Continuous physostigmine infusion in rats with excitotoxic lesions of the nucleus basalis magnocellularis: effects on performance in the water maze task and cortical cholinergic markers.
Acute peripheral administration of physostigmine inhibits cortical acetylcholinesterase (AChE) for about 1 hr in the rat and improves performance on learning and memory paradigms after excitotoxic lesions of the nucleus basalis magnocellularis (NBM) in rats. This study examined the effects of continuous systemic infusion of physostigmine using osmotic minipumps. One week of continuous physostigmine infusion in normal animals inhibited cortical AChE activity in a dose-dependent manner. Doses causing near maximal (0.06 mg/kg/hr) and ED50 (0.0075 mg/kg/hr) inhibition of cortical AChE activity were used to determine the effects of continuous physostigmine administration on spatial learning in the water maze in rats with bilateral ibotenic acid lesions of the NBM. Physostigmine had no effect on the acquisition of the maze task but prevented the retention deficit measured in untreated NBM-lesioned rats. Physostigmine treatment also improved the search strategy during the spatial probe trial compared to the untreated NBM-lesioned rats. The two doses of physostigmine examined did not produce differential responses on behavioral measures. Although NBM lesions significantly depleted cortical AChE activity, physostigmine treatment reduced the activity further in a dose-dependent manner. Whereas neither the lesion nor the low dose of physostigmine altered cortical receptor binding, the higher dose of physostigmine significantly down-regulated cortical muscarinic receptor binding by 28%. These data demonstrate that enhancement of acetylcholine neurotransmission can improve memory loss and spatial strategy associated with excitotoxic NBM lesions.
Mandel
R J
RJ
Neurology Service Veteran's Administration Medical Center, San Diego, California.
Chen
A D
AD
Connor
D J
DJ
Thal
L J
LJ
D000110:Acetylcholinesterase / Q000032:analysis; D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D001479:Basal Ganglia / Q000502:physiology*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000201:enzymology; D002795:Choline O-Acetyltransferase / Q000032:analysis; D007262:Infusions, Intravenous; D007858:Learning / Q000187:drug effects*; D008297:Male; D008568:Memory / Q000187:drug effects*; D010275:Parasympathetic Nervous System / Q000187:drug effects*; D010830:Physostigmine / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D011976:Receptors, Muscarinic / Q000187:drug effects; D013377:Substantia Innominata / Q000502:physiology*
D011976:Receptors, Muscarinic; D010830:Physostigmine; D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase