Tetrahydroaminoacridine improves the spatial acquisition deficit produced by nucleus basalis lesions in rats.
We administered tetrahydroaminoacridine (THA), a cholinesterase inhibitor, to rats with bilateral nucleus basalis magnocellularis lesions and measured their performance in a spatial learning task. The subjects, 34 male Fischer-344 rats, received bilateral excitotoxic NBM lesions; 10 other rats served as unlesioned controls. Two weeks later the animals were tested in a circular water maze for time and distance swum to find a submerged platform. We tested three different doses (5.0, 2.5, and 1.25 mg/kg) of daily subcutaneous THA against a lesioned control group receiving saline and a fifth group of untreated unlesioned controls. The saline-treated lesioned group showed a significant impairment of acquisition. The 1.25 mg/kg group performed significantly better than the lesioned controls with respect to latency. Analysis of swim speed data showed slowing in the 2.5 and 5.0 mg/kg groups. Analysis of the distance swum to find the platform, an untimed task that corrects for the difference in swim speeds, showed statistically significant improvement in all three treated groups. Additionally, spatial memory for the platform location was improved by two of the three doses of THA tested. Passive avoidance retention was not impaired by our lesion. All lesioned groups had comparable reductions of cortical choline acetyltransferase. Our data show significantly improved spatial learning with THA. These data provide an additional rationale for further clinical testing of THA and other centrally active cholinergic agents in diseases with cholinergic loss.
Kwo-On-Yuen
P F
PF
Department of Neurosciences, University of California, San Diego, La Jolla 92093.
Mandel
R
R
Chen
A D
AD
Thal
L J
LJ
D000110:Acetylcholinesterase / Q000032:analysis; D000609:Aminoacridines / Q000494:pharmacology*; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001479:Basal Ganglia / Q000502:physiology*; D001522:Behavior, Animal / Q000187:drug effects; D002799:Cholinergic Fibers / Q000187:drug effects; D004195:Disease Models, Animal; D008297:Male; D008568:Memory / Q000502:physiology*; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D013377:Substantia Innominata / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D013619:Tacrine / Q000493:pharmacokinetics / Q000494:pharmacology*
D000609:Aminoacridines; D013619:Tacrine; D000110:Acetylcholinesterase