JBBS  Vol.4 No.4 , April 2014
Ventral Tegmental Area Neuronal Activity Correlates to Animals’ Behavioral Response to Chronic Methylphenidate Recorded from Adolescent SD Male Rats
Methylphenidate (MPD) is considered as the first-line pharmacotherapy to treat ADHD. More recently, MPD has also been used as a cognitive enhancement recreationally. Its therapeutic effects are not fully understood, nor are the long term effects of the drug on brain development. The ventral tegmental area (VTA) neuronal activity was recorded from freely behaving adolescent rats using a wireless recording system. Five groups were used: saline, 0.6, 2.5, 5.0 and 10.0 mg/kg MPD. The experiment lasted for 10 days. This study demonstrated that VTA neurons respond to MPD in a dose response characteristic and the same dose of MPD can cause both behavioral sensitization and behavioral tolerance. The neuronal unit activity was evaluated based on the animals’ behavioral activity following chronic MPD administration. The study showed that the animals’ behavioral response to different acute MPD of 0.6, 2.5 and 10.0 mg/kg doses responded in a dose response characteristics. Moreover, the same chronic dose of 0.6, 2.5, and 10.0 mg/kg MPD elicits in some animals’ behavioral sensitization and in some others behavioral tolerance. Therefore, the neuronal activity recorded from animals expressing behavioral sensitization was analyzed separately from the neuronal activity recorded from of behaviorally tolerant animals and it was found that the VTA units of the behaviorally sensitization animals responded significantly different to the drug than those VTA units recorded from animals expressing behavioral tolerance.

Cite this paper
Jones, Z. , Vazquez, C. and Dafny, N. (2014) Ventral Tegmental Area Neuronal Activity Correlates to Animals’ Behavioral Response to Chronic Methylphenidate Recorded from Adolescent SD Male Rats. Journal of Behavioral and Brain Science, 4, 168-189. doi: 10.4236/jbbs.2014.44020.
[1]   Lee, S.H., Seo, W.S., Sung, H.M., Choi, T.Y., Kim, S.Y., Choi, S.J., Koo, B.H. and Lee, J.H. (2012) Effect of Methylphenidate on Sleep Parameters in Children with ADHD. Psychiatry Investigation, 9, 384-390.

[2]   Shenker, A. (1992) The Mechanism of Action of Drugs Used to Treat Attention-Deficit Hyperactivity Disorder: Focus on Catecholamine Receptor Pharmacology. Advances in Pediatrics, 39, 337-382.

[3]   Solanto, M.V. (1998) Neuropsychopharmacological Mechanisms of Stimulant Drug Action in Attention-Deficit Hyperactivity Disorder: A Review and Integration. Behavioural Brain Research, 94, 127-152.

[4]   Newcorn, J.H. (2000) A Glimpse into Key Issues in ADHD. CNS Spectrums, 5, 25.

[5]   Froehlich, T.E., Lanphear, B.P., Epstein, J.N., Barbaresi, W.J., Katusic, S.K. and Kahn, R.S. (2007) Prevalence, Recognition, and Treatment of Attention-Deficit/Hyperactivity Disorder in a National Sample of US Children. Archives of Pediatrics and Adolescent Medicine, 161, 857-864.

[6]   Polanczyk, G. and Rohde, L.A. (2007) Epidemiology of Attention-Deficit/Hyperactivity Disorder across the Lifespan. Current Opinion in Psychiatry, 20, 386-392.

[7]   Wilens, T.E., Biederman, J. and Spencer, T.J. (2002) Attention Deficit/Hyperactivity Disorder across the Lifespan. Annual Review of Medicine, 53, 113-131.

[8]   Challman, T.D. and Lipsky, J.J. (2000) Methylphenidate: Its Pharmacology and Uses. Mayo Clinic Proceedings, 75, 711-721.

[9]   Swanson, J.M., Cantwell, D., Lerner, M., McBurnett, K. and Hanna, G. (1991) Effects of Stimulant Medication on Learning in Children with ADHD. Journal of Learning Disabilities, 24, 219-230.

[10]   Arnsten, A.F. and Dudley, A.G. (2005) Methylphenidate Improves Prefrontal Cortical Cognitive Function through Alpha 2 Adrenoceptor and Dopamine D1 Receptor Actions: Relevance to Therapeutic Effects in Attention Deficit Hyperactivity Disorder. Behavioral and Brain Functions, 1, 2.

[11]   Goldman, L.S., Genel, M., Bezman, R.J. and Slanetz, P.J. (1998) Diagnosis and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents. Council on Scientific Affairs, American Medical Association. The Journal of the American Medical Association, 279, 1100-1107.

