, Volume 231, Issue 13, pp 2705–2716 | Cite as

Dissociable effects of the noncompetitive NMDA receptor antagonists ketamine and MK-801 on intracranial self-stimulation in rats

  • Todd M. Hillhouse
  • Joseph H. Porter
  • S. Stevens Negus
Original Investigation



The noncompetitive NMDA antagonist ketamine produces rapid antidepressant effects in treatment-resistant patients suffering from major depressive and bipolar disorders. However, abuse liability is a concern.


This study examined abuse-related effects of ketamine using intracranial self-stimulation (ICSS) in rats. The higher-affinity NMDA antagonist MK-801 and the monoamine reuptake inhibitor cocaine were examined for comparison.


Male Sprague Dawley rats were implanted with electrodes targeting the medial forebrain bundle and trained to respond to brain stimulation under a frequency–rate ICSS procedure. The first experiment compared the potency and time course of ketamine (3.2–10.0 mg/kg) and MK-801 (0.032–0.32 mg/kg). The second experiment examined effects of repeated dosing with ketamine (3.2–20.0 mg/kg/day) and acute cocaine (10.0 mg/kg).


Following acute administration, ketamine (3.2–10 mg/kg) produced only dose- and time-dependent depressions of ICSS and failed to produce an abuse-related facilitation of ICSS at any dose or pretreatment time. In contrast, MK-801 (0.032–0.32 mg/kg) produced a mixed profile of rate-increasing and rate-decreasing effects; ICSS facilitation was especially prominent at an intermediate dose of 0.18 mg/kg. Repeated dosing with ketamine produced dose-dependent tolerance to the rate-decreasing effects of ketamine (10.0 and 18.0 mg/kg) but failed to unmask expression of ICSS facilitation. Termination of ketamine treatment failed to produce withdrawal-associated decreases in ICSS. As reported previously, 10.0 mg/kg cocaine facilitated ICSS.


The dissociable effects of ketamine and MK-801 suggest differences in the pharmacology of these nominally similar NMDA antagonists. Failure of ketamine to facilitate ICSS contrasts with other evidence for the abuse liability of ketamine.


