Skip to main content

Advertisement

SpringerLink
Log in

Effects of chemotherapeutic agents 5-fluorouracil and methotrexate alone and combined in a mouse model of learning and memory

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

Abstract

Rationale

The concern that adjuvant cancer chemotherapy agents cause cognitive impairment in a significant number of patients has been expressed by patients and healthcare providers, but clinical studies have yielded conflicting results to date.

Objective

We directly tested two commonly used chemotherapeutic agents in a mouse model of learning and memory.

Materials and methods

In the present study, mice were conditioned to respond for a liquid reinforcer (Ensure solution) in the presence of an audible tone on day 1 as a measure of acquisition and were then required to perform the same response on day 2 as a measure of retrieval and retention. Methotrexate and 5-fluorouracil were administered prior to the day 1 session.

Results

Methotrexate (1.0–32 mg/kg) alone failed to alter mean latency acquisition, retrieval, or reinforced response rates. Similar to scopolamine, a known amnesic in this assay, 5-fluorouracil (3-75 mg/kg) failed to alter response rates or acquisition latency on day 1 but significantly altered latency to retrieve a previously learned response on day 2. In combination, 3.2 mg/kg methotrexate plus 75 mg/kg 5-fluorouracil significantly increased day 1 and day 2 acquisition and retrieval latencies without altering response rates or motivation to respond as measured by progressive ratio responding.

Conclusion

Taken together, these data demonstrate that 5-fluorouracil causes increased latencies for retrieval of previously learned behavioral responses and that combination of chemotherapeutic agents may produce greater delays than either agent alone, including when neither agent alone does so.

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

Similar content being viewed by others

References

  • Ahles TA, Saykin AJ (2002) Breast cancer chemotherapy-related cognitive dysfunction. Clin Breast Cancer 3(Suppl 3):S84–S90

    PubMed  CAS  Google Scholar 

  • Ahles TA, Saykin AJ (2007) Candidate mechanisms for chemotherapy-induced cognitive changes. Nat Rev Cancer 7:192–201

    Article  PubMed  CAS  Google Scholar 

  • Albritton RL, Coen DM, Golan DE (2005) Principles of combination chemotherapy. In: Golan DE, Tashjian AH, Armstrong EJ et al (eds) Principles of pharmacology, the pathophysiologic basis of drug therapy. Lippincott Williams & Wilkins, Philadelphia, PA, pp 603–613

    Google Scholar 

  • Barrett JE, Vanover KE (2003) Assessment of learning and memory using the autoshaping of operant responding in mice. Current Protocols in Neuroscience. 8.5F.1–8.5F. Chapter 8

  • Brezden CB, Phillips KA, Abdolell M, Bunston T, Tannock IF (2000) Cognitive function in breast cancer patients receiving adjuvant chemotherapy. J Clin Oncol 18:2695–701

    PubMed  CAS  Google Scholar 

  • Chabner BA, Ratain MJ (2007) Clarification regarding “phase II trials published in 2002: a cross-specialty comparison showing significant design differences between oncology trials and other medical specialties” and the accompanying commentary, “phase II cancer trials: out of control?”. Clin Cancer Res 13:6540

    Article  PubMed  Google Scholar 

  • Coveney JR, Sparber SB (1982) Phencyclidine retards autoshaping at a dose which does not suppress the required response. Pharmacol Biochem Behav 16:937–942

    Article  PubMed  CAS  Google Scholar 

  • Davenport JW (1974) Combined autoshaping-operant (AO) training: CS-UCS interval in rats. Bulletin of the Psychomonic Society 3:383–385

    Google Scholar 

  • Davis L, Lindley C (2005) Neoplastic disorders and their treatment: general principles. In: Koda-Kimble MA, Young LY, Kradjan WA, Guglielmo BJ (eds) Applied therapeutics: the clinical use of drugs. Lippincott, Williams & Wilkins, Philadelphia, pp 88–124

