Skip to main content
SpringerLink
Log in

Nicotinic receptors differentially modulate the induction and expression of behavioral sensitization to methylphenidate in rats

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

Abstract

Rationale

Nicotinic acetylcholine receptors (nAChRs) regulate sensitization to stimulant drugs such as d-amphetamine and cocaine.

Objectives

The current study determined if nAChRs modulate the induction and/or expression of behavioral sensitization to high methylphenidate doses.

Methods

In experiment 1, rats received saline or mecamylamine (3 mg/kg, sc), followed by saline or methylphenidate (5.6 or 10 mg/kg, sc) during 10 daily sessions; the effect of methylphenidate (1–17 mg/kg, sc) alone was determined 14 days later. In experiment 2, rats received saline or dihydro-β-erythroidine (DHβE; 3 mg/kg, sc), followed by saline or 5.6 mg/kg of methylphenidate. In experiment 3, rats received saline or methylphenidate (5.6 or 10 mg/kg, sc) alone for 10 days; the effect of acute mecamylamine (3 mg/kg, sc) on the response to methylphenidate (1–17 mg/kg, sc) was determined 14 days later. Locomotor activity, sniffing, rearing, grooming, and stereotypy ratings were dependent measures.

Results

Methylphenidate produced dose-dependent increases in locomotor activity, sniffing, and stereotypy on day 1 and these effects were enhanced on day 10, indicative of sensitization. Mecamylamine attenuated methylphenidate-induced stereotypy only on day 1, but reduced locomotor activity, sniffing, rearing, and stereotypy on day 10 and during the methylphenidate challenge phase; similar results were obtained with DHβE. However, acute mecamylamine did not alter the effects of the methylphenidate challenge following the induction of sensitization to methylphenidate alone.

Conclusions

Although nAChRs do not appear to regulate the expression of methylphenidate-induced behavioral sensitization, inhibition of high-affinity β2 subunit nAChRs attenuates the induction of behavioral sensitization to high doses of methylphenidate.

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

Abbreviations

nAChR:

Nicotinic acetylcholine receptor

ADHD:

Attention-deficit/hyperactivity disorder

DHβE:

Dihydro-β-erythoroidine

ACh:

Acetylcholine

DA:

Dopamine

5-HT:

Serotonin

NAcc:

Nucleus accumbens

VTA:

Ventral tegmental area

References

  • Albuquerque EX, Akaike A, Shaw KP, Rickett DL (1984) The interaction of anticholinesterase agents with the acetylcholine receptor-ionic channel complex. Fundam Appl Toxicol 4:S27–33

    Article  PubMed  CAS  Google Scholar 

  • Anagnostaras SG, Robinson TE (1996) Sensitization to the psychomotor stimulant effects of amphetamine: modulation by associative learning. Behav Neurosci 110:1397–1414

    Article  PubMed  CAS  Google Scholar 

  • Badiani A, Robinson TE (2004) Drug-induced neurobehavioral plasticity: the role of environmental context. Behav Pharmacol 15:327–339

    Article  PubMed  CAS  Google Scholar 

  • Badiani A, Camp DM, Robinson TE (1997) Enduring enhancement of amphetamine sensitization by drug-associated environmental stimuli. J Pharmacol Exp Ther 282:787–794

    PubMed  CAS  Google Scholar 

  • Bevins RA, Bardo MT (1998) Morphine-conditioned changes in locomotor activity: role of the conditioned stimulus. Exp Clin Psychopharmacol 6:131–138

    Article  PubMed  CAS  Google Scholar 

  • Bevins RA, Peterson JL (2004) Individual differences in rats' reactivity to novelty and the unconditioned and conditioned locomotor effects of methamphetamine. Pharmacol Biochem Behav 79:65–74

    Article  PubMed  CAS  Google Scholar 

  • Bevins RA, Eurek S, Besheer J (2005) Timing of conditioned responding in a nicotine locomotor conditioning preparation: manipulations of the temporal arrangement between context cues and drug administration. Behav Brain Res 159:135–143