[12]   Arria, A.M. and Wish, E.D. (2006) Nonmedical Use of Prescription Stimulants among Students. Pediatric Annals, 35, 565-571.

[13]   Imbert, B., Cohen, J. and Simon, N. (2013) Intravenous Abuse of Methylphenidate. Journal of Clinical Psychopharmacology, 33, 720-721.

[14]   Kallman, W.M. and Isaac, W. (1975) The Effects of Age and Illumination on the Dose-Response Curves for Three Stimulants. Psychopharmacologia, 40, 313-318.

[15]   Patrick, K.S. and Markowitz, J.S. (1997) Pharmacology of Methylphenidate, Amphetamine Enantiomers and Pemoline in Attention-Deficit Hyperactivity Disorder. Human Psychopharmacology: Clinical and Experimental, 12, 527-546.

[16]   Lakhan, S.E. and Kirchgessner, A. (2012) Prescription Stimulants in Individuals with and without Attention Deficit Hyper-activity Disorder: Misuse, Cognitive Impact, and Adverse Effects. Brain and Behavior, 2, 661-677.

[17]   Kallman, W.M. and Isaac, W. (1975) The Effects of Age and Illumination on the Dose-Response Curves for Three Stimulants. Psychopharmacologia, 40, 313-318.

[18]   Andersen, S.L. and Teicher, M.H. (2000) Sex Differences in Dopamine Receptors and Their Relevance to ADHD. Neuroscience & Biobehavioral Reviews, 24, 137-141.

[19]   Brenhouse, H.C. and Andersen, S.L. (2011) Developmental Trajectories during Adolescence in Males and Females: A Cross-Species Understanding of Underlying Brain Changes. Neuroscience & Biobehavioral Reviews, 35, 1687-1703.

[20]   Huttenlocher, P.R. (1974) Dendritic Development in Neocortex of Children with Mental Defect and Infantile Spams. Neurology, 24, 203-210.

[21]   Rakic, P., Bourgeois, J.P., Eckenhoff, M.F., Zecevic, N. and Goldman-Rakic, P.S. (1986) Concurrent Overproduction of Synapses in Diverse Regions of the Primate Cerebral Cortex. Science, 232, 232-235.

[22]   Brandon, C.L., Marinelli, M. and White, F.J. (2003) Adolescent Exposure to Methylphenidate Alters the Activity of Rat Midbrain Dopamine Neurons. Biological Psychiatry, 54, 1338-1344.

[23]   Canese, R., Adriani, W., Marco, E.M., De Pasquale, F., Lorenzini, P., De Luca, N., Fabi, F., Podo, F. and Laviola, G. (2009) Peculiar Response to Methylphenidate in Adolescent Compared to Adult Rats: A phMRI Study. Psychopharmacology, 203, 143-153.

[24]   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.

[25]   Yang, P.B., Atkins, K.D. and Dafny, N. (2011) Behavioral Sensitization and Cross-Sensitization between Methylphenidate Amphetamine, and 3,4-Methylenedioxymethamphetamine (MDMA) in Female SD Rats. European Journal of Pharmacology, 661, 72-85.

[26]   Kuczenski, R. and Segal, D.S. (2001) Locomotor Effects of Acute and Repeated Threshold Doses of Amphetamine and Methylphenidate: Relative Roles of Dopamine and Norepinephrine. Journal of Pharmacology and Experimental Therapeutics, 296, 876-883.

[27]   Walker, Q.D., Morris, S.E., Arrant, A.E., Nagel, J.M., Parylak, S., Zhou, G., Caster, J.M. and Kuhn, C.M. (2010) Dopamine Uptake Inhibitors but Not Dopamine Releasers Induce Greater Increases in Motor Behavior and Extracellular Dopamine in Adolescent Rats than in Adult Male Rats. Journal of Pharmacology and Experimental Therapeutics, 335, 124-132.

[28]   Gronier, B. (2011) In Vivo Electrophysiological Effects of Methylphenidate in the Prefrontal Cortex: Involvement of Dopamine D1 and Alpha 2 Adrenergic Receptors. European Neuropsychopharmacology, 21, 192-204.

[29]   Kauer, J.A. (2004) Learning Mechanisms in Addiction: Synaptic Plasticity in the Ventral Tegmental Area as a Result of Exposure to Drugs of Abuse. Annual Review of Physiology, 66, 447-475.

[30]   Koob, G.F. (1992) Drugs of Abuse: Anatomy, Pharmacology and Function of Reward Pathways. Trends in Pharmacological Sciences, 13, 177-184.

[31]   Nestler, E.J. (1992) Molecular Mechanisms of Drug Addiction. The Journal of Neuroscience, 12, 2439-2450.

[32]   Wise, R.A. (1996) Addictive Drugs and Brain Stimulation Reward. Annual Review of Neuroscience, 19, 319-340.