Ketamine MK-801 Intracranial self-stimulation Depression Bipolar Cocaine Rats 


  1. Altarifi AA, Negus SS (2011) Some determinants of morphine effects on intracranial self-stimulation in rats: dose, pretreatment time, repeated treatment, and rate dependence. Behav Pharmacol 22:663–673. doi:10.1097/FBP.0b013e32834aff54 PubMedCentralPubMedCrossRefGoogle Scholar
  2. Altarifi AA, Miller LL, Negus SS (2012) Role of μ-opioid receptor reserve and μ-agonist efficacy as determinants of the effects of μ-agonists on intracranial self-stimulation in rats. Behav Pharmacol 23:678–692PubMedCrossRefGoogle Scholar
  3. Altarifi AA, Rice KC, Negus SS (2013) Abuse-related effects of μ-opioid analgesics in an assay of intracranial self-stimulation in rats: modulation by chronic morphine exposure. Behav Pharmacol 24:459–470. doi:10.1097/FBP.0b013e328364c0bd PubMedCrossRefGoogle Scholar
  4. Ardayfio PA, Benvenga MJ, Chaney SF, Love PL, Catlow J, Swanson SP, Marek GJ (2008) The 5-hydroxytryptamine2a receptor antagonist R-(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl-4-piperidinemethanol (M100907) attenuates impulsivity after both drug-induced disruption (dizocilpine) and enhancement (antidepressant drugs) of differential-reinforcement-of-low-rate 72-s behavior in the rat. J Pharmacol Exp Ther 327:891–897PubMedCrossRefGoogle Scholar
  5. Bauer CT, Banks ML, Blough BE, Negus SS (2013a) Rate-dependent effects of monoamine releasers on intracranial self-stimulation in rats: implications for abuse liability assessment. Behav Pharmacol 24:448–458. doi:10.1097/FBP.0b013e328363d1a4 PubMedCentralPubMedCrossRefGoogle Scholar
  6. Bauer CT, Banks ML, Blough BE, Negus SS (2013b) Use of intracranial self-stimulation to evaluate abuse-related and abuse-limiting effects of monoamine releasers in rats. Br J Pharmacol 168:850–862. doi:10.1111/j.1476-5381.2012.02214.x PubMedCentralPubMedCrossRefGoogle Scholar
  7. Beardsley PM, Hayes BA, Balster RL (1990) The self-administration of MK-801 can depend upon drug-reinforcement history, and its discriminative stimulus properties are phencyclidine-like in rhesus monkeys. J Pharmacol Exp Ther 252:953–959PubMedGoogle Scholar
  8. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS et al (2000) Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 47:351–354PubMedCrossRefGoogle Scholar
  9. Bespalov A, Lebedev A, Panchenko G, Zvartau E (1999) Effects of abused drugs on thresholds and breaking points of intracranial self-stimulation in rats. Eur Neuropsychopharmacol 9:377–383PubMedCrossRefGoogle Scholar
  10. Bonano JS, Glennon RA, De Felice LJ, Banks ML, Negus SS (2013) Abuse-related and abuse-limiting effects of methcathinone and the synthetic “bath salts” cathinone analogs methylenedioxypyrovalerone (MDPV), methylone and mephedrone on intracranial self-stimulation in rats. Psychopharmacology. doi:10.1007/s00213-013-3223-5 PubMedGoogle Scholar
  11. Branch MN (1984) Rate dependency, behavioral mechanisms, and behavioral pharmacology. J Exp Anal Behav 42:511–522PubMedCentralPubMedCrossRefGoogle Scholar
  12. Bresink I, Danysz W, Parsons CG, Mutschler E (1995) Different binding affinities of NMDA receptor channel blockers in various brain regions—indication of NMDA receptor heterogeneity. Neuropharmacology 34:533–540PubMedCrossRefGoogle Scholar
  13. Broadbear J, Winger G, Woods J (2004) Self-administration of fentanyl, cocaine and ketamine: effects on the pituitary—adrenal axis in rhesus monkeys. Psychopharmacology (Berl) 176:398–406CrossRefGoogle Scholar
  14. Byrd LD (1982) Comparison of the behavioral effects of phencyclidine, ketamine, d-amphetamine and morphine in the squirrel monkey. J Pharmacol Exp Ther 220:139–144PubMedGoogle Scholar
  15. Carlezon WA Jr, Chartoff EH (2007) Intracranial self-stimulation (ICSS) in rodents to study the neurobiology of motivation. Nat Protoc 2:2987–2995PubMedCrossRefGoogle Scholar
  16. Carlezon WA Jr, Wise RA (1993) Morphine-induced potentiation of brain stimulation reward is enhanced by MK-801. Brain Res 620:339–342PubMedCrossRefGoogle Scholar
  17. Carlezon WA, Wise RA (1996) Rewarding actions of phencyclidine and related drugs in nucleus accumbens shell and frontal cortex. J Neurosci 16:3112–3122PubMedGoogle Scholar
