Differential effects of chronic haloperidol and olanzapine exposure on brain cholinergic markers and spatial learning in rats.
BACKGROUND
In psychiatric patients, haloperidol (HAL) induces a number of adverse extrapyramidal and cognitive symptoms, which appear to be less problematic with olanzapine (OLZ). In animals, HAL may initiate a number of harmful effects on central nervous system neurons, including damage to cholinergic pathways - an effect that could be especially deleterious to those experiencing memory dysfunction. The identification of the neurobiological substrates of such effects in animal models may help to improve the algorithms used for proper drug selection especially for long-term neuroleptic use.


OBJECTIVE
The aim of this study was to compare the effects of chronic (45-day and 90-day), continuous oral exposure to HAL with OLZ for effects on cognitive performance and cholinergic markers in rats.


METHODS
After chronic neuroleptic exposure (and a 4-day washout) spatial memory performance was measured in a water maze task, and choline acetyltransferase (ChAT) immunoreactivity was assessed with immunofluorescence staining.


RESULTS
In water maze experiments, HAL and OLZ (relative to vehicle) administered for 90 days (but not 45 days) significantly impaired learning performance (i.e., higher mean latencies across several trials to reach a hidden platform). HAL administered for 90 days was associated with impairment across a greater number of trials than OLZ and it also impaired probe trial performance, as indicated by a reduced number of crossings over the previous platform area (when compared with OLZ or vehicle). Both 45 days and 90 days of HAL treatment reduced ChAT staining in the cortex and hippocampus when compared with OLZ or vehicle.


CONCLUSIONS
The results in the rat suggest that OLZ (relative to HAL) may be more desirable as an antipsychotic for patients suffering from memory dysfunction especially for those in which cholinergic deficits may already be present.
Terry
A V
AV
Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy (Augusta Campus), Medical College of Georgia, Augusta, GA 30912-2450, USA.
Hill
W D
WD
Parikh
V
V
Evans
D R
DR
Waller
J L
JL
Mahadik
S P
SP
D000818:Animals; D001569:Benzodiazepines; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D002799:Cholinergic Fibers / Q000187:drug effects; D004334:Drug Administration Schedule; D004924:Escape Reaction / Q000187:drug effects; D006220:Haloperidol / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D011939:Mental Recall / Q000187:drug effects*; D008856:Microscopy, Fluorescence; D000077152:Olanzapine; D009949:Orientation / Q000187:drug effects*; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D011950:Receptors, Cholinergic / Q000187:drug effects*
D011950:Receptors, Cholinergic; D001569:Benzodiazepines; D010890:Pirenzepine; D002795:Choline O-Acetyltransferase; D006220:Haloperidol; D000077152:Olanzapine