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 mu M) cau sed a small inward current and a 10-fold increase in the potency of AC h to produce inward (excitatory) currents. No effect was seen on curre nts activated by carbachol, a muscarinic agonist not degraded by choli nesterases. High concentrations of THA (30-300 mu M) caused larger inw ard currents and a decrease in cell conductance. At these concentratio ns THA inhibited inward currents induced by carbachol (IC50 = 33 mu M) and by substance P, which reportedly excites locus ceruleus neurons v ia the same ionic mechanism as muscarinic agonists. Furthermore, outwa rd currents activated by opioids could be completely blocked (IC50 = 1 5 mu M). Also affected was the action potential waveform, which was sl ower to rise, longer in duration and smaller in amplitude. The results suggest that THA has predominantly excitatory effects on locus cerule us neurons-both by greatly enhancing the actions of ACh and by produci ng a small inward current. At high concentrations effects are mixed an d include inhibition of muscarinic currents as well as of resting and agonist-induced inwardly rectifying potassium currents. The block of o pioid currents by THA was not consistent with inhibition of a cationic conductance as recently proposed.