    Article  PubMed  CAS  Google Scholar 

  • Bickerdike MJ, Abercrombie ED (1997) Striatal acetylcholine release correlates with behavioral sensitization in rats withdrawn from chronic amphetamine. J Pharmacol Exp Ther 282:818–826

    PubMed  CAS  Google Scholar 

  • Blokhina EA, Kashkin VA, Zvartau EE, Danysz W, Bespalov AY (2005) Effects of nicotinic and NMDA receptor channel blockers on intravenous cocaine and nicotine self-administration in mice. Eur Neuropsychopharmacol 15:219–225

    Article  PubMed  CAS  Google Scholar 

  • Borycz J, Zapata A, Quiroz C, Volkow ND, Ferre S (2008) 5-HT(1B) Receptor-mediated serotoninergic modulation of methylphenidate-induced locomotor activation in rats. Neuropsychopharmacology 33:619–626

    Article  PubMed  CAS  Google Scholar 

  • Brebner K, Wong TP, Liu L, Liu Y, Campsall P, Gray S, Phelps L, Phillips AG, Wang YT (2005) Nucleus accumbens long-term depression and the expression of behavioral sensitization. Science 310:1340–1343

    Article  PubMed  CAS  Google Scholar 

  • Breese GR, Cooper BR, Hollister AS (1975) Involvement of brain monoamines in the stimulant and paradoxical inhibitory effects of methylphenidate. Psychopharmacologia 44:5–10

    Article  PubMed  CAS  Google Scholar 

  • Bryan KS, Ellison G (1975) Cholinergic modulation of an opposed effect of d-amphetamine and methylphenidate on the rearing response. Psychopharmacologia 43:169–173

    Article  PubMed  CAS  Google Scholar 

  • Champtiaux N, Kalivas PW, Bardo MT (2006) Contribution of dihydro-beta-erythroidine sensitive nicotinic acetylcholine receptors in the ventral tegmental area to cocaine-induced behavioral sensitization in rats. Behav Brain Res 168:120–126

    Article  PubMed  CAS  Google Scholar 

  • Exley R, Cragg SJ (2008) Presynaptic nicotinic receptors: a dynamic and diverse cholinergic filter of striatal dopamine neurotransmission. Br J Pharmacol 153(Suppl 1):S283–S297

    Article  PubMed  CAS  Google Scholar 

  • Exley R, Clements MA, Hartung H, McIntosh JM, Cragg SJ (2008) Alpha6-containing nicotinic acetylcholine receptors dominate the nicotine control of dopamine transmission in nucleus accumbens. Neuropsychopharmacology 33:2158–2166

    Article  PubMed  CAS  Google Scholar 

  • Fletcher PJ, Sinyard J, Higgins GA (2006) The effects of the 5-HT(2C) receptor antagonist SB242084 on locomotor activity induced by selective, or mixed, indirect serotonergic and dopaminergic agonists. Psychopharmacology 187:515–525

    Article  PubMed  CAS  Google Scholar 

  • Fog R (1972) On stereotypy and catalepsy: studies on the effects of amphetamines and neuroleptics in rats. Acta Neurol Scand Suppl 50:3–66

    PubMed  CAS  Google Scholar 

  • Fuemmeler BF, Kollins SH, McClernon FJ (2007) Attention deficit hyperactivity disorder symptoms predict nicotine dependence and progression to regular smoking from adolescence to young adulthood. J Pediatr Psychol 32:1203–1213

    Article  PubMed  Google Scholar 

  • Gehricke JG, Loughlin SE, Whalen CK, Potkin SG, Fallon JH, Jamner LD, Belluzzi JD, Leslie FM (2007) Smoking to self-medicate attentional and emotional dysfunctions. Nicotine Tob Res 9:S523–S536

