Physostigmine reversal of scopolamine-induced hypofrontality

J Cereb Blood Flow Metab. 1997 Feb;17(2):220-8. doi: 10.1097/00004647-199702000-00012.

Abstract

The muscarinic receptor antagonist scopolamine produces a transient memory deficit in healthy humans. This deficit has been offered as a model of the cholinergic deficit of Alzheimer's disease (AD). However, we have previously shown that scopolamine produces a deficit of cortical perfusion maximal in the frontal lobe, dissimilar to the parietal cortex deficit characteristic of AD. The current experiment was aimed at replicating and extending this observation by critically testing the central cholinergic origin of both cognitive and perfusion deficits. Nine healthy subjects participated in regional cerebral blood flow (rCBF) measurements at baseline, after scopolamine (7.2 micrograms/kg i.v.), and after both physostigmine (22 micrograms/kg i.v.) and neostigmine (7 or 11 micrograms/kg i.v.). rCBF was quantified by the xenon 133 inhalation method. As expected, scopolamine reduced cortical perfusion, mainly in the frontal cortex, and produced a memory deficit. Physostigmine, but not neostigmine, reversed all three variables partially or completely. These results support the hypothesis that all three consequences of scopolamine, namely, reduction of mean flow, frontal deficit, and memory impairment, are cholinergically mediated. Furthermore, because neostigmine poorly crosses the blood-brain barrier, these findings confirm that the effect is centrally mediated and cannot be explained by peripheral effects. However, they also confirm the frontal cortex locus of action for both scopolamine and its reversal by physostigmine and therefore suggest a major dissimilarity to the characteristic rCBF appearance of AD. This study extends our previous preliminary findings with tacrine and strengthens the suggestion that only nicotinic receptors are associated with the characteristic parietal deficit of AD.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetylcholine / physiology*
  • Adult
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / psychology
  • Amnesia / chemically induced
  • Amnesia / diagnostic imaging
  • Amnesia / drug therapy*
  • Blood-Brain Barrier
  • Cerebrovascular Circulation / drug effects*
  • Frontal Lobe / blood supply*
  • Frontal Lobe / diagnostic imaging
  • Frontal Lobe / physiopathology
  • Hemodynamics / drug effects
  • Humans
  • Male
  • Mental Recall / drug effects
  • Muscarinic Antagonists / adverse effects*
  • Neostigmine / pharmacokinetics
  • Neostigmine / pharmacology
  • Parasympathomimetics / pharmacology
  • Parasympathomimetics / therapeutic use*
  • Physostigmine / pharmacology
  • Physostigmine / therapeutic use*
  • Radionuclide Imaging
  • Receptors, Muscarinic / drug effects
  • Receptors, Muscarinic / physiology
  • Scopolamine / adverse effects*
  • Scopolamine / antagonists & inhibitors
  • Xenon Radioisotopes

Substances

  • Muscarinic Antagonists
  • Parasympathomimetics
  • Receptors, Muscarinic
  • Xenon Radioisotopes
  • Neostigmine
  • Physostigmine
  • Scopolamine
  • Acetylcholine