    Google Scholar 

  • Dietrich J, Han R, Yang Y, Mayer-Proschel M, Noble M (2006) CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents in vitro and in vivo. J Biol 5:22.1–22.23

    Article  Google Scholar 

  • Donovan KA, Small BJ, Andrykowski MA, Schmitt FA, Munster P, Jacobsen PB (2005) Cognitive functioning after adjuvant chemotherapy and/or radiotherapy for early-stage breast carcinoma. Cancer 104:2499–507

    Article  PubMed  Google Scholar 

  • Gusella M, Crepaldi G, Barile C, Bononi A, Menon D, Toso S, Scapoli D, Stievano L, Ferrazzi E, Grigoletto F, Ferrari M, Padrini R (2006) Pharmacokinetic and demographic markers of 5-fluorouracil toxicity in 181 patients on adjuvant therapy for colorectal cancer. Ann Oncol 17:1656–1660

    Article  PubMed  CAS  Google Scholar 

  • Hermelink K, Untch M, Lux MP, Kreienberg R, Beck T, Bauerfeind I, Munzel K (2007) Cognitive function during neoadjuvant chemotherapy for breast cancer: results of a prospective, multicenter, longitudinal study. Cancer 109:1905–1913

    Article  PubMed  CAS  Google Scholar 

  • Hodos W (1961) Progressive ratio as a measure of reward strength. Science 134:943–944

    Article  PubMed  CAS  Google Scholar 

  • Hodos W, Kalman G (1963) Effects of increment size and reinforcer volume on progressive ratio performance. J Exp Anal Behav 6:387–392

    Article  PubMed  CAS  Google Scholar 

  • Inagaki M, Yoshikawa E, Matsuoka Y, Sugawara Y, Nakano T, Akechi T, Wada N, Imoto S, Murakami K, Uchitomi Y (2007) Smaller regional volumes of brain gray and white matter demonstrated in breast cancer survivors exposed to adjuvant chemotherapy. Cancer 109:146–156

    Article  PubMed  Google Scholar 

  • Jenkins VA, Bloomfield DJ, Shilling VM, Edginton TL (2005) Does neoadjuvant hormone therapy for early prostate cancer affect cognition? Results from a pilot study. BJU Int 96:48–53

    Article  PubMed  CAS  Google Scholar 

  • Jin Y, Li J, Rong LF, Lu XW, Huang Y, Xu SY (2005) Pharmacokinetics and tissue distribution of 5-fluorouracil encapsulated by galactosylceramide liposomes in mice. Acta Pharmacol Sin 26:250–256

    Article  PubMed  CAS  Google Scholar 

  • Kennett GA, Curzon G (1988) Evidence that hypophagia induced by mCPP and TFMPP requires 5-HT1C and 5-HT1B receptors; hypophagia induced by RU 24969 only requires 5-HT1B receptors. Psychopharmacology (Berl) 96:93–100

    Article  CAS  Google Scholar 

  • Kennett GA, Wood MD, Bright F, Cilia J, Piper DC, Gager T, Thomas D, Baxter GS, Forbes IT, Ham P, Blackburn TP (1996) In vitro and in vivo profile of SB 206553, a potent 5-HT2C/5-HT2B receptor antagonist with anxiolytic-like properties. Br J Pharmacol 117:427–434

    PubMed  CAS  Google Scholar 

  • Kingma A, van Dommelen RI, Mooyaart EL, Wilmink JT, Deelman BG, Kamps WA (2001) Slight cognitive impairment and magnetic resonance imaging abnormalities but normal school levels in children treated for acute lymphoblastic leukemia with chemotherapy only. J Pediatr 139:413–420

    Article  PubMed  CAS  Google Scholar 

  • Kralovanszky J, Katona C, Jeney A, Pandi E, Noordhuis P, Erdelyi-Toth V, Otvos L, Kovacs P, Van der Wilt CL, Peters GJ (1999) 5-Ethyl-2′-deoxyuridine, a modulator of both antitumour action and pharmacokinetics of 5-fluorouracil. J Cancer Res Clin Oncol 125:675–684

