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

Acta Neuropsychiatrica
Dilhan Esen-SehirFlorian Freudenberg

Abstract

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. 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. 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 ...Continue Reading

References

May 1, 1990·Pharmacology, Biochemistry, and Behavior·J BruhwylerM Mercier
Jan 1, 1984·Annual Review of Pharmacology and Toxicology·J UrquhartK L Willis
Dec 15, 1993·Biological Psychiatry·S B SchwarzkopfN N Boutros
Oct 8, 1997·Mammalian Genome : Official Journal of the International Mammalian Genome Society·D C RogersJ E Martin
Dec 31, 1997·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·N R SwerdlowM A Geyer
Feb 13, 1999·International Clinical Psychopharmacology·D TaylorR Murray
Aug 27, 1999·Progress in Neurobiology·M Koch
Mar 17, 2000·Brain Research. Brain Research Reviews·N C Andreasen
Dec 28, 2000·Behavioural Brain Research·J LehmannJ Feldon
Feb 18, 2005·NeuroRx : the Journal of the American Society for Experimental NeuroTherapeutics·William M Pardridge
Sep 21, 2005·The New England Journal of Medicine·Jeffrey A LiebermanUNKNOWN Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators
Dec 16, 2005·Molecular Psychiatry·T R Insel, E M Scolnick
Jun 27, 2006·Biological Psychiatry·Craig M Powell, Tsuyoshi Miyakawa
Nov 30, 2007·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·William T Carpenter, James I Koenig
Apr 23, 2008·Current Protocols in Neuroscience·M A Geyer, N R Swerdlow
Nov 18, 2008·Schizophrenia Bulletin·Peter F BuckleyDavid J Castle
Apr 29, 2009·Behavioural Brain Research·Susan B PowellMark A Geyer
Jun 6, 2009·The International Journal of Neuropsychopharmacology·Andrea GogosSusan Rossell
Jun 9, 2009·Journal of Neuroscience Methods·Nelson G PublicoverKenneth W Hunter
Feb 17, 2010·Progress in Neuro-psychopharmacology & Biological Psychiatry·Tomás PálenícekJirí Horácek
Sep 21, 2010·Clinical Neuropharmacology·Susanne EnglischMathias Zink
Dec 17, 2010·The Open Medicinal Chemistry Journal·Akito Yasuhara, Shigeyuki Chaki
Apr 5, 2011·Behavioural Brain Research·Anand GururajanDaniel Thomas Malone
Apr 6, 2011·Behavioral Neuroscience·David FeifelGilia Melendez
Oct 1, 2011·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Bita Moghaddam, Daniel Javitt
Nov 30, 2011·Current Drug Safety·Michele Raja
Jun 27, 2014·Expert Opinion on Therapeutic Targets·Kenji Hashimoto

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antipsychotic Drugs

Antipsychotic drugs are a class of medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia and bipolar disorder. Discover the latest research on antipsychotic drugs here