Hostname: page-component-78c5997874-8bhkd Total loading time: 0 Render date: 2024-10-31T22:57:27.041Z Has data issue: false hasContentIssue false

Establishing an effective dose for chronic intracerebroventricular administration of clozapine in mice

Published online by Cambridge University Press:  19 August 2019

Dilhan Esen-Sehir
Affiliation:
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University Frankfurt, Frankfurt, Germany The Faculty of Biological Sciences, Goethe University Frankfurt, Frankfurt, Germany
Michael J. Courtney
Affiliation:
Neuronal Signalling Laboratory, Turku Centre for Biotechnology, University of Turku, Turku, Finland
Robert A. Bittner
Affiliation:
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University Frankfurt, Frankfurt, Germany
Andreas Reif
Affiliation:
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University Frankfurt, Frankfurt, Germany
Florian Freudenberg*
Affiliation:
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University Frankfurt, Frankfurt, Germany
*
Author for correspondence: Florian Freudenberg, Email: Florian.Freudenberg@kgu.de

Abstract

Objective:

Despite its numerous side effects, clozapine is still the most effective antipsychotics making it an ideal reference substance to validate the efficacy of novel compounds for the treatment of schizophrenia. However, blood–brain barrier permeability for most new molecular entities is unknown, requiring central delivery. Thus, we performed a dose-finding study for chronic intracerebroventricular (icv) delivery of clozapine in mice.

Methods:

Specifically, we implanted wild-type C57BL/6J mice with osmotic minipumps (Alzet) delivering clozapine at a rate of 0.15 µl/h at different concentrations (0, 3.5, 7 and 14 mg/ml, i.e. 0, 12.5, 25 and 50 µg/day). Mice were tested weekly in a modified SHIRPA paradigm, for locomotor activity in the open field and for prepulse inhibition (PPI) of the acoustic startle response (ASR) for a period of 3 weeks.

Results:

None of the clozapine concentrations caused neurological deficits or evident gross behavioural alterations in the SHIRPA paradigm. In male mice, clozapine had no significant effect on locomotor activity or PPI of the ASR. In female mice, the 7 and 14 mg/ml dose of clozapine significantly affected both open field activity and PPI, while 3.5 mg/ml of clozapine increased PPI but had no effects on locomotor activity.

Conclusion:

Our findings indicate that 7 mg/ml may be the optimal dose for chronic icv delivery of clozapine in mice, allowing comparison to screen for novel antipsychotic compounds.

