Behavioral and Cross Sensitization after Repeated Exposure to Modafinil and Apomorphine in Rats




Shang-Tang Chang;Che-Se Tung;Yu-Lung Lin;Chia-Hsin Chuang;An-Rong Lee;Yia-Ping Liu

Key Words

APO ; behavioral sensitization ; cross-sensitization ; dopamine ; MOD


The Chinese Journal of Physiology

Volume or Term/Year and Month of Publication

53卷5期(2010 / 10 / 31)

Page #

318 - 327

Content Language


English Abstract

Repeated exposure to psychostimulant drugs has been known to produce behavioral sensitization, a phenomenon explicitly indexed by locomotion (LM) and stereotyped movements (SM). So far, no evidence has demonstrated that this phenomenon can be displayed following the administration of modafinil (MOD) in animal study. We, therefore, assessed the possibility of behavioral sensitization of MOD and a direct dopamine agonist, apomorphine (APO), and cross-sensitization of these two drugs with one other. Pretreatment with MOD (64 mg/kg) or APO (0.5 mg/kg or 1.0 mg/kg) for 10 consecutive days was followed by a short-term (3 days) or long-term (21 days) withdrawal. Rats were then challenged with the drug and reciprocally re-challenged with the counterpart drug. The results showed that following short-term and long-term washout periods, both MOD and APO successfully induced sensitization in LM and SM. There was no cross-sensitization; an even lesser magnitude in LM when MOD-sensitized rats were challenged with APO was observed. However, after both the short-term and long-term withdrawal periods, APO (1.0 mg/kg)-sensitized rats showed cross-sensitization in LM and SM to MOD (64 mg/kg) challenge. The magnitude of APO-MOD cross-sensitization was lesser than the behavioral sensitization induced by APO alone. Our results indicated behavioral sensitization could be induced in rats exposed to MOD. In addition, changes in dopaminergic receptor activities could be involved in cross-sensitization of APO to MOD but not vice versa.