    Article  PubMed  CAS  Google Scholar 

  • Lee GD, Longo DL, Wang Y, Rifkind JM, Abdul-Raman L, Mamczarz JA, Duffy KB, Spangler EL, Taub DD, Mattson MP, Ingram DK (2006) Transient improvement in cognitive function and synaptic plasticity in rats following cancer chemotherapy. Clin Cancer Res 12:198–205

    Article  PubMed  CAS  Google Scholar 

  • Liy-Salmeron G, Meneses A (2007) Role of 5-HT1-7 receptors in short- and long-term memory for an autoshaping task: intrahippocampal manipulations. Brain Res 1147:140–147

    Article  PubMed  CAS  Google Scholar 

  • Lobo ED, Balthasar JP (2003) Pharmacokinetic-pharmacodynamic modeling of methotrexate-induced toxicity in mice. J Pharm Sci 92:1654–1664

    Article  PubMed  CAS  Google Scholar 

  • Macleod JE, DeLeo JA, Hickey WF, Ahles TA, Saykin AJ, Bucci DJ (2007) Cancer chemotherapy impairs contextual but not cue-specific fear memory. Behav Brain Res 181:168–172

    Article  PubMed  CAS  Google Scholar 

  • Madhyastha S, Somayaji SN, Rao MS, Nalini K, Bairy KL (2002) Hippocampal brain amines in methotrexate-induced learning and memory deficit. Can J Physiol Pharmacol 80:1076–1084

    Article  PubMed  CAS  Google Scholar 

  • Mayer LD, Janoff AS (2007) Optimizing combination chemotherapy by controlling drug ratios. Mol Interv 7:216–223

    Article  PubMed  CAS  Google Scholar 

  • Mignone RG, Weber ET (2006) Potent inhibition of cell proliferation in the hippocampal dentate gyrus of mice by the chemotherapeutic drug thioTEPA. Brain Res 1111:26–29

    Article  PubMed  CAS  Google Scholar 

  • Mullenix PJ, Kernan WJ, Schunior A, Howes A, Waber DP, Sallan SE, Tarbell NJ (1994) Interactions of steroid, methotrexate, and radiation determine neurotoxicity in an animal model to study therapy for childhood leukemia. Pediatr Res 35:171–178

    Article  PubMed  CAS  Google Scholar 

  • Mundy WR, Iwamoto ET (1987) Studies on desglycinamide arginine vasopressin and scopolamine in a modified/lever-touch autoshaping model of learning/memory in rats. Pharmacol Biochem Behav 27:307–315

    Article  PubMed  CAS  Google Scholar 

  • Ohdo S, Inoue K, Yukawa E, Higuchi S, Nakano S, Ogawa N (1997) Chronotoxicity of methotrexate in mice and its relation to circadian rhythm of DNA synthesis and pharmacokinetics. Jpn J Pharmacol 75:283–290

    Article  PubMed  CAS  Google Scholar 

  • Ooi A, Ohkubo T, Higashigawa M, Kawasaki H, Kakito H, Kagawa Y, Kojima M, Sakurai M (2001) Plasma, intestine and tumor levels of 5-fluorouracil in mice bearing L1210 ascites tumor following oral administration of 5-fluorouracil, UFT (mixed compound of tegafur and uracil), carmofur and 5′-deoxy-5-fluorouridine. Biol Pharm Bull 24:1329–1331

    Article  PubMed  CAS  Google Scholar 

  • O’Shaughnessy JA (2002) Effects of epoetin alfa on cognitive function, mood, asthenia, and quality of life in women with breast cancer undergoing adjuvant chemotherapy. Clin Breast Cancer 3(Suppl 3):S116–S120

    Article  PubMed  CAS  Google Scholar 

  • Peters GJ, Schornagel JH, Milano GA (1993) Clinical pharmacokinetics of anti-metabolites. Cancer Surv 17:123–156

