Some Actions of 9-Amino-1,2,3,4-Tetrahydroacridine (THA) on Cholinergic Transmission and Membrane Currents in Rat Sympathetic Ganglia

THA (Tacrine) is an anticholinesterase drug reported to alleviate cognitive deficit in Alzheimer's disease. We have used rat isolated superior cervical sympathetic ganglia as a model mammalian cholinergic neural system to study effects of THA on cholinergic synaptic transmission and postsynaptic membrane currents. At 0.1 - 3 microM, THA augmented the postsynaptic depolarizations and inward clamp currents produced by acetylcholine but not by the cholinesterase-resistant analogue, DMPP. Higher concentrations depressed these responses to both acetylcholine and DMPP, and reduced the acetylcholine-induced increase in membrane current noise. At 1 microM, THA did not affect the amplitude or time-course of fast (nicotinic) excitatory postsynaptic currents (epscs) evoked by single orthodromic volleys, but higher concentrations induced a biphasic epsc decay. In contrast, low concentrations of THA (1 - 3 microM) greatly augmented and prolonged the muscarinic slow epsc evoked by repetitive orthodromic volleys: this effect was blocked by 1 microM atropine. Concentrations above 0.1 mM produced a membrane depolarization and inhibited a variety of membrane ionic currents, including voltage-gated Ca current and subsequent Ca-activated K currents, and voltage-gated M- and A-type K currents. It is concluded that the principal effect of THA is to inhibit cholinesterase, and that the main consequence of this is to augment and prolong the muscarinic slow epsc. In contrast, the nicotinic fast epsc is not increased but instead may be reduced through a nicotinic channel-blocking action. Although THA could also block several other ion channels the concentrations required were too high to contribute significantly to its principal pharmacological actions on ganglionic transmission.     

Modulation of Neuropeptide-lnduced Membrane Currents by Protein Kinase C in Xenopus Oocytes Injected with GH3 Pituitary Cell Poly(A)+ RNA

Protein kinase C was activated in Xenopus laevis oocytes by phorbol ester treatment and its effects on the inositol trisphosphate/Ca²⁺ transmembrane signalling pathway analysed. Induction of the pathway was achieved by ligand stimulation of TRH receptors translated from GH₃ pituitary cell mRNA. In voltage-clamped oocytes bath application of peptide, injection of guanosine 5'-(3-O-thio) triphosphate (GTPγS), inositol trisphosphate or Ca²⁺ all elicited inward membrane currents. Treatment of oocytes with tumour-promoting phorbol esters for 35 min almost completely abolished the ligand and GTPγS-induced responses. In contrast, phorbol ester treatment enhanced inositol trisphosphate-generated membrane currents. Ca²⁺-mediated responses remained unaffected by tumour promoters. The data indicate a dual role for protein kinase C in the modulation of transmembrane signalling: a feedback mechanism prevents phosphoinositide turnover whereas a feedforward reaction triggers the effect of intracellular inositol trisphosphate on the Ca²⁺ release.