Summary
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 (t 1/2 = 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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Atweh S, Simon JR, Kuhar MJ (1975) Utilization of sodium-dependent high affinity choline uptake in vitro as a measure of the activity of cholinergic neurons in vivo. Life Sci 17:1535–1543
Burki HR (1979) Biochemical methods for predicting the occurrence of tardive dyskinesia. Commun Psychopharmacol 3:7–15
Caccia S, Fong MH, Guiso G (1985a) Disposition of the psychotropic drugs buspirone, MJ-13805 and piribedil, and of their common active metabolite 1-(2-pyrimidinyl)-piperazine in the rat. Xenobiotica 15:835–844
Caccia S, Fong MH, Urso R (1985b) Ionization constants and partition coefficients of 1-arylpiperazine derivatives. J Pharm Pharmacol 37:567- 570
Consolo S, Ladinsky H, Garattini S (1974) Effect of several dopaminergic drugs and trihexyphenidyl on cholinergic parameters in the rat striatum. J Pharm Pharmacol 26:275–277
Consolo S, Ladinsky H, Bianchi S (1975) Decrease in rat striatal acetylcholine levels by some direct and indirect acting dopaminergic antagonists. Eur J Pharmacol 33:345–351
Consolo S, Ladinsky H, Samanin R, Bianchi S, Ghezzi D (1978) Supersensitivity of the cholinergic response to apomorphine in the striatum following denervation or disuse supersensitivity of dopaminergic receptors in the rat. Brain Res 155:45–54
DeLean A, Munson PJ, Rodbard D (1978) Simultaneous analysis of families of sigmoidal curves: Application to bioassay, radio-ligand assay, and physiological dose-response curves. Am J Physiol 235:E97-E102
Eison MS, Taylor DP, Riblet LA, Temple DL Jr (1984) Determination of functionally-relevant serum levels of MJ 13859–1 in the dog relationship to blockade of amphetamine stereotypy. Meth Find Exp Clin Pharmacol 6:255–259
Fonnum F (1975) A rapid radiochemical method for the determination of choline acetyltransferase. J Neurochem 24:407–409
Freeman JJ, Macri JR, Choi RL, Jenden DJ (1979) Studies on the behavioral and biochemical effects of hemicholinium in vivo. J Pharmacol Exp Ther 210:91–97
Glowinski J, Iversen LL (1966) Regional studies of catecholamines in the rat brain. I. The disposition of [3H]dopamine and [3H]dopa in various regions of the brain. J Neurochem 13:655–669
Gonzalez MA, Tozer TN, Chang DTT (1975) Nonlinear tissue disposition: Salicylic acid in rat brain. J Pharm Sci 64:99–103
Guyenet PG, Agid Y, Javoy F, Beaujouan JC, Rossier J, Glowinski J (1975) Effects of dopaminergic receptor agonists and antagonists on the activity of the neo-striatal cholinergic system. Brain Res 84:227–244
Ladinsky H, Consolo S, Bianchi S, Samamin R, Ghezzi D (1975) Cholinergic-dopaminergic interaction in the striatum: The effect of 6-hydroxydopamine or pimozide treatment on the increased striatal acetylcholine levels induced by apomorphine, piribedil and d-amphetamine. Brain Res 84:221–226
Ladinsky H, Consolo S, Bianchi S, Jori A (1976) Increase in striatal acetylcholine by picrotoxin in the rat: Evidence for a gabergic-dopaminergic link. Brain Res 108:351–361
Ladinsky H, Consolo S, Ghezzi D, Samanin R (1978) Link between dopaminergic and cholinergic neurons in the striatum as evidenced by pharmacological, biochemical and lesion studies. In: Garattini S, Pujol F, Samanin R (eds) Interactions between putative neurotransmitters in the brain. Raven Press, New York, pp 3–21
Ladinsky H, Consolo S, Samanin R, Algeri S, Ponzio F (1980) Long-term effects of haloperidol, clozapine and methadone on rat striatal cholinergic and dopaminergic dynamics. Adv Biochem Psychopharm 24:259–265
Lloyd KG (1978) Neurotransmitter interactions related to central dopamine neurons. Essays Neurochem Neuropharm 3:129–207
McCaman MW, Tomey LR, McCaman RE (1968) Radiomimetric assay of acetylcholinesterase activity in submicrogram amounts of tissue. Life Sci 7:233–244
McGeer PL, Grewaal DS, McGeer EG (1974) Influence of non-cholinergic drugs on rat striatal acetylcholine levels. Brain Res 80:211–217
McMillen BA (1985) Acute and subchronic effects of MJ-13859, a potential antipsychotic drug, on rat brain dopaminergic function. J Pharmacol Exp Ther 233:369–375
Riblet LA, Eison MS, Taylor DP, Temple DL, Yevich JP (1982) Pharmacological profile of a potential antipsychotic agent: MJ-13859–1. Society of Neuroscience Abstract 8:470
Riblet LA, Taylor DP, Eison MS, Temple DL Jr, Yevich JP (1983) MJ-13980-1: A promising antipsychotic agent without predicted potential for extrapyramidal liability. In: Federation of American Societies for Experimental Biology. 67th Annual Meeting, Chicago, Illinois, April 10–15 [Abstract] 1153
Sacchi Landriani G, Guardabasso V, Rocchetti M (1983) NL-FIT: A microcomputer program for non-linear fitting. Comput Programs Biomed 16:35–42
Saelens JK, Allen MP, Simke JP (1970) Determination of acetylcholine and choline by an enzymatic assay. Arch Int Pharmacodyn Ther 186:279–286
Sethy VH, Van Woert MH (1974) Modification of striatal acetylcholine concentration by dopamine receptor agonists and antagonists. Res Commun Chem Pathol Pharmacol 8:13–28
White FJ, Wang RY (1986) Effects of tiaspirone (BMY-13859) and a chemical congener (BMY-13980) on A9 and A10 dopamine neurons in the rat. Neuropharmacology 25:995–1001
Author information
Authors and Affiliations
Additional information
Send offprint requests to S. Consolo at the above address
Rights and permissions
About this article
Cite this article
Kolasa, K., Palazzi, E., Salmoiraghi, P. et al. Mode of action of tiaspirone on the central cholinergic system. Naunyn-Schmiedeberg's Arch Pharmacol 340, 259–264 (1989). https://doi.org/10.1007/BF00168507
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00168507