title: Negative effects of chronic oral chlorpromazine and olanzapine treatment on the performance of tasks designed to assess spatial learning and working memory in rats.
abstract: Learning potential and memory capacity are factors that strongly predict the level of rehabilitation and the long-term functional outcome in patients with schizophrenia. Unfortunately, however, the effects of antipsychotic drugs (i.e. the primary treatments for schizophrenia) on these components of cognition are unclear, particularly when they are administered chronically (i.e. a standard clinical practice). In this rodent study we evaluated the effects of different time periods (ranging from 2 weeks to 6 months) of oral treatment with the first generation antipsychotic chlorpromazine (10.0 mg/kg/day), or the second generation antipsychotic olanzapine (10.0 mg/kg/day) on the repeated acquisition of a water maze task (i.e. a method of assessing spatial learning potential in a repeated testing format). We assessed locomotor function (in an open field) and employed a radial arm maze (RAM) task to assess antipsychotic effects (5.0 and 10.0 mg/kg/day doses) on spatial working memory during the treatment period between 15 days and 2 months. Finally, we conducted experiments using liquid chromatography/tandem mass spectrometry (LC-MS/MS) to evaluate the therapeutic relevance of our method of drug delivery (oral administration in drinking water). In the water maze experiments, both antipsychotics were associated with impairments in acquisition in the earlier test sessions that could eventually be overcome with repeated testing while olanzapine also impaired retention in probe trials. Both antipsychotics were also associated with impairments in delayed non-match-to-position trials in the RAM and some impairments of motor function (especially in the case of olanzapine) as indicated by slightly reduced swim speeds in the water maze and decreased activity in some components of the open field assessment. Finally, LC-MS/MS studies indicated that the method of antipsychotic administration generated clinically relevant plasma levels in the rat. These animal data indicate that chronic oral treatment with chlorpromazine or olanzapine can impair the performance of tasks designed to assess specific components of cognition that are affected in schizophrenia.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA 30912-2300, USA. aterry@mail.mcg.edu
authors.forename: A V
authors.initials: AV
authors.lastname: Terry
authors.forename: S E
authors.initials: SE
authors.lastname: Warner
authors.forename: L
authors.initials: L
authors.lastname: Vandenhuerk
authors.forename: A
authors.initials: A
authors.lastname: Pillai
authors.forename: S P
authors.initials: SP
authors.lastname: Mahadik
authors.forename: G
authors.initials: G
authors.lastname: Zhang
authors.forename: M G
authors.initials: MG
authors.lastname: Bartlett
mesh_terms: D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000097:blood; D019540:Area Under Curve; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines / Q000008:administration & dosage* / Q000097:blood; D002746:Chlorpromazine / Q000008:administration & dosage* / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005106:Exploratory Behavior / Q000187:drug effects; D018737:Hand Strength / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects* / Q000502:physiology; D008570:Memory, Short-Term / Q000187:drug effects*; D009043:Motor Activity / Q000187:drug effects; D000077152:Olanzapine; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D013028:Space Perception / Q000187:drug effects*
chemical_list: D014150:Antipsychotic Agents; D001569:Benzodiazepines; D000077152:Olanzapine; D002746:Chlorpromazine
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2007 Jul 1;854(1-2):68-76
references.pmid: 17452027
references.citation: J Psychiatry Neurosci. 2003 May;28(3):197-209
references.pmid: 12790160
references.citation: Neuroscience. 2007 Dec 5;150(2):413-24
