GABA receptors and benzodiazepine binding sites modulate hippocampal acetylcholine release in vivo.
In the present study, the regulation of acetylcholine release from the ventral hippocampus by gamma-aminobutyric acid (GABA) was investigated in vivo. GABA receptor agonists and antagonists were administered locally in the medial septum and the adjacent vertical limb of the diagonal band of Broca, or in the hippocampus by retrograde dialysis. Acetylcholine release was measured in the ventral hippocampus. In addition, the modulation of acetylcholine release via septal benzodiazepine binding sites was assessed by intraseptal administration of an agonists and an antagonist at the benzodiazepine binding site. Intraseptal administration of the GABA(A) receptor agonist muscimol and the GABA(B) receptor agonist baclofen, but not the agonist of the benzodiazepine binding site midazolam, decreased acetylcholine release in the hippocampus. The GABA(A) receptor antagonist bicuculline and the antagonist of the benzodiazepine binding site flumazenil, but not the GABA(B) receptor antagonist 3-N-(3,4,-dichlorobenzyl) aminopropyl-P-diethoxymethyphosphinic acid (CGP 52432) increased acetylcholine release in the hippocampus upon intraseptal administration. The same GABA receptor ligands were administered in the ventral hippocampus. CGP 52432 induced a small increase in acetylcholine release, whereas baclofen, muscimol and bicuculline did not affect local acetylcholine release. Thus, endogenous GABA causes tonic inhibition of acetylcholine release in the ventral hippocampus via septal GABA(A) receptors and, to a lesser extent, via GABA(B) receptors in the medial septum and hippocampus. The GABAergic inhibition in the medial septum is reduced by antagonists of the benzodiazepine binding site.
Moor
E
E
University Centre for Pharmacy, Department of Medicinal Chemistry, Groningen, The Netherlands. e.moor@farm.rug.nl
DeBoer
P
P
Westerink
B H
BH
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001569:Benzodiazepines / Q000378:metabolism*; D001665:Binding Sites / Q000187:drug effects; D005442:Flumazenil / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008024:Ligands; D008297:Male; D008874:Midazolam / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018079:Receptors, GABA / Q000187:drug effects / Q000378:metabolism*; D012688:Septum Pellucidum / Q000187:drug effects / Q000378:metabolism
D018755:GABA Agonists; D018756:GABA Antagonists; D018757:GABA Modulators; D008024:Ligands; D018079:Receptors, GABA; D001569:Benzodiazepines; D005442:Flumazenil; D000109:Acetylcholine; D008874:Midazolam