Type
Original Article
Copyright
© Scandinavian College of Neuropsychopharmacology 2019 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Abrams, DJ, Zheng, L, Choo, KS, Yang, JJ, Wei, W, Anchordoquy, TJ, Zawia, NH, Stevens, KE (2008) An initial animal proof-of-concept study for central administration of clozapine to schizophrenia patients. Schizophrenia Research 100(1–3), 8696.CrossRefGoogle ScholarPubMed
Anderson, SG, Livingston, M, Couchman, L, Smith, DJ, Connolly, M, Miller, J, Flanagan, RJ, Heald, AH (2015) Sex differences in plasma clozapine and norclozapine concentrations in clinical practice and in relation to body mass index and plasma glucose concentrations: a retrospective survey. Annals of General Psychiatry 14(1), 39.CrossRefGoogle ScholarPubMed
Andreasen, NC (2000) Schizophrenia: the fundamental questions. Brain Research Reviews 31(2–3), 106112.CrossRefGoogle ScholarPubMed
Bailey, KR and Crawley, JN (2009) Anxiety-related behaviors in mice. In Buccafusco, JJ (ed), Methods of Behavior Analysis in Neuroscience. Boca Raton, FL: CRC Press/Taylor & Francis.Google ScholarPubMed
Bishop, KM and Wahlsten, D (1999) Sex and species differences in mouse and rat forebrain commissures depend on the method of adjusting for brain size. Brain Research 815(2), 358366.CrossRefGoogle ScholarPubMed
Braff, DL, Geyer, MA and Swerdlow, NR (2001) Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies. Psychopharmacology (Berl) 156(2–3), 234258.CrossRefGoogle ScholarPubMed
Brambilla, P, Barale, F, Caverzasi, E, Tognoni, G and Barbui, C (2002) Clozapine-treated subjects with treatment-resistant schizophrenia: a systematic review of experimental and observational studies. International Clinical Psychopharmacology 17(4), 189195.CrossRefGoogle ScholarPubMed
Brown, AS and Meyer, U (2018) Maternal immune activation and neuropsychiatric illness: a translational research perspective. The American Journal of Psychiatry 175(11), 10731083.CrossRefGoogle ScholarPubMed
Bruhwyler, J, Chleide, E, Liégeois, JF, Delarge, J and Mercier, M (1990) Anxiolytic potential of sulpiride, clozapine and derivatives in the open-field test. Pharmacology Biochemistry and Behavior 36(1), 5761.CrossRefGoogle ScholarPubMed
Buckley, PF, Miller, BJ, Lehrer, DS and Castle, DJ (2009) Psychiatric comorbidities and schizophrenia. Schizophrenia Bulletin 35(2), 383402.CrossRefGoogle Scholar
Carpenter, WT and Koenig, JI (2008) The evolution of drug development in schizophrenia: past issues and future opportunities. Neuropsychopharmacology 33, NIH Public Access, 20612079.CrossRefGoogle ScholarPubMed
Duncan, GE, Moy, SS, Lieberman, JA and Koller, BH (2006) Effects of haloperidol, clozapine, and quetiapine on sensorimotor gating in a genetic model of reduced NMDA receptor function. Psychopharmacology (Berl) 184(2), 190200.CrossRefGoogle Scholar
Englisch, S, Inta, D, Eer, A and Zink, M (2010) Bupropion for depression in schizophrenia. Clinical Neuropharmacology 33(5), 257259.CrossRefGoogle Scholar
Feifel, D, Shilling, PD and Melendez, G (2011) Clozapine and PD149163 elevate prepulse inhibition in Brown Norway rats. Behavioral Neuroscience 125(2), 268272.CrossRefGoogle ScholarPubMed
Fellner, C (2017) New schizophrenia treatments address unmet clinical needs. Physical Therapy 42(2), 130134.Google ScholarPubMed
Freudenberg, F, Alttoa, A and Reif, A (2015) Neuronal nitric oxide synthase (NOS1) and its adaptor, NOS1AP, as a genetic risk factors for psychiatric disorders. Genes, Brain and Behavior 14(1), 4663.CrossRefGoogle ScholarPubMed
Freudenberg, F, O’Leary, A, Aguiar, DC and Slattery, DA (2018) Challenges with modelling anxiety disorders: a possible hindrance for drug discovery. Expert Opinion on Drug Discovery 13(4), 279281.CrossRefGoogle ScholarPubMed
