Mode of action of tiaspirone on the central cholinergic system

K. Kolasa, E. Palazzi, P. Salmoiraghi, G. Guiso, S. Caccia, S. Garattini, S. Consolo

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Tiaspirone, a potential antipsychotic drug, reduced the acetylcholine content of rat hemispheric brain regions (striatum 35%, hippocampus 20%, cortex 32% with no effect on N. accumbens) at an oral dose of 40 mg/kg. Choline content was uniformly raised in the same brain regions. A kinetic study showed that the drug is evenly distributed in the brain. Tiaspirone's effects on acetylcholine and choline in the striatum were not related in time. The fall off (30–240 min) of tiaspirone's effect on choline content paralleled the decline in striatal drug concentration (t1/2 = 240 min) whereas that on acetylcholine did not. No tolerance was observed to an acute challenge with tiaspirone on acetylcholine and choline in the striatum after 11 days' subchronic treatment. In vitro the drug had no effect on striatal choline acetyltransferase and acetylcholinesterase activities up to a concentration of 300 μM. The muscarinic agonist oxotremorine did not interfere with the acetylcholine decrease produced by the drug suggesting that muscarinic receptors are not essential for this effect. Tiaspirone, however, was found to be a competitive, reversible inhibitor of the sodium-dependent high-affinity choline uptake (SDHACU) by crude hippocampal and striatal synaptosomal preparations, giving IC50 values of respectively 3.69 μM and 1.14 μM. The compound did not alter SDHACU ex vivo despite the fact that it readily crosses the blood-brain barrier and achieves brain concentrations equivalent to its in vitro IC50 concentration. Tiaspirone antagonized the striatal acetylcholine increasing effect of apomorphine, a selective dopaminergic receptor agonist, supporting the idea that the drug affects the striatal cholinergic system by a primary action on dopamine receptors. The results indicate that tiaspirone behaves as an atypical neuroleptic on cholinergic system, with the extra effects of increasing choline content and inhibiting SDHACU in vitro.

Original languageEnglish
Pages (from-to)259-264
Number of pages6
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Issue number3
Publication statusPublished - 1989


  • Acetylcholine
  • Atypical neuroleptic
  • BMY 13859 (tiaspirone)
  • Dopamine
  • Rat striatum

ASJC Scopus subject areas

  • Pharmacology

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    Kolasa, K., Palazzi, E., Salmoiraghi, P., Guiso, G., Caccia, S., Garattini, S., & Consolo, S. (1989). Mode of action of tiaspirone on the central cholinergic system. Naunyn-Schmiedeberg's Archives of Pharmacology, 340(3), 259-264.