    Article  PubMed  Google Scholar 

  • Gerasimov MR, Franceschi M, Volkow ND, Gifford A, Gatley SJ, Marsteller D, Molina PE, Dewey SL (2000a) Comparison between intraperitoneal and oral methylphenidate administration: a microdialysis and locomotor activity study. J Pharmacol Exp Ther 295:51–57

    PubMed  CAS  Google Scholar 

  • Gerasimov MR, Franceschi M, Volkow ND, Rice O, Schiffer WK, Dewey SL (2000b) Synergistic interactions between nicotine and cocaine or methylphenidate depend on the dose of dopamine transporter inhibitor. Synapse 38:432–437

    Article  PubMed  CAS  Google Scholar 

  • Gonzalez LP, Ellinwood EH Jr (1984) Cholinergic modulation of stimulant-induced behavior. Pharmacol Biochem Behav 20:397–403

    Article  PubMed  CAS  Google Scholar 

  • Grace A (2001) Psychostimulant actions on dopamine and limbic system function: relevance to the pathophysiology and treatment of ADHD. In: Solanto MV, Arnsten AFT, Catellanos FX (eds) Stimulant drugs and ADHD: basic and clinical neuroscience. Oxford University Press, New York, pp 134–157

    Google Scholar 

  • Grady SR, Salminen O, Laverty DC, Whiteaker P, McIntosh JM, Collins AC, Marks MJ (2007) The subtypes of nicotinic acetylcholine receptors on dopaminergic terminals of mouse striatum. Biochem Pharmacol 74:1235–1246

    Article  PubMed  CAS  Google Scholar 

  • Grenhoff J, Aston-Jones G, Svensson TH (1986) Nicotinic effects on the firing pattern of midbrain dopamine neurons. Acta Physiol Scand 128:351–358

    Article  PubMed  CAS  Google Scholar 

  • Grillner P, Svensson TH (2000) Nicotine-induced excitation of midbrain dopamine neurons in vitro involves ionotropic glutamate receptor activation. Synapse 38:1–9

    Article  PubMed  CAS  Google Scholar 

  • Hansen ST, Mark GP (2007) The nicotinic acetylcholine receptor antagonist mecamylamine prevents escalation of cocaine self-administration in rats with extended daily access. Psychopharmacology 194:53–61

    Article  PubMed  CAS  Google Scholar 

  • Janowsky DS, El-Yousef MK, Davis JM, Sekerke HJ (1972) Cholinergic antagonism of methylphenidate-induced stereotyped behavior. Psychopharmacologia 27:295–303

    Article  CAS  Google Scholar 

  • Kalinichev M, White DA, Holtzman SG (2004) Individual differences in locomotor reactivity to a novel environment and sensitivity to opioid drugs in the rat. I. Expression of morphine-induced locomotor sensitization. Psychopharmacology 177:61–67

    Article  PubMed  CAS  Google Scholar 

  • Kalivas PW (1995) Interactions between dopamine and excitatory amino acids in behavioral sensitization to psychostimulants. Drug Alcohol Depend 37:95–100

    Article  PubMed  CAS  Google Scholar 

  • Karler R, Calder LD, Bedingfield JB (1996) A novel nicotinic-cholinergic role in behavioral sensitization to amphetamine-induced stereotypy in mice. Brain Res 725:192–198

    PubMed  CAS  Google Scholar 

  • Keath JR, Iacoviello MP, Barrett LE, Mansvelder HD, McGehee DS (2007) Differential modulation by nicotine of substantia nigra versus ventral tegmental area dopamine neurons. J Neurophysiol 98:3388–3396

    Article  PubMed  CAS  Google Scholar 

  • Kenny PJ, File SE, Neal MJ (2000) Evidence for a complex influence of nicotinic acetylcholine receptors on hippocampal serotonin release. J Neurochem 75:2409–2414