Geyer, MA and Swerdlow, NR (2001) Measurement of startle response, prepulse inhibition, and habituation. Current Protocols in Neuroscience 3(1), 8.7.18.7.15.CrossRefGoogle Scholar
Gogos, A, Kwek, P and van den Buuse, M (2012) The role of estrogen and testosterone in female rats in behavioral models of relevance to schizophrenia. Psychopharmacology (Berl) 219(1), 213224.CrossRefGoogle Scholar
Gogos, A, van den Buuse, M and Rossell, S (2009) Gender differences in prepulse inhibition (PPI) in bipolar disorder: men have reduced PPI, women have increased PPI. The International Journal of Neuropsychopharmacology 12(9), 1249.CrossRefGoogle ScholarPubMed
Gray, L, van den Buuse, M, Scarr, E, Dean, B and Hannan, AJ (2009) Clozapine reverses schizophrenia-related behaviours in the metabotropic glutamate receptor 5 knockout mouse: association with N-methyl-d-aspartic acid receptor up-regulation. The International Journal of Neuropsychopharmacology 12(1), 45.CrossRefGoogle ScholarPubMed
Gururajan, A, Taylor, DA and Malone, DT (2012) Cannabidiol and clozapine reverse MK-801-induced deficits in social interaction and hyperactivity in Sprague–Dawley rats. Journal of Psychopharmacology 26(10), 13171332.CrossRefGoogle ScholarPubMed
Gururajan, A, Taylor, DA and Malone, DT (2011) Effect of cannabidiol in a MK-801-rodent model of aspects of Schizophrenia. Behavioural Brain Research 222(2), 299308.CrossRefGoogle Scholar
Hashimoto, K (2014) Targeting of NMDA receptors in new treatments for schizophrenia. Expert Opinion on Therapeutic Targets 18(9), 10491063.CrossRefGoogle Scholar
He, Q, Liu, J, Liang, J, Liu, X, Li, W, Liu, Z, Ding, Z, Tuo, D (2018) Towards improvements for penetrating the blood–brain barrier—recent progress from a material and pharmaceutical perspective. Cells 7(4).CrossRefGoogle Scholar
Horacek, J, Bubenikova-Valesova, V, Kopecek, M, Palenicek, T, Dockery, C, Mohr, P, Höschl, C (2006) Mechanism of action of atypical antipsychotic drugs and the neurobiology of schizophrenia. CNS Drugs 20(5), 389409.CrossRefGoogle ScholarPubMed
Insel, TR and Scolnick, EM (2006) Cure therapeutics and strategic prevention: raising the bar for mental health research. Molecular Psychiatry 11(1), 1117.CrossRefGoogle ScholarPubMed
Kahn, RS, Fleischhacker, WW, Boter, H, Davidson, M, Vergouwe, Y, Keet, IP, Gheorghe, MDP, Rybakowski, JK, Galderisi, S, Libiger, J, Hummer, M, Dollfus, S, López-Ibor, JJ, Hranov, LG, Gaebel, W, Peuskens, J, Lindefors, N, Riecher-Rössler, A, Grobbee, DE, EUFEST study group (2008) Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet 371(9618), 10851097.CrossRefGoogle ScholarPubMed
Kane, J, Honigfeld, G, Singer, J and Meltzer, H (1988) Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Archives of General Psychiatry 45(9), 789796.CrossRefGoogle ScholarPubMed
Koch, M (1999) The neurobiology of startle. Progress in Neurobiology 59(2), 107128.CrossRefGoogle ScholarPubMed
Krause, M, Huhn, M, Schneider-Thoma, J, Bighelli, I, Gutsmiedl, K and Leucht, S (2019) Efficacy, acceptability and tolerability of antipsychotics in patients with schizophrenia and comorbid substance use. A systematic review and meta-analysis. European Neuropsychopharmacology 29(1), 3245.CrossRefGoogle ScholarPubMed
Lehmann, J, Pryce, CR and Feldon, J (1999) Sex differences in the acoustic startle response and prepulse inhibition in Wistar rats. Behavioural Brain Research 104(1–2), 113117.CrossRefGoogle ScholarPubMed
Lewis, SW, Barnes, TRE, Davies, L, Murray, RM, Dunn, G, Hayhurst, KP, Markwick, A, Lloyd, H, Jones, PB (2005) Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. Schizophrenia Bulletin 32(4), 715723.CrossRefGoogle Scholar
