Differential effects of haloperidol, risperidone, and clozapine exposure on cholinergic markers and spatial learning performance in rats

Alvin V Terry, William D Hill, Vinay Parikh, Jennifer L Waller, Denise R. Evans, Sahebarao P. Mahadik

Research output: Contribution to journalArticle

74 Citations (Scopus)

Abstract

Haloperidol (HAL), a potent typical antipsychotic, continues to be a frequently prescribed medication for behavioral disturbances associated particularly with schizophrenia despite well-documented adverse effects associated with its chronic use. Animal experimentshave even indicated that HAL can damage cholinergic pathways and thus could be especially deleterious to those experiencing cognitive deficits. However, several recent clinical studies indicate that atypicalantipsychotics may actually improve cognitive function in somepatients, although this assertion requires further investigation. The purpose ofthis study was to comparethe effects of prior chronic (45-or 90-day) oralexposure to HAL and the a typical antipsychoticsrisperidone (RISP) and clozapine (CLOZ) on cognitive performance andcentralcholinergic markers in rats. Allanalyses were done after 4 days of drug washout in orderto minimize direct drug effects. Learningperformance and choline acetyl transferase (ChAT) levels were assessed in a water maze task and with immunofluorescence staining, respectively. HAL significantly impaired learning performance after 90 but not after 45 days of treatment when compared to both vehicle controls and the atypicalagents, while RISP slightly improved task performance. Both 45 and 90 days of previous HAL exposure reduced ChAT staining in severalbrain regions, includingthe cortex, caudate-putamen, and hippo campus. ChAT staining in the caudate-putamenand hippocampus was also decreased after 90 days of RISP exposure, raisingthe possibility of deleterious cognitive effects after exposureto this dosage for longer periods of time. The results suggest that antipsychotic drugs exert differential and temporally dependent effectson central cholinergic neurons and learning performance.

Original languageEnglish (US)
Pages (from-to)300-309
Number of pages10
JournalNeuropsychopharmacology
Volume28
Issue number2
DOIs
StatePublished - Jan 1 2003

Fingerprint

Risperidone
Clozapine
Haloperidol
Cholinergic Agents
Transferases
Choline
Staining and Labeling
Antipsychotic Agents
Learning
Cholinergic Neurons
Putamen
Task Performance and Analysis
Pharmaceutical Preparations
Cognition
Fluorescent Antibody Technique
Hippocampus
Schizophrenia
Spatial Learning
Water
Therapeutics

Keywords

  • Antipsychotics
  • Choline acetyltransferase
  • Cognitive performance
  • Rat
  • Risperidone

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

Cite this

Differential effects of haloperidol, risperidone, and clozapine exposure on cholinergic markers and spatial learning performance in rats. / Terry, Alvin V; Hill, William D; Parikh, Vinay; Waller, Jennifer L; Evans, Denise R.; Mahadik, Sahebarao P.

In: Neuropsychopharmacology, Vol. 28, No. 2, 01.01.2003, p. 300-309.

Research output: Contribution to journalArticle

@article{eaf84655fddc4c69bfdde3c165581f6e,
title = "Differential effects of haloperidol, risperidone, and clozapine exposure on cholinergic markers and spatial learning performance in rats",
abstract = "Haloperidol (HAL), a potent typical antipsychotic, continues to be a frequently prescribed medication for behavioral disturbances associated particularly with schizophrenia despite well-documented adverse effects associated with its chronic use. Animal experimentshave even indicated that HAL can damage cholinergic pathways and thus could be especially deleterious to those experiencing cognitive deficits. However, several recent clinical studies indicate that atypicalantipsychotics may actually improve cognitive function in somepatients, although this assertion requires further investigation. The purpose ofthis study was to comparethe effects of prior chronic (45-or 90-day) oralexposure to HAL and the a typical antipsychoticsrisperidone (RISP) and clozapine (CLOZ) on cognitive performance andcentralcholinergic markers in rats. Allanalyses were done after 4 days of drug washout in orderto minimize direct drug effects. Learningperformance and choline acetyl transferase (ChAT) levels were assessed in a water maze task and with immunofluorescence staining, respectively. HAL significantly impaired learning performance after 90 but not after 45 days of treatment when compared to both vehicle controls and the atypicalagents, while RISP slightly improved task performance. Both 45 and 90 days of previous HAL exposure reduced ChAT staining in severalbrain regions, includingthe cortex, caudate-putamen, and hippo campus. ChAT staining in the caudate-putamenand hippocampus was also decreased after 90 days of RISP exposure, raisingthe possibility of deleterious cognitive effects after exposureto this dosage for longer periods of time. The results suggest that antipsychotic drugs exert differential and temporally dependent effectson central cholinergic neurons and learning performance.",
keywords = "Antipsychotics, Choline acetyltransferase, Cognitive performance, Rat, Risperidone",
author = "Terry, {Alvin V} and Hill, {William D} and Vinay Parikh and Waller, {Jennifer L} and Evans, {Denise R.} and Mahadik, {Sahebarao P.}",
year = "2003",
month = "1",
day = "1",
doi = "10.1038/sj.npp.1300039",
language = "English (US)",
volume = "28",
pages = "300--309",
journal = "Neuropsychopharmacology",
issn = "0893-133X",
publisher = "Nature Publishing Group",
number = "2",