[33]   Tang, B. and Dafny, N. (2013) Behavioral and Dorsal Raphe Neuronal Activity Following Acute and Chronic Methylphenidate in Freely Behaving Rats. Brain Research Bulletin, 98, 53-63.

[34]   Sherwood, N. and Timiras, P.S. (1970) A Stereotaxic Atlas of the Developing Rat Brain.

[35]   Chong, S.L., Claussen, C.M. and Dafny, N. (2012) Nucleus Accumbens Neuronal Activity in Freely Behaving Rats Is Modulated Following Acute and Chronic Methylphenidate Administration. Brain Research Bulletin, 87, 445-456.

[36]   Claussen, C.M. and Dafny, N. (2012) Acute and Chronic Methylphenidate Modulates the Neuronal Activity of the Caudate Nucleus Recorded from Freely Behaving Rats. Brain Research Bulletin, 87, 387-396.

[37]   Dafny, N. (1980) Multiunit Recording from Medial Basal Hypothalamus Following Acute and Chronic Morphine Treatment. Brain Research, 190, 584-592.

[38]   Dafny, N. (1982) The Hypothalamus Exhibits Electrophysiologic Evidence for Morphine Tolerance and Dependence. Experimental Neurology, 77, 66-77.

[39]   Dafny, N. and Terkel, J. (1990) Hypothalamic Neuronal Activity Associated with Onset of Pseudopregnancy in the Rat. Neuroendocrinology, 51, 459-467.

[40]   Salek, R.L., Claussen, C.M., Perez, A. and Dafny, N. (2012) Acute and Chronic Methylphenidate Alters Prefrontal Cortex Neuronal Activity Recorded from Freely Behaving Rats. European Journal of Pharmacology, 679, 60-67.

[41]   Algahim, M.F., Yang, P.B., Wilcox, V.T., Burau, K.D., Swann, A.C. and Dafny, N. (2009) Prolonged Methylphenidate Treatment Alters the Behavioral Diurnal Activity Pattern of Adult Male Sprague-Dawley Rats. Pharmacology Biochemistry and Behavior, 92, 93-99.

[42]   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.

[43]   Gaytan, O., Yang, P., Swann, A. and Dafny, N. (2000) Diurnal Differences in Sensitization to Methylphenidate. Brain Research, 864, 24-39.

[44]   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.

[45]   Podet, A., Lee, M.J., Swann, A.C. and Dafny, N. (2010) Nucleus Accumbens Lesions Modulate the Effects of Methylphenidate. Brain Research Bulletin, 82, 293-301.

[46]   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.

[47]   Yang, P.B., Swann, A.C. and Dafny, N. (2006) Sensory-Evoked Potentials Recordings from the Ventral Tegmental Area, Nucleus Accumbens, Prefrontal Cortex, and Caudate Nucleus and Locomotor Activity Are Modulated in Dose-Response Characteristics by Methylphenidate. Brain Research, 1073-1074, 164-174.

[48]   Yang, P.B., Swann, A.C. and Dafny, N. (2006) Chronic Methylphenidate Modulates Locomotor Activity and Sensory Evoked Responses in the VTA and NAc of Freely Behaving Rats. Neuropharmacology, 51, 546-556.

[49]   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 Functions, 2, 3.

[50]   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.

[51]   Yang, P.B., Swann, A.C. and Dafny, N. (2007) Chronic Administration of Methylphenidate Produces Neurophysiological and Behavioral Sensitization. Brain Research, 1145, 66-80.

[52]   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, 223-244.

[53]   White, S.R. and Yadao, C.M. (2000) Characterization of Methylphenidate Exposures Reported to a Regional Poison Control Center. Archives of Pediatrics and Adolescent Medicine, 154, 1199-1203.

[54]   Crutchley, A. and Temlett, J.A. (1999) Methylphenidate (Ritalin) Use and Abuse. South African Medical Journal, 89, 1076-1079.

[55]   Eichlseder, W. (1985) Ten Years of Experience with 1,000 Hyperactive Children in a Private Practice. Pediatrics, 76, 176-184.

[56]   Gatley, S.J., Volkow, N.D., Gifford, A.N., Fowler, J.S., Dewey, S.L., Ding, Y.S. and Logan, J. (1999) Dopamine-Transporter Occupancy after Intravenous Doses of Cocaine and Methylphenidate in Mice and Humans. Psychopharmacology, 146, 93-100.

[57]   Gerasimov, M.R., Franceschi, M., Volkow, N.D., Gifford, A., Gatley, S.J., Marsteller, D., Molina, P.E. and Dewey, S.L. (2000) Comparison between Intraperitoneal and Oral Methylphenidate Administration: A Microdialysis and Locomotor Activity Study. Journal of Pharmacology and Experimental Therapeutics, 295, 51-57.