    PubMed  CAS  Google Scholar 

  • Reiriz AB, Reolon GK, Preissler T, Rosado JO, Henriques JA, Roesler R, Schwartsmann G (2006) Cancer chemotherapy and cognitive function in rodent models: memory impairment induced by cyclophosphamide in mice. Clin Cancer Res 12:5000; author reply 5000-1

    Article  PubMed  CAS  Google Scholar 

  • Richardson NR, Roberts DC (1996) Progressive ratio schedules in drug self-administration studies in rats: a method to evaluate reinforcing efficacy. J Neurosci Methods 66:1–11

    Article  PubMed  CAS  Google Scholar 

  • Richmond MA, Nichols BP, Deacon RM, Rawlins JN (1997) Effects of scopolamine and hippocampal lesions on negative patterning discrimination performance in rats. Behav Neurosci 111:1217–1227

    Article  PubMed  CAS  Google Scholar 

  • Saykin AJ, Wishart HA (2003) Mild cognitive impairment: conceptual issues and structural and functional brain correlates. Semin Clin Neuropsychiatry 8:12–30

    Article  PubMed  Google Scholar 

  • Saykin AJ, Wishart HA, Rabin LA, Santulli RB, Flashman LA, West JD, McHugh TL, Mamourian AC (2006) Older adults with cognitive complaints show brain atrophy similar to that of amnestic MCI. Neurology 67:834–842

    Article  PubMed  CAS  Google Scholar 

  • Schagen SB, van Dam FS, Muller MJ, Boogerd W, Lindeboom J, Bruning PF (1999) Cognitive deficits after postoperative adjuvant chemotherapy for breast carcinoma. Cancer 85:640–650

    Article  PubMed  CAS  Google Scholar 

  • Schagen SB, Hamburger HL, Muller MJ, Boogerd W, van Dam FS (2001) Neurophysiological evaluation of late effects of adjuvant high-dose chemotherapy on cognitive function. J Neurooncol 51:159–165

    Article  PubMed  CAS  Google Scholar 

  • Schagen SB, Muller MJ, Boogerd W, Rosenbrand RM, van Rhijn D, Rodenhuis S, van Dam FS (2002a) Late effects of adjuvant chemotherapy on cognitive function: a follow-up study in breast cancer patients. Ann Oncol 13:1387–1397

    Article  PubMed  CAS  Google Scholar 

  • Schagen SB, Muller MJ, Boogerd W, Van Dam FS (2002b) Cognitive dysfunction and chemotherapy: neuropsychological findings in perspective. Clin Breast Cancer 3(Suppl 3):S100–S108

    PubMed  Google Scholar 

  • Schagen SB, Muller MJ, Boogerd W, Mellenbergh GJ, van Dam FS (2006) Change in cognitive function after chemotherapy: a prospective longitudinal study in breast cancer patients. J Natl Cancer Inst 98:1742–1745

    Article  PubMed  CAS  Google Scholar 

  • Seigers R, Schagen SB, Beerling W, Boogerd W, van Tellingen O, van Dam FS, Koolhaas JM, Buwalda B (2008) Long-lasting suppression of hippocampal cell proliferation and impaired cognitive performance by methotrexate in the rat. Behav Brain Res 186:168–175

    Article  PubMed  CAS  Google Scholar 

  • Shannon HE, Eberle EL (2006) Effects of biasing the location of stimulus presentation, and the muscarinic cholinergic receptor antagonist scopolamine, on performance of a 5-choice serial reaction time attention task in rats. Behav Pharmacol 17:71–85

    Article  PubMed  CAS  Google Scholar 

  • Silberfarb PM, Philibert D, Levine PM (1980) Psychosocial aspects of neoplastic disease: II. Affective and cognitive effects of chemotherapy in cancer patients. Am J Psychiatry 137:597–601

    PubMed  CAS  Google Scholar 

  • Silverman DH, Dy CJ, Castellon SA, Lai J, Pio BS, Abraham L, Waddell K, Petersen L, Phelps ME, Ganz PA (2007) Altered frontocortical, cerebellar, and basal ganglia activity in adjuvant-treated breast cancer survivors 5–10 years after chemotherapy. Breast Cancer Res Treat 103:303–311

