Behavioural, biochemical and histological effects of AF64A following injection into the third ventricle of the mouse.
Behavioural, biochemical and histological effects were assessed following AF64A injected into the third ventricle of female NMRI mice. Doses from 3 to 7 nmol produced significant changes in behaviour, causing hyperactivity, reduced hole-board exploration, rotational behaviour in a symmetrical Y-maze corresponding to a loss of alternation, abnormal behaviour in a plus-maze task of fear/anxiety with markedly increased exploration of the open arms and finally deficits in passive avoidance responding and spatial orientation in a Morris-type water maze. In this latter test, a cue learning deficit was noted for the two highest doses only. No histological changes of consequence were observed up to 5 nmol. Beyond this dose, at 6 and particularly 7 nmol, necrosis of parts of the hippocampus and septum was apparent. ChAT and AChE activity were decreased in the hippocampus but not in the cortex although the decreases were smaller than generally reported for AF64A-treated rats. ChAT and AChE reductions correlated highly with hyperactivity in the open-field and to a lesser extent, with spatial learning deficits. Monoaminergic activity was also affected in the hippocampus, but not in the cortex, at 4 nmol and above. NE and particularly 5-HT and 5-HIAA levels were reduced although the rate of 5-HT turnover was unaltered. A highly significant correlation was obtained between 5-HT effects and the increased open arm exploration in the plus-maze task of fear/anxiety. The behavioural effects and biochemical changes lasted at least 8-9 weeks postop.
UCB Pharma, Pharmaceutical Research Center, Braine-l'Alleud, Belgium.
Y
Y
Lamberty
A J
AJ
Gower
J
J
Gobert
I
I
Hanin
E
E
Wulfert
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001388:Aziridines / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects*; D001931:Brain Mapping; D002794:Choline / Q000031:analogs & derivatives* / Q000494:pharmacology; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D002799:Cholinergic Fibers / Q000187:drug effects*; D004193:Discrimination Learning / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004924:Escape Reaction / Q000187:drug effects; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects; D007276:Injections, Intraventricular; D007858:Learning / Q000187:drug effects*; D008568:Memory / Q000187:drug effects*; D011939:Mental Recall / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000378:metabolism; D009949:Orientation / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D012018:Reflex / Q000187:drug effects
D001388:Aziridines; D018377:Neurotransmitter Agents; C044894:ethylcholine aziridinium; D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase; D002794:Choline