate Enhances NMDA-Receptor Response in Medial Prefrontal Cortex via Sigma-1 Receptor: A Novel Mechanism for Methylphenidate Action. PLoS ONE, 12, e51910.
[28] Cone, E.J. (1995) Pharmacokinetics and Pharmacodynamics of Cocaine. Journal of Analytical Toxicology, 19, 459-478.
[29] Kuczenski, R. and Segal, D.S. (1999) Sensitization of Amphetamine-Induced Stereotyped Behaviors during the Acute Response. Journal of Pharmacology and Experimental Therapeutics, 288, 699-709.
[30] Dafny, N. and Yang, P.B. (2006) The Role of Age, Genotype, Sex, and Route of Acute and Chronic Administration of Methylphenidate: A Review of Its Locomotor Effects. Brain Research Bulletin, 68, 393-405.
[31] Hoffman, B.B., Lefkowitz, R.J., Hardman, J.G., Limbird, L.E., Ruddon, R.W. and Gilman, A.D. (1996) Catecholamines and Sympathomimetic Drugs, and Adrenergic Receptor-Antagonist. Goodman and Gilman’s, 1996. The Pharmacological Basis of Therapeutics, 64, 199-250.
[32] Patrick, K.S. and Markowitz, J.S. (1997) Pharmacology of Methylphenidate, Amphetamine Enantiomers, and Pemoline in Attention Deficit/Hyperactivity Disorder. Human Psychopharmacology, 12, 527-546.
[33] Salinas, A.G., Nguyen, C.T., Ahmadi-Tehrani, D. and Morrisett, R.A. (2012) Reduced Ethanol Consumption and Preference in Cocaine- and Amphetamine-Regulated Transcript (CART) Knockout Mice. Addiction Biology, 24, 175-184.
[34] Challman, T.D. and Lipsky, J.J. (2000) Methylphenidate: Its Pharmacology and Uses. Mayo Clinic Proceedings, 75, 711-721.
[35] Jaffe, S.L. (1991) Intranasal Abuse of Prescribed Methylphenidate by an Alcohol and Drug Abusing Adolescent with ADHD. Journal of American Academy of Child and Adolescent Psychiatry, 30, 773-775.
[36] Kollins, S.H. (2003) Comparing the Abuse Potential of Methylphenidate versus Other Stimulants: A Review of Available Evidence and Relevance to the ADHD Patient. Journal of Clinical Psychiatry, 64, 14-18.
[37] Lee, M.J., Yang, P.B., Wilcox, V.T., Burau, K.D., Swann, A.C. and Dafny, N. (2009) Does Repetitive Ritalin Injection Produce Long-Term Effects on SD Female Adolescent Rats? Neuropharmacology, 57, 201-207.
[38] Patrick, K.S., Straughn, A.B., Reeves 3rd, O.T., Bernstein, H., Bell, G.H., Anderson, E.R. and Malcolm, R.J. (2013) Drug Metabolism Disposition, 41, 197-205.
[39] Wolf, M.E. (1998) The Role of Excitatory Amino Acids in Behavioral Sensitization to Psychomotor Stimulants. Progress in Neurobiology, 54, 679-720.
[40] Bell, G.H., Griffin 3rd, W.C. and Patrick, K.S. (2011) Oral and Transdermal DL-Methylphenidate-Ethanol Interactions in C57BL/6J Mice: Potentiation of Locomotor Activity with Oral Delivery. Pharmacology Biochemistry and Behavior, 100, 264-270.
[41] Vendruscolo, L.F., Izidio, G.S., Takahashi, R.N. and Ramos, A. (2008) Chronic Methylphenidate Treatment during Adolescence Increases Anxiety-Related Behaviors and Ethanol Drinking in Adult Spontaneously Hypertensive Rats. Behavioral Pharmacology, 19, 21-27.
[42] Soeters, H.S., Howells, F.M. and Russell, V.A. (2008) Methylphenidate Does Not Increase Ethanol Consumption in a Rat Model for Attention-Deficit Hyperactivity Disorder: The Spontaneously Hypertensive Rat. Metabolic Brain Disease, 23, 303-314.
[43] Volkow, N.D., Wang, G.J., Fowler, J.S. and Ding, Y.S. (2005) Imaging the Effects of Methylphenidate on Brain Dopamine: New Model on Its Therapeutic Actions for Attention-Deficit/Hyperactivity Disorder. Biological Psychiatry, 57, 1410-1415.