    Article  PubMed  CAS  Google Scholar 

  • Stafford D, LeSage MG, Glowa JR (1998) Progressive-ratio schedules of drug delivery in the analysis of drug self-administration: a review. Psychopharmacology (Berl) 139:169–184

    Article  CAS  Google Scholar 

  • Stemmer SM, Stears JC, Burton BS, Jones RB, Simon JH (1994) White matter changes in patients with breast cancer treated with high-dose chemotherapy and autologous bone marrow support. AJNR Am J Neuroradiol 15:1267–1273

    PubMed  CAS  Google Scholar 

  • Stock HS, Rosellini RA, Abrahamsen GC, McCaffrey RJ, Ruckdeschel JC (1995) Methotrexate does not interfere with an appetitive Pavlovian conditioning task in Sprague–Dawley rats. Physiol Behav 58:969–973

    Article  PubMed  CAS  Google Scholar 

  • Tchen N, Juffs HG, Downie FP, Yi QL, Hu H, Chemerynsky I, Clemons M, Crump M, Goss PE, Warr D, Tweedale ME, Tannock IF (2003) Cognitive function, fatigue, and menopausal symptoms in women receiving adjuvant chemotherapy for breast cancer. J Clin Oncol 21:4175–4183

    Article  PubMed  Google Scholar 

  • van Dam FS, Schagen SB, Muller MJ, Boogerd W, vd Wall E, Droogleever Fortuyn ME, Rodenhuis S (1998) Impairment of cognitive function in women receiving adjuvant treatment for high-risk breast cancer: high-dose versus standard-dose chemotherapy. J Natl Cancer Inst 90:210–218

    Article  PubMed  Google Scholar 

  • Vanover KE, Barrett JE (1998) An automated learning and memory model in mice: pharmacological and behavioral evaluation of an autoshaped response. Behav Pharmacol 9:273–283

    PubMed  CAS  Google Scholar 

  • Ward SJ, Lefever TW, Jackson C, Tallarida RJ, Walker EA (2008) Effects of a CB1 receptor antagonist and 5-HT2C receptor agonist alone and in combination on motivation for palatable food: a dose-addition analysis study in mice. J Pharmacol Exp Ther 325:567–576

    Article  PubMed  CAS  Google Scholar 

  • Wieneke MH, Dienst ER (1995) Neuropsychological assessment of cognitive functioning following chemotherapy for breast cancer. Psychooncology 4:61–66

    Article  Google Scholar 

  • Winocur G, Vardy J, Binns MA, Kerr L, Tannock I (2006) The effects of the anti-cancer drugs, methotrexate and 5-fluorouracil, on cognitive function in mice. Pharmacol Biochem Behav 85:66–75

    Article  PubMed  CAS  Google Scholar 

  • Yanovski JA, Packer RJ, Levine JD, Davidson TL, Micalizzi M, D’Angio G (1989) An animal model to detect the neuropsychological toxicity of anticancer agents. Med Pediatr Oncol 17:216–221

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to acknowledge Timothy Lefever for his technical assistance and Drs. Swati Nagar, Ronald J. Tallarida, and Rachel Clark-Vetri for their discussions and assistance with dose scaling.

Conflict of interest statement

The authors have no conflicts of interest to disclose.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Temple University School of Pharmacy, 3307 North Broad Street, Philadelphia, PA, 19140, USA

    John J. Foley, Robert B. Raffa & Ellen A. Walker

Authors
  1. John J. Foley
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert B. Raffa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ellen A. Walker
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ellen A. Walker.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Foley, J.J., Raffa, R.B. & Walker, E.A. Effects of chemotherapeutic agents 5-fluorouracil and methotrexate alone and combined in a mouse model of learning and memory. Psychopharmacology 199, 527–538 (2008). https://doi.org/10.1007/s00213-008-1175-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-008-1175-y

Keywords

Search

Navigation