Effects of amiloride and 5-(N,N-hexamethylene)amiloride on dopaminergic and cholinergic neurotransmission.
In order to establish the role of the Na+/H+ exchange transport on neurotransmission, we investigated the effects of amiloride and of 5-(N,N-hexamethylene)amiloride (HMA) on dopamine (DA) and acetylcholine (ACh) release and on receptor-mediated modulation of DA and ACh release. Superfused rabbit striatal slices prelabeled with [3H]DA and [14C]choline were stimulated electrically in the presence and absence of several concentrations of these agents. Amiloride (3-10 microM) and HMA (0.3-10 microM) reduced the basal efflux and the stimulation evoked overflow of total 3H and of [3H]-3,4-dihydroxyphenylacetic acid and inhibited monoamine oxidase activity. The inhibition of stimulation evoked overflow of total 3H was blocked by pretreatment with nomifensine but not by sulpiride. Amiloride had no effect on the basal efflux and the stimulation evoked overflow of ACh or it did modify apomorphine-induced inhibition of DA and ACh release. However, at 3 to 10 microM, HMA enhanced the basal efflux of 3H; this effect was not prevented either by uptake inhibition with nomifensine or by low extracellular calcium. These results suggest that amiloride-sensitive Na+ transport and the amiloride and HMA-sensitive Na+/H+ antiporter play no role on the secretion of DA and ACh, or on the mechanisms by which activation of pre- and postsynaptic DA receptors lead to inhibition of neurotransmitter release. Amiloride- and HMA-induced monoamine oxidase inhibition accounts for the effects of amiloride and HMA on DA efflux and overflow. The guanidine moiety present in the amiloride and HMA molecules is most likely responsible for these effects.
Zubieta
J K
JK
Department of Pharmacology, University of North Carolina, Chapel Hill.
Cragoe
E J
EJ
Cubeddu
L X
LX
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000109:Acetylcholine / Q000378:metabolism*; D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D004298:Dopamine / Q000378:metabolism*; D004558:Electric Stimulation; D066298:In Vitro Techniques; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009627:Nomifensine / Q000494:pharmacology; D010293:Pargyline / Q000494:pharmacology; D011817:Rabbits; D017923:Sodium-Hydrogen Exchangers; D009435:Synaptic Transmission / Q000187:drug effects*
D002352:Carrier Proteins; D008996:Monoamine Oxidase Inhibitors; D017923:Sodium-Hydrogen Exchangers; D015102:3,4-Dihydroxyphenylacetic Acid; C057360:5-(N,N-hexamethylene)amiloride; D009627:Nomifensine; D000584:Amiloride; D010293:Pargyline; D001058:Apomorphine; D000109:Acetylcholine; D004298:Dopamine