Lieberman, JA, Stroup, TS, McEvoy, JP, Swartz, MS, Rosenheck, RA, Perkins, DO, Keefe, RS, Davis, SM, Davis, CE, Lebowitz, BD, Severe, J, Hsiao, JK, Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators (2005) Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. The New England Journal of Medicine 353(12), 12091223.CrossRefGoogle ScholarPubMed
Löscher, W (2007) The pharmacokinetics of antiepileptic drugs in rats: consequences for maintaining effective drug levels during prolonged drug administration in rat models of epilepsy. Epilepsia 48(7), 12451258.CrossRefGoogle ScholarPubMed
Mauri, MC, Paletta, S, Maffini, M, Colasanti, A, Dragogna, F, Di Pace, C, Altamura, AC (2014) Clinical pharmacology of atypical antipsychotics: an update. EXCLI Journal 13, 11631191.Google ScholarPubMed
McEvoy, J, Lieberman, JA, Stroup, TS, Davis, SM, Meltzer, HY, Rosenheck, RA, Swartz, MS, Perkins, DO, Keefe, RS, Davis, CE, Severe, J, Hsiao, JK, CATIE Investigators (2006) Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. The American Journal of Psychiatry 163(4), 600.CrossRefGoogle Scholar
Mc Fie, S, Sterley, T-L, Howells, FM and Russell, VA (2012) Clozapine decreases exploratory activity and increases anxiety-like behaviour in the Wistar–Kyoto rat but not the spontaneously hypertensive rat model of attention-deficit/hyperactivity disorder. Brain Research 1467, 91103.CrossRefGoogle Scholar
McOmish, CE, Burrows, E, Howard, M, Scarr, E, Kim, D, Shin, H-S, Dean, B, van den Buuse, M, Hannan, AJ (2008) Phospholipase C-β1 knockout mice exhibit endophenotypes modeling schizophrenia which are rescued by environmental enrichment and clozapine administration. Molecular Psychiatry 13(7), 661672.CrossRefGoogle ScholarPubMed
Mead, A, Li, M and Kapur, S (2008) Clozapine and olanzapine exhibit an intrinsic anxiolytic property in two conditioned fear paradigms: contrast with haloperidol and chlordiazepoxide. Pharmacology Biochemistry and Behavior 90(4), 551562.CrossRefGoogle ScholarPubMed
Moghaddam, B (2004) Targeting metabotropic glutamate receptors for treatment of the cognitive symptoms of schizophrenia. Psychopharmacology (Berl) 174(1), 3944.CrossRefGoogle ScholarPubMed
Moghaddam, B and Javitt, D (2012) From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology 37(1), 415.CrossRefGoogle Scholar
Nelson, JF, Felicio, LS, Randall, PK, Sims, C and Finch, CE (1982) A longitudinal study of estrous cyclicity in aging C57BL/6J mice: I. Cycle frequency, length and vaginal cytology. Biology of Reproduction 27(2), 327339.Google ScholarPubMed
Páleníček, T, Hliňák, Z, Bubeníková-Valešová, V, Novák, T and Horáček, J (2010) Sex differences in the effects of N,N-diethyllysergamide (LSD) on behavioural activity and prepulse inhibition. Progress in Neuro-Psychopharmacology & Biological Psychiatry 34(4), 588596.CrossRefGoogle Scholar
Pardridge, WM (2005) The bloodbrain barrier: bottleneck in brain drug development. NeuroRx 2(1), 314.CrossRefGoogle ScholarPubMed
Paxinos, G and Franklin, KBJ (2001) Mouse Brain in Stereotaxic Coordinates. San Diego, CA: Academic Press.Google Scholar
Powell, CM and Miyakawa, T (2006) Schizophrenia-relevant behavioral testing in rodent models: a uniquely human disorder? Biological Psychiatry 59(12), 11981207.CrossRefGoogle ScholarPubMed
Powell, SB, Zhou, X and Geyer, MA (2009) Prepulse inhibition and genetic mouse models of schizophrenia. Behavioural Brain Research 204(2), 282294.Google ScholarPubMed
Raja, M (2011) Clozapine safety, 35 years later. Current Drug Safety 6(3), 164184.CrossRefGoogle ScholarPubMed
Rajji, TK, Mulsant, BH, Davies, S, Kalache, SM, Tsoutsoulas, C, Pollock, BG, Remington, G (2015) Prediction of working memory performance in schizophrenia by plasma ratio of clozapine to N-desmethylclozapine. The American Journal of Psychiatry 172(6), 579585.CrossRefGoogle ScholarPubMed