Topic Category 醫藥衛生 > 基礎醫學
  1. Liao, R. M.,Lin, H. L.(2008).Differential effects of lesions in the subareas of medial prefrontal cortex on the development of behavioral sensitization to amphetamine: the role of environmental context.Chinese. J. Physiol.,51,394-401.
  2. Wu, H. H.,Lee, C. R.,Lin, S. K.,Yeh, P. H.,Pan, W. H.(2006).A single intrategmental amphetamine exposure induces transient behavioral sensitization in the rats.Chinese J. Physiol.,49,14-21.
  3. Akimoto, K.,Hamamura, T.,Kazahaya, Y.,Akiyama, K.,Otsuki, S.(1990).Enhanced extracellular dopamine level may be the fundamental neuropharmacological basis of cross-behavioral sensitization between methamphetamine and cocaine-an in vivo dialysis study in freely moving rats.Brain Res.,507,344-346.
  4. Ballon, J. S.,Feifel, D.(2006).A systematic review of modafinil: Potential clinical uses and mechanisms of action.J. Clin. Psychiatry,67,554-566.
  5. Battisti, J. J.,Uretsky, N. J.,Wallace, L. J.(1999).Sensitization of apomorphine-induced stereotyped behavior in mice is context dependent.Psychopharmacology (Berl),146,42-48.
  6. Castro, R.,Abreu, P.,Calzadilla, C. H.,Rodriguez, M.(1985).Increased or decreased locomotor response in rats following repeated administration of apomorphine depends on dosage interval.Psychopharmacology (Berl),85,333-339.
  7. Chen, C. R.,Qu, W. M.,Qiu, M. H.,Xu, X. H.,Yao, M. H.,Urade, Y.,Huang, Z. L.(2007).Modafinil exerts a dose-dependent antiepileptic effect mediated by adrenergic alpha1 and histaminergic H1 receptors in mice.Neuropharmacology,53,534-541.
  8. Dackis, C. A.,Kampman, K. M.,Lynch, K. G.,Pettinati, H. M.,O''Brien, C. P.(2005).A double-blind, placebo-controlled trial of modafinil for cocaine dependence.Neuropsychopharmacology,30,205-211.
  9. De Sereville, J. E.,Boer, C.,Rambert, F. A.,Duteil, J.(1994).Lack of pre-synaptic dopaminergic involvement in modafinil activity in anaesthetized mice: in vivo voltammetry studies.Neuropharmacology,33,755-761.
  10. Deroche-Gamonet, V.,Darnaudery, M.,Bruins-Slot, L.,Piat, F.,Le Moal, M.,Piazza, P. V.(2002).Study of the addictive potential of modafinil in naive and cocaine-experienced rats.Psychopharmacology (Berl),161,387-395.
  11. Duteil, J.,Rambert, F. A.,Pessonnier, J.,Hermant, J. F.,Gombert, R.,Assous, E.(1990).Central alpha 1-adrenergic stimulation in relation to the behaviour stimulating effect of modafinil; studies with experimental animals.Eur. J. Pharmacol.,180,49-58.
  12. Edgar, D. M.,Seidel, W. F.(1997).Modafinil induces wakefulness without intensifying motor activity or subsequent rebound hypersomnolence in the rat.J. Pharmacol. Exp. Ther.,283,757-769.
  13. Engber, T. M.,Dennis, S. A.,Jones, B. E.,Miller, M. S.,Contreras, P. C.(1998).Brain regional substrates for the actions of the novel wakepromoting agent modafinil in the rat: comparison with amphetamine.Neuroscience,87,905-911.
  14. Ferraro, L.,Tanganelli, S.,O''Connor, W. T.,Antonelli, T.,Rambert, F.,Fuxe, K.(1996).The vigilance promoting drug modafinil increases dopamine release in the rat nucleus accumbens via the involvement of a local GABAergic mechanism.Eur. J. Pharmacol.,306,33-39.
  15. Goeders, N. E.(2003).The impact of stress on addiction.Eur. Neuropsychopharmacol.,13,435-441.
  16. Jasinski, D. R.(2000).An evaluation of the abuse potential of modafinil using methylphenidate as a reference.J. Psychopharmacol.,14,53-60.
  17. Karila, L.,Gorelick, D.,Weinstein, A.,Noble, F.,Benyamina, A.,Coscas, S.,Blecha, L.,Lowenstein, W.,Martinot, J. L.,Reynaud, M.,Lepine, J. P.(2008).New treatments for cocaine dependence: a focused review.Int. J. Neuropsychopharmacol.,11,425-438.
  18. Kauer, J. A.,Malenka, R. C.(2007).Synaptic plasticity and addiction.Nat. Rev. Neurosci.,8,844-858.
  19. Kinon, B. J.,Merson, D.,Kane, J. M.(1984).Effect of daily dose of chronic haloperidol and chronic apomorphine on behavioral hypersensitivity in the rat.Psychopharmacology (Berl),84,347-351.
  20. Kruszewski, S. P.(2006).Euphorigenic and abusive properties of modafinil.Am. J. Psychiatry,163,549.
  21. Kumar, R.(2008).Approved and investigational uses of modafinil: an evidence-based review.Drugs,68,1803-1839.
