Comparative Study of Tiapride and Neuroleptics with Anti-Dopamine Activity on Convulsive Seizure in Mice Hisashi SATOH, Hajime NAKANISHI, Kiyoharu SHIRAKAWA, Yoshiro KOHJIMOTO, Tomoyuki KUWAKI,Takaharu ONO and Fumio SHIBAYAMA ResearchLaboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6 Kashima,Yodogawa-ku, Osaka 532, Japan AcceptedSeptember 22, 1986 Abstract-The effects of tiapride on the convulsive seizures induced by pen tylenetetrazole, strychnine, picrotoxin and bemegride, and on electric seizure are reported and compared with those of sulpiride, chlorpromazine, haloperidol and reserpine. The number of deaths and intensity of convulsion increased dose dependently and also with the increase in amplitude of electric shock. Tiapride and a similar compound, sulpiride, did not affect these seizures, whereas chlor promazine potentiated strychnine-induced and electric seizure. Haloperidol and reserpine potentiated electric seizure, and chlorpromazine and reserpine tended to potentiate bemegride-induced seizure. Reserpine also tended to potentiate pentylenetetrazole-induced seizure. These results suggest that tiapride would be clinically safer than other drugs with anti-dopamine activity, except for sulpiride. Tiapride, N-[2-(diethylamino)ethyl]-5 gride were used as convulsants. A preliminary (methylsulfonyl)-o-anisamide, has a chemical experiment was conducted to determine the structure and binding specificity to dopamine death-inducing threshold of the four con receptor similar to sulpiride, and it has been vulsants. Animals were used in groups of used to treat elderly patients with organic 10 to 20. The number of animals that died psychosis (1 ). Neuroleptics with anti within 1 hr after dosing with a convulsant dopamine activity are also used in aged was used to determine the death-inducing patients with organic psychosis, but these threshold of each compound. Each threshold drugs occasionally induce seizure (2-4). dose of convulsant was given to 10 or 20 Because the seizure-inducing potential of animals to examine the effect of the test tiapride has not been examined, we studied drugs. its effect on the convulsion induced by Electric seizure: Each dose of the test pentylenetetrazole, strychnine, picrotoxin and drugs was given to 10 animals. Electric bemegride as well as on electric seizure, and current was increased 0.5 mA per sec. The these effects were compared with those of amplitude of the current (mA) inducing sulpiride, chlorpromazine, haloperidol and clonic or tonic convulsion was measured, reserpine. that is, each amplitude was expressed as the threshold of the respective convulsion. Materials and Methods Drugs: The test drugs were tiapride Animals: Female ICR mice aged 6 weeks hydrochloride, sulpiride (Delagrange), chlor and weighing 17.2-30.0 g (Shizuoka promazine hydrochloride (synthesized at our Agricultural Cooperative Association for Laboratories), haloperidol (Janssen) and Laboratory Animals) were used. reserpine (Serpasil® for injection, Takeda). Convulsants-induced seizure: Pentylene Convulsants used in this study were pen tetrazole, strychnine, picrotoxin and beme tylenetetrazole (Tokyo Kasei), strychnine nitrate (Sigma), picrotoxin (Nakarai) and pentylenetetrazole, 40 and 70 mg/kg; bemegride (Wako). All drugs except halo strychnine, 1.25 and 1.5 mg/kg; picrotoxin, peridol and sulpiride were dissolved in saline 7 and 9 mg/kg; and bemegride, 20 and 30 or distilled water. Haloperidol and sulpiride mg/kg, i.p. were dissolved in a minimum amount of Effect of drugs on death: The effect of the 20% acetic acid and 1 N sulfuric acid, test drugs on pentylenetetrazole induced respectively, and the pH of the solution was seizure is shown in Table 2. Reserpine dose adjusted to 7.0 with 1 N sodium hydroxide. dependently potentiated the death of animals Reserpine was diluted with distilled water. treated with 40 mg/kg of pentylenetetrazole. All the convulsants were given i.p. The test The other drugs had no effect. drugs except for reserpine were given p.o. The effect of the drugs on strychnine 1 hr before challenge. Reserpine was given induced seizure is shown in Table 3. Only i.p. 24 hr before challenge. chlorpromazine significantly potentiated the Statistics: Statistical significance was death-inducing effect of strychnine. calculated by Student's t-test or Fisher's The effect of the drugs on picrotoxin exact probability test (5). induced seizure is shown in Table 4. None of the drugs affected the seizure. Results The effect of the drugs on bemegride Death-inducing threshold of convulsants: induced seizure is shown in Table 5. Table 1 shows the death-inducing threshold Chlorpromazine and reserpine slightly poten of each convulsant. All the convulsants tiated the effect of bemegride. The other caused