Tetrahydro-9-aminoacridine has mixed actions on muscarinic currents and blocks opioid currents in rat locus ceruleus neurons.
Actions of tetrahydro-9-aminoacridine (THA) on membrane properties of locus ceruleus neurons were examined using intracellular recording in superfused brain slices. Low concentrations of THA (300 nM-3 microM) caused a small inward current and a 10-fold increase in the potency of ACh to produce inward (excitatory) currents. No effect was seen on currents activated by carbachol, a muscarinic agonist not degraded by cholinesterases. High concentrations of THA (30-300 microM) caused larger inward currents and a decrease in cell conductance. At these concentrations THA inhibited inward currents induced by carbachol (IC50 = 33 microM) and by substance P, which reportedly excites locus ceruleus neurons via the same ionic mechanism as muscarinic agonists. Furthermore, outward currents activated by opioids could be completely blocked (IC50 = 15 microM). Also affected was the action potential waveform, which was slower to rise, longer in duration and smaller in amplitude. The results suggest that THA has predominantly excitatory effects on locus ceruleus neurons--both by greatly enhancing the actions of ACh and by producing a small inward current. At high concentrations effects are mixed and include inhibition of muscarinic currents, as well as of resting and agonist-induced inwardly rectifying potassium currents. The block of opioid currents by THA was not consistent with inhibition of a cationic conductance as recently proposed.
Osborne
P B
PB
Department of Pharmacology D06, University of Sydney, Australia.
Christie
M J
MJ
D000109:Acetylcholine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D008125:Locus Coeruleus / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D018721:Muscarinic Agonists / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D015221:Potassium Channels / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000187:drug effects / Q000502:physiology*; D013619:Tacrine / Q000494:pharmacology*
D002800:Cholinesterase Inhibitors; D018721:Muscarinic Agonists; D015221:Potassium Channels; D011957:Receptors, Opioid; D013619:Tacrine; D002217:Carbachol; D000109:Acetylcholine