  18. Corbett D (1989) Possible abuse potential of the NMDA antagonist MK-801. Behav Brain Res 34:239–246PubMedCrossRefGoogle Scholar
  19. de la Peña JBI, Lee HC, de la Peña IC, Woo TS, Yoon SY, Lee HL et al (2012) Rewarding and reinforcing effects of the NMDA receptor antagonist—benzodiazepine combination, Zoletil®: difference between acute and repeated exposure. Behav Brain Res 233:434–442. doi:10.1016/j.bbr.2012.05.038 PubMedCrossRefGoogle Scholar
  20. De Luca M, Badiani A (2011) Ketamine self-administration in the rat: evidence for a critical role of setting. Psychopharmacology (Berl) 214:549–556CrossRefGoogle Scholar
  21. De Vry J, Jentzsch KR (2003) Role of the NMDA receptor NR2B subunit in the discriminative stimulus effects of ketamine. Behav Pharmacol 14:229–235PubMedCrossRefGoogle Scholar
  22. Diazgranados N, Ibrahim L, Brutsche NE et al (2010) A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry 67:793–802PubMedCentralPubMedCrossRefGoogle Scholar
  23. Engin E, Treit D, Dickson CT (2009) Anxiolytic- and antidepressant-like properties of ketamine in behavioral and neurophysiological animal models. Neuroscience 161:359–369PubMedCrossRefGoogle Scholar
  24. French ED (1994) Phencyclidine and the midbrain dopamine system: electrophysiology and behavior. Neurotoxicol Teratol 16:355–362PubMedCrossRefGoogle Scholar
  25. Gilmour G, Pioli E, Dix S, Smith J, Conway M, Jones W, Loomis S, Mason R, Shahabi S, Tricklebank M (2009) Diverse and often opposite behavioural effects of NMDA receptor antagonists in rats: implications for “NMDA antagonist modelling” of schizophrenia. Psychopharmacology (Berl) 205:203–216CrossRefGoogle Scholar
  26. Grant KA, Colombo G, Grant J, Rogawski MA (1996) Dizocilpine-like discriminative stimulus effects of low-affinity uncompetitive NMDA antagonists. Neuropharmacology 35:1709–1719PubMedCrossRefGoogle Scholar
  27. Herberg LJ, Rose IC (1989) The effect of MK-801 and other antagonists of NMDA-type glutamate receptors on brain-stimulation reward. Psychopharmacology (Berl) 99:87–90CrossRefGoogle Scholar
  28. Hillhouse TM, Porter JH (2014) Ketamine, but not MK-801, produces antidepressant-like effects in rats responding on a differential-reinforcement-of-low-rate operant schedule. Behav Pharmacol 25:80–91. doi:10.1097/FBP.0000000000000014 PubMedCrossRefGoogle Scholar
  29. Hirota K, Hashimoto Y, Lambert DG (2002) Interaction of intravenous anesthetics with recombinant human M1-M3 muscarinic receptors expressed in Chinese hamster ovary cells. Anesth Analg 95:1607–1610PubMedCrossRefGoogle Scholar
  30. Institute of Laboratory Animal Resources (2011) Guide for the care and use of laboratory animals. 8th ed. Institute of Laboratory Animals Resources, Commission of Life Sciences, National Research Council, Washington DCGoogle Scholar
  31. Katsidoni V, Kastellakis A, Panagis G (2013) Biphasic effects of Δ9-tetrahydrocannabinol on brain stimulation reward and motor activity. Int J Neuropsychopharmacol 16:2273–2284PubMedCrossRefGoogle Scholar
  32. Kelleher RT, Morse WH (1968) Determinants of the specificity of behavioral effects of drugs. Ergeb Physiol 60:1–56PubMedGoogle Scholar
  33. Kenny PJ, Gasparini F, Markou A (2003) Group II metabotropic and α-Amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainate glutamate receptors regulate the deficit in brain reward function associated with nicotine withdrawal in rats. J Pharmacol Exp Ther 306:1068–1076PubMedCrossRefGoogle Scholar
  34. Killinger BA, Peet MM, Baker LE (2010) Salvinorin A fails to substitute for the discriminative stimulus effects of LSD or ketamine in Sprague–Dawley rats. Pharmacol Biochem Behav 96:260–265PubMedCrossRefGoogle Scholar
  35. Koek W, Woods JH, Winger GD (1988) MK-801, a proposed noncompetitive antagonist of excitatory amino acid neurotransmission, produces phencyclidine-like behavioral effects in pigeons, rats and rhesus monkeys. J Pharmacol Exp Ther 245:969–974PubMedGoogle Scholar
  36. Koike H, Iijima M, Chaki S (2011) Involvement of AMPA receptor in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression. Behav Brain Res 224:107–111PubMedCrossRefGoogle Scholar