[44] Volkow, N.D., G.J., Wang, F., Telang, J.S., Fowler, J., Logan, M., Jayne, Y., Ma, Pradhan, K. and Wong, C. (2007) Profound Decreases in Dopamine Release in Striatum in Detoxified Alcoholics: Possible Orbitofrontal Involvement. Journal of Neuroscience, 27, 12700-12706.
[45] Markowitz, J.S., DeVane, C.L., Boulton, D.W., Nahas, Z., Risch, S.C., Diamond, F. and Patrick, K.S. (2000) Ethylphenidate Formation in Human Subjects after the Administration of a Single Dose of Methylphenidate and Ethanol. Drug Metabolism and Disposition, 28, 620-624.
[46] Williard, R.L., Middaugh, L.D., Zhu, H.J. and Patrick, K.S. (2007) Methylphenidate and Its Ethanol Transesterification Metabolite Ethylphenidate: Brain Disposition, Monoamine Transporters and Motor Activity. Behavioral Pharmacology, 18, 39-51.
[47] Weight, F.F., Lovinger, D.M. and White, G. (1991) Alcohol Inhibition of NMDA Channel Function. Alcohol and Alcoholism-Supplements, 1, 163-169.
[48] Imperato, A., Honroe, T. and Jensen, L.H. (1990) Dopamine Release in the Nucleus Accumbens Is under Glutamatergic Control through Non-NMDA Receptors: A Study in Freely-Moving Rats. Brain Research, 530, 223-228.
[49] Kalivas, P.W., Sorg, B.A. and Hooks, S.M. (1993) The Pharmacology and Neural Circuitry of Sensitization to Psycho-stimulants. Behavioural Pharmacology, 4, 315-334.
[50] Kalivas, P.W., Pierce, R.C., Cornish, J. and Sorg, B.A. (1998) A Role of Sensitization in Craving and Relapse in Cocaine Addiction. Journal of Psychopharmacology, 12, 49-53.
[51] Kalivas, P.W. and Stewart, J. (1991) Dopamine Transmission in the Initiation and Expression of Drug- and Stress-Induced Sensitization of Motor Activity. Brain Research Reviews, 16, 233-244.
[52] Wanchoo, S.J., Lee, M.J., Swann, A.C. and Dafny, N. (2010) Bilateral Six-Hydroxydopamine Administration to PFC Prevents the Expression of Behavioral Sensitization to Methylphenidate. Brain Research, 1312, 80-100.
[53] Kalivas, P.W. (2005) A Role of Glutamate Transmission in Addiction to Psychostimulants. Addiction Biology, 5, 325-329.
[54] Prieto-Gómez, B., Vázquez-Alvarez, A.M., Martínez-Pena, J.L., Reyes-Vázuez, C., Yang, P.B. and Dafny, N. (2005) Methylphenidate and Amphetamine Modulate Differently the NMDA and AMPA Glutaminergic Transmission of Dopaminergic Neurons in the Ventral Tegmental Area. Life Sciences, 77, 635-649.
[55] Wanchoo, S.J., Swann, A.C. and Dafny, N. (2009) Descending Glutamatergic Pathways of PFC Are Involved in Acute and Chronic Action of Methylphenidate. Brain Research, 1301, 68-79.
[56] Martin-Fardon, R., Strong, E.M. and Weiss, F. (2012) Effect of σ1 Receptor Antagonism on Ethanol and Natural Reward Seeking. Neuroreport, 23, 809-813.
[57] Adriani, W., Leo, D., Guarino, M., Natoli, A., Di Consiglio, E., De Angelis, G., Traina, E., Testai, E., Perrone-Capano, C. and Laviola, G. (2006) Short-Term Effects of Adolescent Methylphenidate Exposure on Brain Striatal Gene Expression and Sexual/Endocrine Parameters in Male Rats. Annals of the New York Academy of Sciences, 1074, 52-73.
[58] Santhakumar, V.M., Wallner, M. and Otis, T.S. (2007) Ethanol Acts Directly on Extrasynaptic Subtypes of GABAA Receptors to Increase Tonic Inhibition. Alcohol, 41, 211-221.
[59] Vizi, E.S., Fekete, A., Karoly, M. and Mike, A. (2010) Non-Synaptic Receptors and Transporters Involved in Brain Functions and Targets of Drug Treatment. British Journal of Pharmacology, 160, 785-809.

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