death dose-dependently. The dose drugs had no effect. effect curve of each convulsant was abrupt. Effect of drugs on electric seizure: The The doses of convulsants used to examine effect of the test drugs on electric seizure is the effects of the test drugs were as follows: shown in Table 6. Chlorpromazine, Table 2. Effect of drugs on pentylenetetrazole-induced seizure All drugs except reserpine were given p.o. 1 hr before injection of pentylenetetrazole. Reserpine was given i.p. 24 hr before injection of pentylenetetrazole. Table 3. Effect of drugs on strychnine-induced seizure All drugs except reserpine were given p.o. 1 hr before injection of strychnine. Reserpine was given i.p. 24 hr before injection of strychnine. *: P<0.05 Table 4. Effect of drugs on picrotoxin-induced seizure All drugs except reserpine were given p.o. 1 hr before injection of picrotoxin. Reserpine was given i.p. 24 hr before injection of picrotoxin. Table 5. Effect of drugs on bemecgride-induced seizure All drugs except reserpine were given p.o. 1 hr before injection of bemergride. Reserpine was given i.p. 24 hr before injection of bemegride. All drugs except reserpine were given p.o. 1 hr before electric stimulation. Reserpine was given i.p. 24 hr before electric stimulation. Figures show the mean±S.E. *: P<0.05 haloperidol and reserpine potentiated the convulsion. Tiapride and sulpiride had no electric seizure, that is, these drugs lowered effect. the amplitude inducing clonic and tonic The effects of the test drugs on seizure are summarized in Table 7. Tiapride, like and an unknown substance are reported to sulpiride, had no effect on any of these be involved in bemegride-induced con seizures, whereas chlorpromazine potentiated vulsion (19). In electric seizure, such strychnine-induced and electric seizures. substances as norepinephrine, serotonin and Haloperidol and reserpine also potentiated adenosine are supposed to participate (9). electric seizure, and chlorpromazine and In contrast, dopamine has little effect on reserpine slightly potentiated bemegride pentylenetetrazole induced and electric induced seizure. Reserpine also slightly seizures (9). potentiated pentylenetetrazole-induced sei Such neuroleptics as chlorpromazine block zure. many amine receptors as well as the dopamine receptor (20, 21), and reserpine lowers the Discussion activity of norepinephrine, serotonin and Reserpine, an amine depleter, lowers the dopamine on the receptor sites. Therefore, seizure threshold in rodents (6). Clinically, these drugs would potentiate the seizure, and neuroleptics with anti-dopamine activity this effect might correlate with the seizure occasionally induce convulsive seizure (2-4), inducing effect in clinical use. In contrast, and reserpine weakens the effect of anti tiapride and sulpiride act only on the convulsants (7). Tiapride is a dopamine dopamine receptor (8). Therefore, the specific antagonist in the central nervous absence of an effect on seizure may be due system (8). However, its effect on the seizure to their selective blocking activity on the threshold has not been examined. In our dopamine receptor. Sulpiride only poorly experiments, tiapride had no effect on the penetrates the blood-brain barrier (22), seizure induced by any of the convulsants or and further experiments are needed to on electric seizure. confirm its effect on seizure in the case of Sulpiride, like tiapride, was also without intraventricular injection. However, the drug effect, but haloperidol, chlorpromazine and is safe for even schizophrenics with epileptic reserpine potentiated or tended to potentiate syndrome (23). the seizure in some experiments. In conclusion, tiapride would be clinically The mechanisms of the convulsants are safer than other anti-dopamine drugs except not clear; however, amine neurons and for sulpiride. some other neurons are supposed to be involved in drug-induced and electric References seizures. Norepinephrine (9, 10), serotonin 1 Shimizu, M., Hasegawa, K., Nishimura, T., (9, 11, 12), GABA (13), acetylcholine (14) Miyasaka, M., Ishino, H. and Yamada, M.: and adenosine (9) are supposed to be Comparison of clinical effects of tiapride, involved in pentylenetetrazole-induced con sulpiride and chlorpromazine in the elderly vulsion. Glycine (15, 16) and GABA (17, patients with organic psychosis using multi 18) are involved in strychnine and picrotoxin center double blind technique. Japan. J. Clin. induced convulsions, respectively. GABA Psychiatry 13, 1017-1031 (1984) 2 Logothetics, J.: Spontaneous epileptic seizures 14 Rastogi, S.K., Puri, J.N., Sinha, J.N. and and electro-encepharographic changes in the Bhargava, K.P.: Involvement of central choli course of phenothiazine therapy. Neurology 17, noceptors in metrazole-induced convulsions.