  37. Kornetsky C, Esposito RU, McLean S, Jacobson JO (1979) Intracranial self-stimulation thresholds: a model for the hedonic effects of drugs of abuse. Arch Gen Psychiatry 36:289–292PubMedCrossRefGoogle Scholar
  38. Kwilasz AJ, Negus SS (2012) Dissociable effects of the cannabinoid receptor agonists Δ9-tetrahydrocannabinol and CP55940 on pain-stimulated versus pain-depressed behavior in rats. J Pharmacol Exp Ther 343:389–400. doi:10.1124/jpet.112.197780 PubMedCentralPubMedCrossRefGoogle Scholar
  39. Lepore M, Liu X, Savage V, Matalon D, Gardner EL (1996) Genetic differences in Δ9-tetrahydrocannabinol-induced facilitation of brain stimulation reward as measured by a rate-frequency curve-shift electrical brain stimulation paradigm in three different rat strains. Life Sci 58:365–372CrossRefGoogle Scholar
  40. Marquis KL, Moreton JE (1987) Animal models of intravenous phencyclinoid self-administration. Pharmacol Biochem Behav 27:385–389PubMedCrossRefGoogle Scholar
  41. McCambridge J, Winstock A, Hunt N, Mitcheson L (2007) 5-Year trends in use of hallucinogens and other adjunct drugs among UK dance drug users. Eur Addict Res 13:57–64PubMedCrossRefGoogle Scholar
  42. McMillan DE, Wright DW, Wenger GR (1992) Effects of phencyclidine-like drugs on responding under multiple fixed ratio, fixed interval schedules. Behav Pharmacol 3:143–147PubMedCrossRefGoogle Scholar
  43. Moreton JE, Meisch RA, Stark L, Thompson T (1977) Ketamine self-administration by the rhesus monkey. J Pharmacol Exp Ther 203:303–309PubMedGoogle Scholar
  44. Murrough JW, Perez AM, Pillemer S, Stern J, Parides MK, Aan Het Rot M et al (2012) Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry 74:250–256. doi:10.1016/j.biopsych.2012.06.022 PubMedCentralPubMedCrossRefGoogle Scholar
  45. Negus SS, Morrissey E, Rosenberg M, Cheng K, Rice K (2010) Effects of kappa opioids in an assay of pain-depressed intracranial self-stimulation in rats. Psychopharmacology (Berl) 210:149–159CrossRefGoogle Scholar
  46. Negus SS, O’Connell R, Morrissey E, Cheng K, Rice KC (2012a) Effects of peripherally restricted κ opioid receptor agonists on pain-related stimulation and depression of behavior in rats. J Pharmacol Exp Ther 340:501–509. doi:10.1124/jpet.111.186783 PubMedCentralPubMedCrossRefGoogle Scholar
  47. Negus SS, Rosenberg MB, Altarifi AA, O’Connell RH, Folk JE, Rice KC (2012b) Effects of the delta opioid receptor agonist SNC80 on pain-related depression of intracranial self-stimulation (ICSS) in rats. J Pain 13:317–327. doi:10.1016/j.jpain.2011.12.003 PubMedCentralPubMedCrossRefGoogle Scholar
  48. Nishimura M, Sato K, Okada T, Yoshiya I, Schloss P, Shimada S, Tohyama M (1998) Ketamine inhibits monoamine transporters expressed in human embryonic kidney 293 cells. Anesthesiology 88:768–774PubMedCrossRefGoogle Scholar
  49. Olds ME (1996) Dopaminergic basis for the facilitation of brain stimulation reward by the NMDA receptor antagonist, MK-801. Eur J Pharmacol 306:23–32PubMedCrossRefGoogle Scholar
  50. Overton D, Shen CF, Ke G, Gazdick L (1989) Discriminable effects of phencyclidine analogs evaluated by multiple drug (PCP versus other) discrimination training. Psychopharmacology (Berl) 97:514–520CrossRefGoogle Scholar
  51. Páleníček T, Fujáková M, Brunovský M, Balíková M, Horáček J, Gorman I et al (2011) Electroencephalographic spectral and coherence analysis of ketamine in rats: correlation with behavioral effects and pharmacokinetics. Neuropsychobiology 63:202–218PubMedCrossRefGoogle Scholar
  52. Pereira Do Carmo G, Stevenson GW, Carlezon WA, Negus SS (2009) Effects of pain- and analgesia-related manipulations on intracranial self-stimulation in rats: further studies on pain-depressed behavior. Pain 144:170–177PubMedCrossRefGoogle Scholar
  53. Réus GZ, Stringari RB, Ribeiro KF, Ferraro AK, Vitto MF, Cesconetto P, Souza CT, Quevedo J (2011) Ketamine plus imipramine treatment induces antidepressant-like behavior and increases CREB and BDNF protein levels and PKA and PKC phosphorylation in rat brain. Behav Brain Res 221:166–171PubMedCrossRefGoogle Scholar