    Article  PubMed  CAS  Google Scholar 

  • Kleven MS, Prinssen EP, Koek W (1996) Role of 5-HT1A receptors in the ability of mixed 5-HT1A receptor agonist/dopamine D2 receptor antagonists to inhibit methylphenidate-induced behaviors in rats. Eur J Pharmacol 313:25–34

    Article  PubMed  CAS  Google Scholar 

  • Klink R, de Kerchove d’Exaerde A, Zoli M, Changeux JP (2001) Molecular and physiological diversity of nicotinic acetylcholine receptors in the midbrain dopaminergic nuclei. J Neurosci 21:1452–1463

    PubMed  CAS  Google Scholar 

  • Koek W, Colpaert FC (1993) Inhibition of methylphenidate-induced behaviors in rats: differences among neuroleptics. J Pharmacol Exp Ther 267:181–191

    PubMed  CAS  Google Scholar 

  • Kuczenski R, Segal DS (1999) Dynamic changes in sensitivity occur during the acute response to cocaine and methylphenidate. Psychopharmacology 147:96–103

    Article  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 57:1391–1396

    Article  PubMed  CAS  Google Scholar 

  • Levin ED, Conners CK, Sparrow E, Hinton SC, Erhardt D, Meck WH, Rose JE, March J (1996) Nicotine effects on adults with attention-deficit/hyperactivity disorder. Psychopharmacology 123:55–63

    Article  PubMed  CAS  Google Scholar 

  • Levin ED, Mead T, Rezvani AH, Rose JE, Gallivan C, Gross R (2000) The nicotinic antagonist mecamylamine preferentially inhibits cocaine vs. food self-administration in rats. Physiol Behav 71:565–570

    Article  PubMed  CAS  Google Scholar 

  • Linderholm KR, Andersson A, Olsson S, Olsson E, Snodgrass R, Engberg G, Erhardt S (2007) Activation of rat ventral tegmental area dopamine neurons by endogenous kynurenic acid: a pharmacological analysis. Neuropharmacology 53:918–924

    Article  PubMed  CAS  Google Scholar 

  • Luthman J, Fredriksson A, Lewander T, Jonsson G, Archer T (1989) Effects of d-amphetamine and methylphenidate on hyperactivity produced by neonatal 6-hydroxydopamine treatment. Psychopharmacology 99:550–557

    Article  PubMed  CAS  Google Scholar 

  • Mansvelder HD, McGehee DS (2000) Long-term potentiation of excitatory inputs to brain reward areas by nicotine. Neuron 27:349–357

    Article  PubMed  CAS  Google Scholar 

  • McClernon FJ, Kollins SH (2008) ADHD and smoking: from genes to brain to behavior. Ann N Y Acad Sci 1141:131–147

    Article  PubMed  CAS  Google Scholar 

  • McDougall SA, Collins RL, Karper PE, Watson JB, Crawford CA (1999) Effects of repeated methylphenidate treatment in the young rat: sensitization of both locomotor activity and stereotyped sniffing. Exp Clin Psychopharmacol 7:208–218

    Article  PubMed  CAS  Google Scholar 

  • Miller DK, Segert IL (2005) Mecamylamine attenuates ephedrine-induced hyperactivity in rats. Pharmacol Biochem Behav 81:165–169

    Article  PubMed  CAS  Google Scholar 

  • Mithani S, Martin-Iverson MT, Phillips AG, Fibiger HC (1986) The effects of haloperidol on amphetamine- and methylphenidate-induced conditioned place preferences and locomotor activity. Psychopharmacology 90:247–252

    Article  PubMed  CAS  Google Scholar 

  • Papke RL, Sanberg PR, Shytle RD (2001) Analysis of mecamylamine stereoisomers on human nicotinic receptor subtypes. J Pharmacol Exp Ther 297:646–656

    PubMed  CAS  Google Scholar 

  • Pidoplichko VI, DeBiasi M, Williams JT, Dani JA (1997) Nicotine activates and desensitizes midbrain dopamine neurons. Nature 390:401–404

