Modulation of acetylcholine release by nicotinic receptors in the rat brain.
Since physostigmine (Phy) is presently used in the experimental treatment of Alzheimer disease (AD) patients by means of intracerebral ventricular (i.c.v.) administration, we designed a study to determine the effect of the drug administered by the same route on the cholinergic system of the rat brain. Particularly, we studied the involvement of nicotinic cholinergic function. The specific conditions required in this experiment were achieved by a series of short-lasting periods of acetylcholinesterase (AChE) inhibition leading to short-lasting increases of acetylcholine (ACh). These were produced by periodic i.c.v. injections of Phy. At 7 days of Phy administration, a small effect on 3H-nicotine binding was seen only in the striatum of the injected side. In rats treated for 13 days, we observed a 120% increase in the stimulated release of 3H-ACh in hippocampal slices of the injected side of the brain. There also was a significant 88% increase in 3H-nicotinic binding in the hippocampus of the same side while muscarinic binding was unchanged. These results suggest a process of upregulation of presynaptic nicotinic autoreceptors in the hippocampus modulating ACh release but no effect on the muscarinic receptors. Our results also suggest that pulses of ACh in analogy to nicotinic stimulation can cause protracted desensitization and eventually inactivation of the receptor leading to its up-regulation. These results are consistent with findings on the release of ACh from cortical biopsies and of a sustained ACh release in the CSF of AD patients following the same treatment.
De Sarno
P
P
Department of Pharmacology, Southern Illinois University School of Medicine, Springfield 62794-9230.
Giacobini
E
E
D000109:Acetylcholine / Q000378:metabolism*; D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D004558:Electric Stimulation; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D009538:Nicotine / Q000378:metabolism; D010830:Physostigmine / Q000494:pharmacology*; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D012016:Reference Values
D011978:Receptors, Nicotinic; D011813:Quinuclidinyl Benzilate; D009538:Nicotine; D010830:Physostigmine; D000110:Acetylcholinesterase; D000109:Acetylcholine