Skip to main content
SpringerLink
Log in

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

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

Abstract

Rationale

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.

Objectives

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.

Methods

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).

Results

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.

Conclusions

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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 23:678–692

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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 327:891–897

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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 252:953–959

    CAS  PubMed  Google Scholar 

  • Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS et al (2000) Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 47:351–354

    Article  CAS  PubMed  Google Scholar 

  • 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 9:377–383

    Article  CAS  PubMed  Google Scholar 

  • 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

    PubMed  Google Scholar 

  • Branch MN (1984) Rate dependency, behavioral mechanisms, and behavioral pharmacology. J Exp Anal Behav 42:511–522

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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 34:533–540

    Article  CAS  PubMed  Google Scholar 

  • 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) 176:398–406

    Article  CAS  Google Scholar 

  • Byrd LD (1982) Comparison of the behavioral effects of phencyclidine, ketamine, d-amphetamine and morphine in the squirrel monkey. J Pharmacol Exp Ther 220:139–144

    CAS  PubMed  Google Scholar 

  • Carlezon WA Jr, Chartoff EH (2007) Intracranial self-stimulation (ICSS) in rodents to study the neurobiology of motivation. Nat Protoc 2:2987–2995

    Article  CAS  PubMed  Google Scholar 

  • Carlezon WA Jr, Wise RA (1993) Morphine-induced potentiation of brain stimulation reward is enhanced by MK-801. Brain Res 620:339–342

    Article  PubMed  Google Scholar 

  • Carlezon WA, Wise RA (1996) Rewarding actions of phencyclidine and related drugs in nucleus accumbens shell and frontal cortex. J Neurosci 16:3112–3122

    CAS  PubMed  Google Scholar 

  • Corbett D (1989) Possible abuse potential of the NMDA antagonist MK-801. Behav Brain Res 34:239–246

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • De Luca M, Badiani A (2011) Ketamine self-administration in the rat: evidence for a critical role of setting. Psychopharmacology (Berl) 214:549–556

    Article  Google Scholar 

  • De Vry J, Jentzsch KR (2003) Role of the NMDA receptor NR2B subunit in the discriminative stimulus effects of ketamine. Behav Pharmacol 14:229–235

    Article  PubMed  Google Scholar 

  • 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 67:793–802

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Engin E, Treit D, Dickson CT (2009) Anxiolytic- and antidepressant-like properties of ketamine in behavioral and neurophysiological animal models. Neuroscience 161:359–369

    Article  CAS  PubMed  Google Scholar 

  • French ED (1994) Phencyclidine and the midbrain dopamine system: electrophysiology and behavior. Neurotoxicol Teratol 16:355–362

    Article  CAS  PubMed  Google Scholar 

  • 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) 205:203–216

    Article  CAS  Google Scholar 

  • Grant KA, Colombo G, Grant J, Rogawski MA (1996) Dizocilpine-like discriminative stimulus effects of low-affinity uncompetitive NMDA antagonists. Neuropharmacology 35:1709–1719

    Article  CAS  PubMed  Google Scholar 

  • Herberg LJ, Rose IC (1989) The effect of MK-801 and other antagonists of NMDA-type glutamate receptors on brain-stimulation reward. Psychopharmacology (Berl) 99:87–90

    Article  CAS  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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 95:1607–1610

    Article  CAS  PubMed  Google Scholar 

  • 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 DC

  • Katsidoni V, Kastellakis A, Panagis G (2013) Biphasic effects of Δ9-tetrahydrocannabinol on brain stimulation reward and motor activity. Int J Neuropsychopharmacol 16:2273–2284

    Article  CAS  PubMed  Google Scholar 

  • Kelleher RT, Morse WH (1968) Determinants of the specificity of behavioral effects of drugs. Ergeb Physiol 60:1–56

    CAS  PubMed  Google Scholar 

  • 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 306:1068–1076

    Article  CAS  PubMed  Google Scholar 

  • 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 96:260–265

    Article  CAS  PubMed  Google Scholar 

  • 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 245:969–974

    CAS  PubMed  Google Scholar 

  • 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 224:107–111

    Article  CAS  PubMed  Google Scholar 

  • 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 36:289–292

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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 58:365–372

    Article  Google Scholar 

  • Marquis KL, Moreton JE (1987) Animal models of intravenous phencyclinoid self-administration. Pharmacol Biochem Behav 27:385–389