    Article  PubMed  CAS  Google Scholar 

  • Pierce RC, Kalivas PW (1995) Amphetamine produces sensitized increases in locomotion and extracellular dopamine preferentially in the nucleus accumbens shell of rats administered repeated cocaine. J Pharmacol Exp Ther 275:1019–1029

    PubMed  CAS  Google Scholar 

  • Rodriguez D, Tercyak KP, Audrain-McGovern J (2007) Effects of inattention and hyperactivity/impulsivity symptoms on development of nicotine dependence from mid adolescence to young adulthood. J Pediatr Psychol 33:563–575

    Article  PubMed  Google Scholar 

  • Roffman JL, Raskin LA (1997) Stereotyped behavior: effects of d-amphetamine and methylphenidate in the young rat. Pharmacol Biochem Behav 58:1095–1102

    Article  PubMed  CAS  Google Scholar 

  • Rush CR, Higgins ST, Vansickel AR, Stoops WW, Lile JA, Glaser PE (2005) Methylphenidate increases cigarette smoking. Psychopharmacology 181:781–789

    Article  PubMed  CAS  Google Scholar 

  • Salminen O, Drapeau JA, McIntosh JM, Collins AC, Marks MJ, Grady SR (2007) Pharmacology of alpha-conotoxin MII-sensitive subtypes of nicotinic acetylcholine receptors isolated by breeding of null mutant mice. Mol Pharmacol 71:1563–1571

    Article  PubMed  CAS  Google Scholar 

  • Schoffelmeer AN, De Vries TJ, Wardeh G, van de Ven HW, Vanderschuren LJ (2002) Psychostimulant-induced behavioral sensitization depends on nicotinic receptor activation. J Neurosci 22:3269–3276

    PubMed  CAS  Google Scholar 

  • Sellings LH, McQuade LE, Clarke PB (2006) Characterization of dopamine-dependent rewarding and locomotor stimulant effects of intravenously-administered methylphenidate in rats. Neuroscience 141:1457–1468

    Article  PubMed  CAS  Google Scholar 

  • Smith JE, Vaughn TC, Co C (2004) Acetylcholine turnover rates in rat brain regions during cocaine self-administration. J Neurochem 88:502–512

    Article  PubMed  CAS  Google Scholar 

  • Solanto MV (2001) Attention-deficit/hyperactivity disorder: clinical features. In: Solanto MV, Arnsten AFT, Catellanos FX (eds) Stimulant drugs and ADHD: basic and clinical neuroscience. Oxford University Press, New York, pp 3–30

    Google Scholar 

  • Torres-Reveron A, Dow-Edwards DL (2005) Repeated administration of methylphenidate in young, adolescent, and mature rats affects the response to cocaine later in adulthood. Psychopharmacology 181:38–47

    Article  PubMed  CAS  Google Scholar 

  • Tzavara ET, Bymaster FP, Overshiner CD, Davis RJ, Perry KW, Wolff M, McKinzie DL, Witkin JM, Nomikos GG (2006) Procholinergic and memory enhancing properties of the selective norepinephrine uptake inhibitor atomoxetine. Mol Psychiatry 11:187–195

    Article  PubMed  CAS  Google Scholar 

  • Upadhyaya HP, Rose K, Wang W, O'Rourke K, Sullivan B, Deas D, Brady KT (2005) Attention-deficit/hyperactivity disorder, medication treatment, and substance use patterns among adolescents and young adults. J Child Adolesc Psychopharmacol 15:799–809

    Article  PubMed  Google Scholar 

  • Uslaner J, Badiani A, Day HE, Watson SJ, Akil H, Robinson TE (2001) Environmental context modulates the ability of cocaine and amphetamine to induce c-fos mRNA expression in the neocortex, caudate nucleus, and nucleus accumbens. Brain Res 920:106–116