[58]   Chelaru, M.I., Yang, P.B. and Dafny, N. (2012) Sex Differences in the Behavioral Response to Methylphenidate in Three Adolescent Rat Strains (WKY, SHR, SD). Behavioural Brain Research, 226, 8-17.

[59]   Bergheim, M., Yang, P.B., Burau, K.D. and Dafny, N. (2012) Adolescent Rat Circadian Activity Is Modulated by Psychostimulants. Brain Research, 1431, 35-45.

[60]   Lee, S.S., Humphreys, K.L., Flory, K., Liu, R. and Glass, K. (2011) Prospective Association of Childhood Attention-Deficit/Hyperactivity Disorder (ADHD) and Substance Use and Abuse/Dependence: A Meta-Analytic Review. Clinical Psychology Review, 31, 328-341.

[61]   Nair-Roberts, R.G., Chatelain-Badie, S.D., Benson, E., White-Cooper, H., Bolam, J.P. and Ungless, M.A. (2008) Stereological Estimates of Dopaminergic, GABAergic and Glutamatergic Neurons in the Ventral Tegmental Area, Substantianigra and Retrorubral Field in the Rat. Neuroscience, 152, 1024-1031.

[62]   Olson, V.G. and Nestler, E.J. (2007) Topographical Organization of GABAergic Neurons within the Ventral Tegmental Area of the Rat. Synapse, 61, 87-95.

[63]   Ranaldi, R. and Wise, R.A. (2001) Blockade of D1 Dopamine Receptors in the Ventral Tegmental Area Decreases Cocaine Reward: Possible Role for Dendritically Released Dopamine. The Journal of Neuroscience, 21, 5841-5846.

[64]   Albin, R.L., Makowiec, R.L., Hollingsworth, Z.R., Dure, L.S., Penney, J.B. and Young, A.B. (1992) Excitatory Amino Acid Binding Sites in the Basal Ganglia of the Rat: A Quantitative Autoradiographic Study. Neuroscience, 46, 35-48.

[65]   Kalivas, P.W. (1993) Neurotransmitter Regulation of Dopamine Neurons in the Ventral Tegmental Area. Brain Research Reviews, 18, 75-113.

[66]   Urban, K.R. and Gao, W.J. (2013) Methylphenidate and the Juvenile Brain: Enhancement of Attention at the Expense of Cortical Plasticity? Medical Hypotheses, 81, 988-994.

[67]   Kim, Y., Teylan, M.A., Baron, M., Sands, A., Nairn, A.C. and Greengard, P. (2009) Methylphenidate-Induced Dendritic Spine Formation and DeltaFosB Expression in Nucleus Accumbens. Proceedings of the National Academy of Sciences, 106, 2915-2920.

[68]   Nestler, E.J. (2008) Review. Transcriptional Mechanisms of Addiction: Role of DeltaFosB. Philosophical Transactions of the Royal Society B: Biological Sciences, 363, 3245-3255.

[69]   Robinson, T.E. and Kolb, B. (1997) Persistent Structural Modifications in Nucleus Accumbens and Prefrontal Cortex Neurons Produced by Previous Experience with Amphetamine. The Journal of Neuroscience, 17, 8491-8497.

[70]   Robinson, T.E. and Kolb, B. (1999) Alterations in the Morphology of Dendrites and Dendritic Spines in the Nucleus Accumbens and Prefrontal Cortex Following Repeated Treatment with Amphetamine or Cocaine. European Journal of Neuroscience, 11, 1598-1604.

[71]   Chao, J. and Nestler, E.J. (2004) Molecular Neurobiology of Drug Addiction. Annual Review of Medicine, 55, 113-132.

[72]   Nestler, E.J. (2004) Molecular Mechanisms of Drug Addiction. Neuropharmacology, 47, 24-32.

[73]   Gray, J.D., Punsoni, M., Tabori, N.E., Melton, J.T., Fanslow, V., Ward, M.J., Zupan, B., Menzer, D., Rice, J., Drake, C.T., Romeo, R.D., Brake, W.G., Torres-Reveron, A. and Milner, T.A. (2007) Methylphenidate Administration to Juvenile Rats Alters Brain Areas Involved in Cognition, Motivated Behaviors, Appetite, and Stress. The Journal of Neuroscience, 27, 7196-7207.

[74]   Lodge, D.J. and Grace, A.A. (2006) The Laterodorsal Tegmentum is Essential for Burst Firing of Ventral Tegmental Area Dopamine Neurons. Proceedings of the National Academy of Sciences of the United States of America, 103, 5167-5172.