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The Acute Effect of Timiperone on the Alpha-MT-Induced Dopamine Fluorescence in Rat Brain

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The Acute Effect of Timiperone on the Alpha-MT-Induced Dopamine Fluorescence in Rat Brain THE KURUME MEDICAL JOURNAL SHORT COMMUNICATION Vol. 29, p.93-95, 1982 The Acute Effect of Timiperone on the Alpha-MT-Induced Dopamine Fluorescence in Rat Brain HIDEKI KOJIMA, KAZUMI SUETAKE, TETSUYUKI TSUTSUMI, SHIGEMI ANRAKU AND KAZUTOYO INANAGA Institute of Brain Diseases, Kurume University School of Medicine, Kurume, 830 Japan Received for publication August 17, 1982 Key words: quantitative microfiuorimetry - timiperone haloperidol - do- pamine turnover - rat brain It has been reported that timiperone, a thod for cellular demonstration of biogenic new butyrophenone, 4'-fluoro-4-[4-(2- monoamines described by Falck and Hillarp thioxo -1-benzimidazolynyl) piperidino] bu- (Falck et al. 1962). The formaldehyde gas tyrophenone, possesses potent antipsychotic treatment was performed at 80•Ž for 1 h. activity (Yamasaki et al. 1977; Sato et al. using paraformaldehyde equilibrated at 75% 1978). Tachizawa and co-workers (1979), relative humidity. The specimens were using a 3H -spiroperidol binding assay, embedded in paraffin. The frontal sections showed that timiperone inhibited specific including the following three dopaminergic 3H - spiroperidol binding in vitro at low terminals [1. n. caudatus putamen, 2. n. concentrations similarly to spiroperidol and accumbens and 3. median eminence (lateral was 5 times as potent as haloperidol. In palisade zone) ] were made according to the present fluorescent histochemical in - the atlas of Konig and Klippel (Konig and vestigation, we studied on the effect of Klippel, 1963). A Zeiss fluorescence micro - timiperone on rat central dopaminergic scope (MPMO1 system), with a 100 W high systems in comparison with that of halo - pressure mercury lamp, a BP 405/8 exciter peridol by means of formaldehyde-induced filter, a FT 425 dichroic mirror and a LP fluorescence microscopy (Falck et al. 1962) 450 barrier filter, was employed for the and quantitative microf luorimetry (Jonsson, quantitative measurement of the dopamine 1971). fluorescence intensity. The signal of the The Wistar strain male rats (200-300 g) photomultiplier was led into a digital volt - were used. Timiperone (0. 1 mg/kg -0. 4 meter for the recording of the fluorescence. mg/kg) and haloperidol (0.5 mg/kg -2.0 Fluorescence was measured in 50 circular mg/kg) were orally given to rats 5 h. be - areas in the above mentioned regions. fore decapitation and DL-alpha-methyl- Background fluorescence was obtained by paratyrosine (alpha-MT, 250 mg/kg) was measuring tissue fluorescence in the region injected i. p. 1 h. after the drug adminis- of the anterior commissure and the yen - tration. Control rats were treated with tromedial nucleus which showed no specific 0.3 % C. M. C (1 ml/kg) and alpha-MT in fluorescence. Net dopamine fluorescence the same way as the neuroleptics treated was obtained by subtraction of background rats. The brains were immediately frozen fluorescence. Results were analysed by in isopentane cooled with liquid nitrogen, Student's t -test. freeze -dried and treated with formaldehyde Fig. 1 shows effects of timiperone and gas in accordance with the specific me - haloperidol on the alpha-MT-induced dopa - 93 94 KOJIMA, ET AL. Fig. 2. Effects of timiperone and halo- peridol on the alpha-MT-induced dopamine Fig. 1. Effects of timiperone and halo- fluorescence disappearance in the n. ac- peridol on the alpha-MT-induced dopamine cumbens. Note