    Article  PubMed  CAS  Google Scholar 

  • Vanderschuren LJ, Kalivas PW (2000) Alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization: a critical review of preclinical studies. Psychopharmacology 151:99–120

    Article  PubMed  CAS  Google Scholar 

  • Vansickel AR, Stoops WW, Glaser PE, Rush CR (2007) A pharmacological analysis of stimulant-induced increases in smoking. Psychopharmacology 193:305–313

    Article  PubMed  CAS  Google Scholar 

  • Weiss SR, Post RM, Pert A, Woodward R, Murman D (1989) Context-dependent cocaine sensitization: differential effect of haloperidol on development versus expression. Pharmacol Biochem Behav 34:655–661

    PubMed  CAS  Google Scholar 

  • Whiteaker P, Marks MJ, Grady SR, Lu Y, Picciotto MR, Changeux JP, Collins AC (2000) Pharmacological and null mutation approaches reveal nicotinic receptor diversity. Eur J Pharmacol 393:123–135

    Article  PubMed  CAS  Google Scholar 

  • Wilens TE, Decker MW (2007) Neuronal nicotinic receptor agonists for the treatment of attention-deficit/hyperactivity disorder: focus on cognition. Biochem Pharmacol 74:1212–1223

    Article  PubMed  CAS  Google Scholar 

  • Williams MJ, Adinoff B (2007) The role of acetylcholine in cocaine addiction. Neuropsychopharmacology 33:1779–1797

    Article  PubMed  CAS  Google Scholar 

  • Wonnacott S (1997) Presynaptic nicotinic ACh receptors. Trends Neurosci 20:92–98

    Article  PubMed  CAS  Google Scholar 

  • Wooters TE, Dwoskin LP, Bardo MT (2006) Age and sex differences in the locomotor effect of repeated methylphenidate in rats classified as high or low novelty responders. Psychopharmacology 188:18–27

    Article  PubMed  CAS  Google Scholar 

  • Wooters TE, Neugebauer NM, Rush CR, Bardo MT (2007) Methylphenidate enhances the abuse-related behavioral effects of nicotine in rats: intravenous self-administration, drug discrimination, and locomotor cross-sensitization. Neuropsychopharmacology 33:1137–1148

    Article  PubMed  CAS  Google Scholar 

  • Yang PB, Swann AC, 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 Res 1073–1074:164–174

    Article  PubMed  CAS  Google Scholar 

  • Yang PB, Swann AC, Dafny N (2007) Chronic administration of methylphenidate produces neurophysiological and behavioral sensitization. Brain Res 1145:66–80

    Article  PubMed  CAS  Google Scholar 

  • Zachariou V, Caldarone BJ, Weathers-Lowin A, George TP, Elsworth JD, Roth RH, Changeux JP, Picciotto MR (2001) Nicotine receptor inactivation decreases sensitivity to cocaine. Neuropsychopharmacology 24:576–589

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We gratefully acknowledge the technical assistance of Blake Dennis and Joshua Cutshall. This work was supported by USPHS grants DA 023853 and DA 017548.

Author information

Authors and Affiliations

  1. Department of Psychology, College of Arts and Sciences, University of Kentucky, Lexington, KY, USA

    Thomas E. Wooters & Michael T. Bardo

  2. Department of Psychology, BBSRB, Room 447, University of Kentucky, Lexington, KY, 40536-0509, USA

    Michael T. Bardo

Authors
  1. Thomas E. Wooters
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael T. Bardo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael T. Bardo.

Additional information

The asterisk (*) found in the body denotes possible inclusion of additional nAChR subunits.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wooters, T.E., Bardo, M.T. Nicotinic receptors differentially modulate the induction and expression of behavioral sensitization to methylphenidate in rats. Psychopharmacology 204, 551–562 (2009). https://doi.org/10.1007/s00213-009-1487-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-009-1487-6

Keywords

Search

Navigation