    Article  CAS  PubMed  Google Scholar 

  • 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 13:57–64

    Article  PubMed  Google Scholar 

  • McMillan DE, Wright DW, Wenger GR (1992) Effects of phencyclidine-like drugs on responding under multiple fixed ratio, fixed interval schedules. Behav Pharmacol 3:143–147

    Article  CAS  PubMed  Google Scholar 

  • Moreton JE, Meisch RA, Stark L, Thompson T (1977) Ketamine self-administration by the rhesus monkey. J Pharmacol Exp Ther 203:303–309

    CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed Central  PubMed  Google Scholar 

  • 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) 210:149–159

    Article  CAS  Google Scholar 

  • 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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 88:768–774

    Article  CAS  PubMed  Google Scholar 

  • Olds ME (1996) Dopaminergic basis for the facilitation of brain stimulation reward by the NMDA receptor antagonist, MK-801. Eur J Pharmacol 306:23–32

    Article  CAS  PubMed  Google Scholar 

  • 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) 97:514–520

    Article  CAS  Google Scholar 

  • 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 63:202–218

    Article  PubMed  Google Scholar 

  • 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 144:170–177

    Article  PubMed  Google Scholar 

  • 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 221:166–171

    Article  PubMed  Google Scholar 

  • Rocha BA, Ward AS, Egilmez Y, Lytle DA, Emmett-Oglesby MW (1996) Tolerance to the discriminative stimulus and reinforcing effects of ketamine. Behav Pharmacol 7:160–168

    CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sanger DJ (1992) NMDA antagonists disrupt timing behaviour in rats. Behav Pharmacol 3:593–600

    CAS  PubMed  Google Scholar 

  • Sanger DJ, Blackman DE (1976) Rate-dependent effects of drugs: a review of the literature. Pharmacol Biochem Behav 4:73–83

    Article  CAS  PubMed  Google Scholar 

  • Seeman P, Ko F, Tallerico T (2005) Dopamine receptor contribution to the action of PCP, LSD and ketamine psychotomimetics. Mol Psychiatry 10:877–883

    Article  CAS  PubMed  Google Scholar 

  • Shek DTL (2007) Tackling adolescent substance abuse in Hong Kong: where we should and should not go. Sci World J 7:2021–2030

    Article  Google Scholar 

  • 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 26:1253–1260

    Article  CAS  PubMed  Google Scholar 

  • 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) 126:249–259

    Article  CAS  Google Scholar 

  • 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 Administration

  • 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 70:2799–2810

    Article  CAS  PubMed  Google Scholar 

  • 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 67:383–389

    Article  CAS  PubMed  Google Scholar 

  • Vlachou S, Markou A (2011) Intracranial self-stimulation. In: Olmstead MC (ed) Animal models of drug addiction. Humana, Totowa, pp 3–56

    Chapter  Google Scholar 

  • 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 503:68–72

    Article  CAS  PubMed  Google Scholar 

  • Winstock AR, Mitcheson L, Gillatt DA, Cottrell AM (2012) The prevalence and natural history of urinary symptoms among recreational ketamine users. BJU Int 110:1762–1766

    Article  PubMed  Google Scholar 

  • Wise RA (1996) Addictive drugs and brain stimulation reward. Annual Review of Neuroscience 19:319–340

    Google Scholar 

  • Wise RA, Bauco P, Carlezon WA, Trojniar W (1992) Self-stimulation and drug reward mechanisms. Ann N Y Acad Sci 654:192–198

    Article  CAS  PubMed  Google Scholar 

  • 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) 154:375–382

    Article  CAS  Google Scholar 

  • 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 218:720–727

    CAS  PubMed  Google Scholar 

  • 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 63:856–864

    Article  CAS  PubMed  Google Scholar 

  • 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 71:939–946

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgement

This research was supported by NIH grant R01 NS070715.

Conflict of interest

None declared.

Author information

Authors and Affiliations

  1. Department of Psychology, Virginia Commonwealth University, PO Box 842018, 806 West Franklin Street, Richmond, 23284, VA, USA

    Todd M. Hillhouse & Joseph H. Porter

  2. Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, PO Box 980613, Richmond, VA 23298, USA

    S. Stevens Negus

Authors
  1. Todd M. Hillhouse
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joseph H. Porter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. Stevens Negus
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S. Stevens Negus.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hillhouse, T.M., Porter, J.H. & Negus, S.S. Dissociable effects of the noncompetitive NMDA receptor antagonists ketamine and MK-801 on intracranial self-stimulation in rats. Psychopharmacology 231, 2705–2716 (2014). https://doi.org/10.1007/s00213-014-3451-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-014-3451-3

Keywords

Search

Navigation