that 0.1 mg/kg of timiperone fluorescence disappearance in the n. cau- caused a significant increase in the dopa- datus putamen. Note that the reduction in mine turnover. the dopamine fluorescence intensity was not found after administration of 0.1 mg/kg of timiperone. mine fluorescence disappearance in the n. caudatus putamen. The reduction of the dopamine fluorescence intensity was not observed after administration of 0.1 mg/ kg of timiperone. Timiperone in a dose of 0.4 mg/kg, however, caused a significant increase in the dopamine turnover (61.10 •} 7.65%). The dopamine fluorescence in- tensities in haloperidol (0.5 mg/kg and 2.0 mg/kg)-treated rats were 76.32•}4.73% (P•Ú0.05) and 73.97•}11.23%, respec- tively. Effects of timiperone and haloper- idol on the alpha-MT induced dopamine fluorescence disappearance in the n. ac- Fig. 3. Effects of timiperone and halo- cumbens have been shown in Fig. 2. Tim- peridol on the alpha-MT-induced dopamine iperone treatment resulted in a marked fluorescence disappearance in the lateral increase in the dopamine turnover. The palisade zone of the median eminence. dopamine fluorescence intensities in tim- iperone (0.1 mg/kg and 0.4 mg/kg)-treated the median eminence under the present rats were 66.14•}5.22% (p•Ú0.05) and condition (Fig. 3). 51.08•}5.18% (p•Ú0.01), respectively. The fact that 0.1 mg/kg of timiperone These were similar to those in haloperidol- induced the reduction of the dopamine treated rats. On the other hand, acute fluorescence in the n. accumbens (not in treatment with timiperone and haloperidol the n. caudatus putamen) suggests that did not change the dopamine turnover in a small dose of timiperone would suppress SHORT COMMUNICATION 95 selectively the dopamine receptors of the A. (1962). Fluorescence of catechol amines meso-limbic system, and supports strongly and related compounds condensed with for- the experimental data that timiperone pos - maldehyde. J. Histochem. Cytochem. 10, 348- sesses potent antipsychotic activity with 354. less likelihood of extrapyramidal adverse JONSSON,G. (1971). Quantitation of fluorescence of biogenic monoamines. Progr. Histochem. reactions (Yamasaki et al. 1977; Sato et Cytochem. 2, 299-334. al. 1978). KONIG, J. F. R. and KLIPPEL, R. A. (1963). The Furthermore, it was histochemically rat brain-a stereotaxic atlas of the forebrain found that timiperone was approximately and lower parts of the brainstem. Williams 5 times as potent as haloperidol in accel- and Wilkins, Baltimore. erating the meso-limbic dopamine turnover SATO, M., ARIMOTO,M., UENO, K., KOJIMA, H., in rat after oral administration of either YAMASAKI,T., SAKURAI,T. and KASAHARA,A. drug. This supports the recent biochemical (1978). Psychotropic agents. 3,4- (4-substi- tuted piperidinyl) -1 - (4 - fluorophenyl) -1-bu- finding that the specific 3H-spiroperidol tanones with potent neuroleptic activity. J. binding inhibition due to timiperone was 5 Med. Chem. 21, 1116-1120. times as potent as haloperidol (Tachizawa TACHIZAWA,H., SUDO, K. and SANO, M. (1979). et al. 1979). Effect of timiperone on 3H-spiroperidol bind- ing to rat striatal dopamine receptors. Euro- Acknowledgements: For generous supply of pean J. Pharmacol. 59, 245-251. timiperone the authors are indebted to Daiichi YAMASAKI,T., SAKURAI,T., KOJIMA,H. and KASA- Seiyaku Co., Ltd., Tokyo, Japan. HARA,A. (1977). Psychopharmacological ef- fects of a new antipsychotic, 1-[1-{3- (4-flu- orobenzoyl) propyl}-4-piperidyl]-2,3-dihydro- References benzimidazole-2-thione (DD 3480). Jpn. J. Pharmachol. 27, suppy 124. FALCK, B., HILLARP, N. -A., THIEME, G. and TORP,.
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