Rogers, DC, Fisher, EM, Brown, SD, Peters, J, Hunter, AJ, Martin, JE (1997) Behavioral and functional analysis of mouse phenotype: SHIRPA, a proposed protocol for comprehensive phenotype assessment. Mamm Genome 8(10), 711713.CrossRefGoogle ScholarPubMed
Saldívar-González, JA, Campos-Rodriguez, UE and Cano-Cruz, MA (2009) Differential effect of clozapine and haloperidol on rats treated with methylphenidate in the open field test. Proceedings of the Western Pharmacology Society 52, 6366.Google ScholarPubMed
Sanchez-Mendoza, EH, Carballo, J, Longart, M, Hermann, DM and Doeppner, TR (2016) Implantation of miniosmotic pumps and delivery of tract tracers to study brain reorganization in pathophysiological conditions. Journal of Visualized Experiments 107, 52932.Google Scholar
Schwarzkopf, SB, McCoy, L, Smith, DA and Boutros, NN (1993) Testretest reliability of prepulse inhibition of the acoustic startle response. Biological Psychiatry 34(12), 896900.Google ScholarPubMed
Simosky, JK, Stevens, KE, Adler, LE and Freedman, R (2003) Clozapine improves deficient inhibitory auditory processing in DBA/2 mice, via a nicotinic cholinergic mechanism. Psychopharmacology (Berl) 165(4), 386396.CrossRefGoogle Scholar
Slavc, I, Cohen-Pfeffer, JL, Gururangan, S, Krauser, J, Lim, DA, Maldaun, M, Schwering, C, Shaywitz, AJ, Westphal, M (2018) Best practices for the use of intracerebroventricular drug delivery devices. Molecular Genetics and Metabolism 124(3), 184188.Google ScholarPubMed
Stroup, TS, Gerhard, T, Crystal, S, Huang, C, Tan, Z, Wall, MM, Mathai, C, Olfson, M (2019) Comparative effectiveness of adjunctive psychotropic medications in patients with schizophrenia. JAMA Psychiatry 76(5), 508.CrossRefGoogle ScholarPubMed
Swerdlow, NR and Geyer, MA (1998) Using an animal model of deficient sensorimotor gating to study the pathophysiology and new treatments of schizophrenia. Schizophrenia Bulletin 24(2), 285301.Google Scholar
Swerdlow, NR, Varty, GB and Geyer, MA (1998) Discrepant findings of clozapine effects on prepulse inhibition of startle: is it the route or the rat? Neuropsychopharmacology 18(1), 5056.Google ScholarPubMed
Tanahashi, S, Yamamura, S, Nakagawa, M, Motomura, E and Okada, M (2012) Clozapine, but not haloperidol, enhances glial d-serine and L-glutamate release in rat frontal cortex and primary cultured astrocytes. British Journal of Pharmacology 165(5), 15431555.CrossRefGoogle Scholar
Tatem, KS, Quinn, JL, Phadke, A, Yu, Q, Gordish-Dressman, H and Nagaraju, K (2014) Behavioral and locomotor measurements using an open field activity monitoring system for skeletal muscle diseases. Journal of Visualized Experiments (91):51785.CrossRefGoogle Scholar
Taylor, D, Ellison, Z, Ementon Shaw, L, Wickham, H and Murray, R (1998) Co-administration of citalopram and clozapine: effect on plasma clozapine levels. International Clinical Psychopharmacology 13(1), 1921.Google ScholarPubMed
Urquhart, J, Fara, JW and Willis, KL (1984) Rate-controlled delivery systems in drug and hormone research. Annual Review of Pharmacology and Toxicology 24(1), 199236.CrossRefGoogle ScholarPubMed
Vollenweider, FX, Barro, M, Csomor, PA and Feldon, J (2006) Clozapine enhances prepulse inhibition in healthy humans with low but not with high prepulse inhibition levels. Biological Psychiatry 60(6), 597603.CrossRefGoogle Scholar
Walsh, RN and Cummins, RA (1976) The Open-Field Test: a critical review. Psychological Bulletin 83(3), 482504.Google ScholarPubMed
Yasuhara, A and Chaki, S (2010) Metabotropic glutamate receptors: potential drug targets for psychiatric disorders. The Open Medicinal Chemistry Journal 4, 2036.CrossRefGoogle ScholarPubMed
Supplementary material: File

Esen-Sehir et al. supplementary material

Tables S1-S3

Download Esen-Sehir et al. supplementary material(File)
File 49.7 KB