  54. Rocha BA, Ward AS, Egilmez Y, Lytle DA, Emmett-Oglesby MW (1996) Tolerance to the discriminative stimulus and reinforcing effects of ketamine. Behav Pharmacol 7:160–168PubMedGoogle Scholar
  55. Rosenberg MB, Carroll FI, Negus SS (2013) Effects of monoamine reuptake inhibitors in assays of acute pain-stimulated and pain-depressed behavior in rats. J Pain 14:246–259. doi:10.1016/j.jpain.2012.11.006 PubMedCentralPubMedCrossRefGoogle Scholar
  56. Sanger DJ (1992) NMDA antagonists disrupt timing behaviour in rats. Behav Pharmacol 3:593–600PubMedGoogle Scholar
  57. Sanger DJ, Blackman DE (1976) Rate-dependent effects of drugs: a review of the literature. Pharmacol Biochem Behav 4:73–83PubMedCrossRefGoogle Scholar
  58. Seeman P, Ko F, Tallerico T (2005) Dopamine receptor contribution to the action of PCP, LSD and ketamine psychotomimetics. Mol Psychiatry 10:877–883PubMedCrossRefGoogle Scholar
  59. Shek DTL (2007) Tackling adolescent substance abuse in Hong Kong: where we should and should not go. Sci World J 7:2021–2030CrossRefGoogle Scholar
  60. Smith DJ, Bouchal RL, DeSanctis CA, Monroe PJ, Amedro JB, Perrotti JM, Crisp T (1987) Properties of the interaction between ketamine and opiate binding sites in vivo and in vitro. Neuropharmacology 26:1253–1260PubMedCrossRefGoogle Scholar
  61. Stephens DN, Cole BJ (1996) AMPA antagonists differ from NMDA antagonists in their effects on operant DRL and delayed matching to position tasks. Psychopharmacology (Berl) 126:249–259CrossRefGoogle Scholar
  62. Substance Abuse and Mental Health Services Administration (2013) Results from the 2012 National Survey on Drug Use and Health: summary of national findings, NSDUH Series H-46, HHS Publication No. (SMA) 13–4795. Rockville, MD: Substance Abuse and Mental Health Services AdministrationGoogle Scholar
  63. Sundstrom JM, Hall FS, Stellar JR, Waugh EJ (2002) Effects of isolation-rearing on intracranial self-stimulation reward of the lateral hypothalamus: baseline assessment and drug challenges. Life Sci 70:2799–2810PubMedCrossRefGoogle Scholar
  64. Suzuki T, Kato H, Aoki T, Tsuda M, Narita M, Misawa M (2000) Effects of the non-competitive NMDA receptor antagonist ketamine on morphine-induced place preference in mice. Life Sci 67:383–389PubMedCrossRefGoogle Scholar
  65. Vlachou S, Markou A (2011) Intracranial self-stimulation. In: Olmstead MC (ed) Animal models of drug addiction. Humana, Totowa, pp 3–56CrossRefGoogle Scholar
  66. Wegener N, Nagel J, Gross R, Chambon C, Greco S, Pietraszek M, Gravius A, Danysz W (2011) Evaluation of brain pharmacokinetics of (+)MK-801 in relation to behaviour. Neurosci Lett 503:68–72PubMedCrossRefGoogle Scholar
  67. Winstock AR, Mitcheson L, Gillatt DA, Cottrell AM (2012) The prevalence and natural history of urinary symptoms among recreational ketamine users. BJU Int 110:1762–1766PubMedCrossRefGoogle Scholar
  68. Wise RA (1996) Addictive drugs and brain stimulation reward. Annual Review of Neuroscience 19:319–340Google Scholar
  69. Wise RA, Bauco P, Carlezon WA, Trojniar W (1992) Self-stimulation and drug reward mechanisms. Ann N Y Acad Sci 654:192–198PubMedCrossRefGoogle Scholar
  70. Woolverton WL, Hecht GS, Agoston GE, Katz JL, Hauck Newman A (2001) Further studies of the reinforcing effects of benztropine analogs in rhesus monkeys. Psychopharmacology (Berl) 154:375–382CrossRefGoogle Scholar
  71. Young AM, Woods JH (1981) Maintenance of behavior by ketamine and related compounds in rhesus monkeys with different self-administration histories. J Pharmacol Exp Ther 218:720–727PubMedGoogle Scholar
  72. Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA et al (2006) A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63:856–864PubMedCrossRefGoogle Scholar
  73. Zarate CA Jr, Brutsche NE, Ibrahim L, Franco-Chaves J, Diazgranados N, Cravchik A et al (2012) Replication of ketamine’s antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry 71:939–946PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Todd M. Hillhouse
    • 1
  • Joseph H. Porter
    • 1
  • S. Stevens Negus
    • 2
  1. 1.Department of PsychologyVirginia Commonwealth UniversityRichmondUSA
  2. 2.Department of Pharmacology and ToxicologyVirginia Commonwealth UniversityRichmondUSA

Personalised recommendations