  22. Laudrup, P.,Wallace, L. J.(1999).Sensitization elicited by directly and indirectly acting dopaminergic agonists: comparison using neural network analysis.Psychopharmacology (Berl),141,169-174.
  23. Mattingly, B. A.,Caudill, A.,Abel, M.(2001).Differential effects of 7-OH-DPAT on the development of behavioral sensitization to apomorphine and cocaine.Pharmacol. Biochem. Behav.,68,417-426.
  24. Mattingly, B. A.,Rowlett, J. K.(1989).Effects of repeated apomorphine and haloperidol treatments on subsequent behavioral sensitivity to apomorphine.Pharmacol. Biochem. Behav.,34,345-347.
  25. Mejias-Aponte, C. A.,Drouin, C.,Aston-Jones, G.(2009).Adrenergic and noradrenergic innervation of the midbrain ventral tegmental area and retrorubral field: prominent inputs from medullary homeostatic centers.J. Neurosci.,29,3613-3626.
  26. Mitchell, H. A.,Bogenpohl, J. W.,Liles, L. C.,Epstein, M. P.,Bozyczko-Coyne, D.,Williams, M.,Weinshenker, D.(2008).Behavioral responses of dopamine beta-hydroxylase knockout mice to modafinil suggest a dual noradrenergic-dopaminergic mechanism of action.Pharmacol. Biochem. Behav.,91,217-222.
  27. Murillo-Rodriguez, E.,Haro, R.,Palomero-Rivero, M.,Millan-Aldaco, D.,Drucker-Colin, R.(2007).Modafinil enhances extracellular levels of dopamine in the nucleus accumbens and increases wakefulness in rats.Behav. Brain Res.,176,353-357.
  28. Pierce, R. C.,Kalivas, P. W.(1997).A circuitry model of the expression of behavioral sensitization to amphetamine-like psychostimulants.Brain Res. Rev.,25,192-216.
  29. Randall, D. C.,Shneerson, J. M.,Plaha, K. K.,File, S. E.(2003).Modafinil affects mood, but not cognitive function, in healthy young volunteers.Hum. Psychopharmacol.,18,163-173.
  30. Rao, Y.,Liu, Z. W.,Borok, E.,Rabenstein, R. L.,Shanabrough, M.,Lu, M.,Picciotto, M. R.,Horvath, T. L.,Gao, X. B.(2007).Prolonged wakefulness induces experience-dependent synaptic plasticity in mouse hypocretin/orexin neurons.J. Clin. Invest.,117,4022-4033.
  31. Robinson, T. E.,Becker, J. B.(1986).Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis.Brain Res.,396,157-198.
  32. Robinson, T. E.,Berridge, K. C.(1993).The neural basis of drug craving: an incentive-sensitization theory of addiction.Brain Res. Rev.,18,247-291.
  33. Rush, C. R.,Kelly, T. H.,Hays, L. R.,Baker, R. W.,Wooten, A. F.(2002).Acute behavioral and physiological effects of modafinil in drug abusers.Behav. Pharmacol.,13,105-115.
  34. Scammell, T. E.,Estabrooke, I. V.,McCarthy, M. T.,Chemelli, R. M.,Yanagisawa, M.,Miller, M. S.,Saper, C. B.(2000).Hypothalamic arousal regions are activated during modafinil-induced wakefulness.J. Neurosci.,20,8620-8628.
  35. Shearer, J.(2008).The principles of agonist pharmacotherapy for psychostimulant dependence.Drug Alcohol Rev.,27,301-308.
  36. Simon, P.,Hemet, C.,Ramassamy, C.,Costentin, J.(1995).Nonamphetaminic mechanism of stimulant locomotor effect of modafinil in mice.Eur. Neuropsychopharmacol.,5,509-514.
  37. Stoops, W. W.,Lile, J. A.,Fillmore, M. T.,Glaser, P. E.,Rush, C. R.(2005).Reinforcing effects of modafinil: influence of dose and behavioral demands following drug administration.Psychopharmacology (Berl),182,186-193.
  38. Thomas, M. J.,Kalivas, P. W.,Shaham, Y.(2008).Neuroplasticity in the mesolimbic dopamine system and cocaine addiction.Br. J. Pharmacol.,154,327-342.
  39. Võikar, V.,Soosaar, A.,Volke, V.,Kõks, S.,Bourin, M.,Männistö, P. T.,Vasar, E.(1999).Apomorphine-induced behavioural sensitization in rats: individual differences, role of dopamine and NMDA receptors.Eur. Neuropsychopharmacol.,9,507-514.
  40. Volkow, N. D.,Fowler, J. S.,Logan, J.,Alexoff, D.,Zhu, W.,Telang, F.,Wang, G. J.,Jayne, M.,Hooker, J. M.,Wong, C.,Hubbard, B.,Carter, P.,Warner, D.,King, P.,Shea, C.,Xu, Y.,Muench, L.,Apelskog-Torres, K.(2009).Effects of modafinil on dopamine and dopamine transporters in the male human brain: clinical implications.J. Am. Med. Assoc.,301,1148-1154.
  41. Wisor, J. P.,Eriksson, K. S.(2005).Dopaminergic-adrenergic interactions in the wake promoting mechanism of modafinil.Neuroscience,132,1027-1034.
  42. Young, J. W.(2009).Dopamine D1 and D2 receptor family contributions to modafinil-induced wakefulness.J. Neurosci.,29,2663-2665.