references.pmid: 17942237
references.citation: Schizophr Bull. 2000;26(1):119-36
references.pmid: 10755673
references.citation: Exp Neurol. 2000 Jun;163(2):495-529
references.pmid: 10833325
references.citation: J Clin Psychopharmacol. 2001 Feb;21(1):14-20
references.pmid: 11199942
references.citation: Neuroscience. 2001;103(2):351-63
references.pmid: 11246150
references.citation: Fortschr Neurol Psychiatr. 2001 Nov;69(11):510-7
references.pmid: 11704898
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2002 Oct;26(6):1047-54
references.pmid: 12452525
references.citation: Psychopharmacology (Berl). 2002 Dec;164(4):360-8
references.pmid: 12457265
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2003 Oct;27(7):1125-43
references.pmid: 14642972
references.citation: J Clin Psychiatry. 2004 Mar;65(3):361-72
references.pmid: 15096076
references.citation: Arch Gen Psychiatry. 1970 Apr;22(4):289-96
references.pmid: 5417623
references.citation: Neuropsychologia. 1979;17(6):669-82
references.pmid: 522981
references.citation: Pharmacol Biochem Behav. 1987 Jan;26(1):1-6
references.pmid: 3562481
references.citation: Arch Gen Psychiatry. 1988 Jan;45(1):79-91
references.pmid: 2892478
references.citation: Pharmacol Biochem Behav. 1988 Dec;31(4):959-62
references.pmid: 3252289
references.citation: Synapse. 1991 Feb;7(2):151-68
references.pmid: 1672782
references.citation: J Pharmacol Exp Ther. 1992 Feb;260(2):576-80
references.pmid: 1346637
references.citation: Brain Res Brain Res Rev. 1993 Jan-Apr;18(1):33-49
references.pmid: 8467349
references.citation: Behav Neurosci. 1995 Aug;109(4):579-93
references.pmid: 7576202
references.citation: Schizophr Res. 1995 Sep;17(1):25-33
references.pmid: 8541247
references.citation: Eur Neuropsychopharmacol. 1996 May;6(2):85-91
references.pmid: 8791032
references.citation: Psychopharmacology (Berl). 1996 Mar;124(1-2):57-73
references.pmid: 8935801
references.citation: Pharmacol Biochem Behav. 1997 Dec;58(4):899-902
references.pmid: 9408193
references.citation: Mol Psychiatry. 1998 Mar;3(2):123-34
references.pmid: 9577836
references.citation: Neuropsychopharmacology. 1999 Apr;20(4):311-21
references.pmid: 10088132
references.citation: Biol Psychiatry. 1999 Aug 1;46(3):392-400
references.pmid: 10435205
references.citation: Eur Neuropsychopharmacol. 1999 Sep;9(5):421-6
references.pmid: 10523049
references.citation: Mol Psychiatry. 2005 Jan;10(1):79-104
references.pmid: 15289815
references.citation: Psychopharmacology (Berl). 2005 Jun;179(4):725-32
references.pmid: 15619109
references.citation: Schizophr Bull. 2005 Jan;31(1):67-72
references.pmid: 15888426
references.citation: CMAJ. 2005 Jun 21;172(13):1703-11
references.pmid: 15967975
references.citation: Neuroscience. 2005;136(2):519-29
references.pmid: 16216423
references.citation: Biol Psychiatry. 2006 Apr 15;59(8):740-6
references.pmid: 16229823
references.citation: Life Sci. 2006 May 22;78(26):3007-12
references.pmid: 16434058
references.citation: J Pharmacol Exp Ther. 2006 Aug;318(2):709-24
references.pmid: 16702442
references.citation: Eur J Pharmacol. 2006 Aug 7;542(1-3):108-15
references.pmid: 16806167
references.citation: Psychopharmacology (Berl). 2006 Nov;188(4):586-96
references.pmid: 16538469
references.citation: J Pharmacol Exp Ther. 2007 Mar;320(3):961-8
references.pmid: 16966470
references.citation: Rapid Commun Mass Spectrom. 2007;21(6):920-8
references.pmid: 17295424
references.citation: Neuroscience. 2007 May 25;146(3):1316-32
references.pmid: 17434684
references.citation: Ther Drug Monit. 2003 Feb;25(1):46-53
references.pmid: 12548144
references.citation: Neuropsychopharmacology. 2003 Feb;28(2):300-9
references.pmid: 12589383
references.citation: J Pharmacol Exp Ther. 2003 May;305(2):625-31
references.pmid: 12606608
references.citation: Psychopharmacology (Berl). 2003 May;167(3):304-14
references.pmid: 12677356
references.citation: Am J Psychiatry. 2007 Jul;164(7):992-4
references.pmid: 17606645