}

TY - JOUR

T1 - Differential effects of haloperidol, risperidone, and clozapine exposure on cholinergic markers and spatial learning performance in rats

AU - Terry, Alvin V

AU - Hill, William D

AU - Parikh, Vinay

AU - Waller, Jennifer L

AU - Evans, Denise R.

AU - Mahadik, Sahebarao P.

PY - 2003/1/1

Y1 - 2003/1/1

N2 - Haloperidol (HAL), a potent typical antipsychotic, continues to be a frequently prescribed medication for behavioral disturbances associated particularly with schizophrenia despite well-documented adverse effects associated with its chronic use. Animal experimentshave even indicated that HAL can damage cholinergic pathways and thus could be especially deleterious to those experiencing cognitive deficits. However, several recent clinical studies indicate that atypicalantipsychotics may actually improve cognitive function in somepatients, although this assertion requires further investigation. The purpose ofthis study was to comparethe effects of prior chronic (45-or 90-day) oralexposure to HAL and the a typical antipsychoticsrisperidone (RISP) and clozapine (CLOZ) on cognitive performance andcentralcholinergic markers in rats. Allanalyses were done after 4 days of drug washout in orderto minimize direct drug effects. Learningperformance and choline acetyl transferase (ChAT) levels were assessed in a water maze task and with immunofluorescence staining, respectively. HAL significantly impaired learning performance after 90 but not after 45 days of treatment when compared to both vehicle controls and the atypicalagents, while RISP slightly improved task performance. Both 45 and 90 days of previous HAL exposure reduced ChAT staining in severalbrain regions, includingthe cortex, caudate-putamen, and hippo campus. ChAT staining in the caudate-putamenand hippocampus was also decreased after 90 days of RISP exposure, raisingthe possibility of deleterious cognitive effects after exposureto this dosage for longer periods of time. The results suggest that antipsychotic drugs exert differential and temporally dependent effectson central cholinergic neurons and learning performance.

AB - Haloperidol (HAL), a potent typical antipsychotic, continues to be a frequently prescribed medication for behavioral disturbances associated particularly with schizophrenia despite well-documented adverse effects associated with its chronic use. Animal experimentshave even indicated that HAL can damage cholinergic pathways and thus could be especially deleterious to those experiencing cognitive deficits. However, several recent clinical studies indicate that atypicalantipsychotics may actually improve cognitive function in somepatients, although this assertion requires further investigation. The purpose ofthis study was to comparethe effects of prior chronic (45-or 90-day) oralexposure to HAL and the a typical antipsychoticsrisperidone (RISP) and clozapine (CLOZ) on cognitive performance andcentralcholinergic markers in rats. Allanalyses were done after 4 days of drug washout in orderto minimize direct drug effects. Learningperformance and choline acetyl transferase (ChAT) levels were assessed in a water maze task and with immunofluorescence staining, respectively. HAL significantly impaired learning performance after 90 but not after 45 days of treatment when compared to both vehicle controls and the atypicalagents, while RISP slightly improved task performance. Both 45 and 90 days of previous HAL exposure reduced ChAT staining in severalbrain regions, includingthe cortex, caudate-putamen, and hippo campus. ChAT staining in the caudate-putamenand hippocampus was also decreased after 90 days of RISP exposure, raisingthe possibility of deleterious cognitive effects after exposureto this dosage for longer periods of time. The results suggest that antipsychotic drugs exert differential and temporally dependent effectson central cholinergic neurons and learning performance.

KW - Antipsychotics

KW - Choline acetyltransferase

KW - Cognitive performance

KW - Rat

KW - Risperidone

UR - http://www.scopus.com/inward/record.url?scp=0037308980&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037308980&partnerID=8YFLogxK

U2 - 10.1038/sj.npp.1300039

DO - 10.1038/sj.npp.1300039

M3 - Article

VL - 28

SP - 300

EP - 309

JO - Neuropsychopharmacology

JF - Neuropsychopharmacology

SN - 0893-133X

IS - 2

ER -