Evaluation of autoreceptor-mediated control of [(3)H]acetylcholine release in rat and human neocortex.
In order to assess the autoinhibitory control of endogenous acetylcholine (ACh) in rat and human neocortex, slices of these tissues were prelabelled with [(3)H]choline, superfused continuously and stimulated electrically using various frequencies in the presence or absence of drugs. The autoinhibitory feedback control of [(3)H]ACh release was operative - despite the absence of blockers of ACh esterase - at stimulation frequencies >/= 3 Hz in rat and >/= 6 Hz in human neocortex tissue. At these frequencies the muscarinic antagonist atropine (0.1 microM) disinhibited the release of [(3)H]ACh in both species. Estimation of the biophase concentration of ACh near the autoreceptor in the rat neocortex from concentration-response curves of the muscarinic agonist oxotremorine revealed that at 3 Hz about 25% of the autoreceptors were activated by endogenously released ACh. This estimation is consistent with an increase in [(3)H]ACh release to about 120% of control values by complete blockade of autoreceptors with atropine. The observation that in human neocortical tissue presynaptic autoinhibition of [(3)H]ACh release is operative at stimulation frequencies >/= 6 Hz suggests that selective blockade of autoinhibition may also increase ACh release in the cortex of Alzheimer's disease patients, without additional blockade of the enzyme acetylcholinesterase.
Albrecht
C
C
Sektion Klinische Neuropharmakologie der Neurologischen Universitätsklinik, Neurozentrum, Breisacher Strasse 64, D-79106 Freiburg, Germany,
Bloss
H G
HG
Jackisch
R
R
Feuerstein
T J
TJ
D000109:Acetylcholine / Q000378:metabolism* / Q000502:physiology; D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D001285:Atropine / Q000494:pharmacology*; D002352:Carrier Proteins / Q000187:drug effects* / Q000502:physiology; D004558:Electric Stimulation / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins; D008875:Middle Aged; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D019579:Neocortex / Q000187:drug effects* / Q000378:metabolism; D010095:Oxotremorine / Q000494:pharmacology; D051381:Rats; D009435:Synaptic Transmission; D050494:Vesicular Acetylcholine Transport Proteins; D033921:Vesicular Transport Proteins
D002352:Carrier Proteins; D026901:Membrane Transport Proteins; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; C493459:SLC18A3 protein, human; C493461:Slc18a3 protein, rat; D050494:Vesicular Acetylcholine Transport Proteins; D033921:Vesicular Transport Proteins; D010095:Oxotremorine; D001285:Atropine; D000109:Acetylcholine