Differential effects of 4-aminopyridine and 2,4-diaminopyridine on the in vivo release of acetylcholine and dopamine in freely moving rats measured by intrastriatal dialysis.
The central effects of 4-aminopyridine (4-AP), a blocking agent of voltage-dependent potassium channels, and its more polar analogue, 2,4-diaminopyridine (2,4-DAP), were studied after i.p. injection and direct intrastriatal administration in rats. The effects of the drugs on the release of acetylcholine (ACh) and dopamine (DA) were quantified by means of an in vivo microdialysis sampling technique. Both neurotransmitters were determined by on-line HPLC analysis. Both aminopyridines increased the release of ACh dose dependently when administered intrastriatally. After peripheral administration, however, 4-AP but not 2,4-DAP induced an increase in the release of ACh. These results are interpreted as being due to the greater lipid solubility of 4-AP compared to 2,4-DAP and hence its better penetration through the blood-brain barrier. Intrastriatal administration of 4-AP induced a much lower increase in the release of DA compared to ACh, whereas there was no change in the release of DA after peripheral administration. These results indicate that the sensitivity of excitable membranes to the releasing effects of 4-AP is not the same for DA- and ACh-containing neurotransmitter systems.
Damsma
G
G
Department of Medicinal Chemistry, University of Groningen, The Netherlands.
Biessels
P T
PT
Westerink
B H
BH
De Vries
J B
JB
Horn
A S
AS
D015761:4-Aminopyridine / Q000031:analogs & derivatives; D000109:Acetylcholine / Q000378:metabolism*; D000631:Aminopyridines / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum; D003956:Dialysis; D004298:Dopamine / Q000378:metabolism*; D007267:Injections; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013779:Tetrodotoxin / Q000494:pharmacology
D000631:Aminopyridines; D013779:Tetrodotoxin; C026805:2,4-diaminopyridine; D015761:4-Aminopyridine; D000109:Acetylcholine; D004298:Dopamine