The Japanese Journal of Pharmacology
Online ISSN : 1347-3506
Print ISSN : 0021-5198
ISSN-L : 0021-5198
Volume 31, Issue 3
Displaying 1-26 of 26 articles from this issue
  • A. WAUQUIER, C.J.E. NIEMEGEERS, P.A.J. JANSSEN
    1981 Volume 31 Issue 3 Pages 305-314
    Published: 1981
    Released on J-STAGE: November 07, 2006
    JOURNAL FREE ACCESS
    Domperidone, a new gastrokinetic with potent antiemetic properties is devoid of central effects, up to high dose levels. To assess the CNS activity of domperidone and metoclopramide, the inhibition of intracranial self-stimulation (ICS) in two different situations, and the influence on EEG in dogs were studied. The dissociation between the antiemetic and central effects of both compounds were evaluated in dogs given a stereotypogenic dose of apomorphine. A significant and doserelated inhibition of ICS (conditioned situation) was obtained with 0.8 and 1.6 mg/kg i.v. domperidone and with 0.125, 0.25 and 0.50 mg/kg i.v. metoclopramide. The ED50 values were 0.79 mg/kg and 0.25 mg/kg respectively. The effect was most pronounced 4 hr after administration with domperidone and 15 min after administration with metoclopramide. In the EEG studies, no specific structure-related effects were found but the total potency was increased with domperidone 0.8 and 1.6 mg/kg i.v. and with metoclopramide 0.063, 0.125, 0.25 and 0.50 mg/kg i.v. This increase was due to a decrease in fast frequencies, an increase of slower frequencies and a slight increase of the amplitude. Sleep-like patterns were not observed with either compound. In the apomorphine-test in dogs, the ratio between the i.v. ED50 values for antagonism of stereotypy and of emesis was 180 (1.8/0.01) for domperidone and 2.67 (0.64/0.24) for metoclopramide. Thus, central effects and antiemetic effects are concomitant with metoclopramide, whereas with domperidone, extremely large doses are required to obtain central effects.
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  • Yoshito KOTANI, Masafumi OKA, Norifumi YONEHARA, Teruo KUDO, Reizo INO ...
    1981 Volume 31 Issue 3 Pages 315-321
    Published: 1981
    Released on J-STAGE: November 07, 2006
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    The objective of our study was to determine whether the pure synthetic substance P(SP) is algesiogenic or analgesic when administered centrally or peripherally. The relationships between SP-induced analgesia and the content of morphine-like factor (MLF) in the brain were also studied. Intracarotid arterial administration of SP (20-200 μg) produced no pseudoaffective responses to pain in six out of nine rats, but in the remaining three, there was an exhibition of these responses. Chlorpheniramine pretreatment antagonized these responses. On cantharidin blister base experiments in humans, SP (10-3 g/ml) produced slight pain and an itchy sensation. SP given intracerebroventricularly produced an analgesia in mice in a dose of 5 ng/mouse, as determined by the acetic acid-induced writhing and hot plate methods. These SP-induced analgesia were antagonized by naloxone pretreatment. SP did not alter the content of MLF in the mouse whole brain. However, SP5-11 not only produced an analgesia but also increased the content of MLF. These results suggest that SP has a slight algesiogenic activity which might be mediated by histamine and a slight analgesic activity which might be mediated by MLF.
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  • Yukio YONETANI, Kazumi IWAKI
    1981 Volume 31 Issue 3 Pages 323-332
    Published: 1981
    Released on J-STAGE: November 07, 2006
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    The presence of extra-hepatic systems for uric acid production and their role in catecholamine-induced hyperuricemia were studied in eviscerated rats with functional hepatectomy. In these animals, the plasma uric acid level progressively increased with a decrease of allantoin, and isoproterenol subcutaneously administered in low doses produced an evident hyperuricemia. The effect of isoproterenol was seen even in nephrectomized animals, but all effects were abolished by pretreatment with allopurinol. Epinephrine and norepinephrine also produced hyperuricemia, though to a lesser extent than isoproterenol. Propranolol inhibited the hyperuricemic effects of isoproterenol and epinephrine, while phentolamine potentiated the effects of epinephrine. Electrical stimulation of the splanchnic nerve also produced hyperuricemia in eviscerated rats with functional hepatectomy, and this state was abolished by pretreatment with propranolol and by adrenalectomy but was not affected by pretreatment with phentolamine. Thus, beta adrenoceptor agonists stimulate production of uric acid in tissues other than the liver and the viscera, and hyperuricemia results. An effect similar to that on the uric acid level was also observed for the levels of plasma lactate, creatinine and glutamic oxalacetic transaminase in rats given isoproterenol.
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  • Hideo KAMEI, Minoru HIRANO, Kimio KAWANO, Shinji MURATA, Hideyo IMANIS ...
    1981 Volume 31 Issue 3 Pages 333-346
    Published: 1981
    Released on J-STAGE: November 07, 2006
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    The pharmacological activities of BB-1502 (9-cyclohexyl-2-n-propoxy-9H-adenine), a potent bronchodilator and inhibitor of cyclic AMP phosphodiesterase, were compared with those of aminophylline in a number of biological systems. In vitro, BB-1502 relaxed guinea pig tracheal tissue at a concentration ca. 600 times lower than that required for aminophylline. The ability of BB-1502 to inhibit cyclic AMP phosphodiesterase of guinea pig lung origin was 15 times greater than that of aminophylline. The direct bronchodilator activity of BB-1502 determined in guinea pigs by the intraduodenal route was 5 times greater and the duration of the action longer than that of aminophylline. In dogs, intraduodenal BB-1502 inhibited bronchoconstriction induced by pilocarpine, histamine, or acetylcholine and the activity of the new compound was 4 to 7 times more potent than that of aminophylline. In experimental asthma studies, orally administered BB-1502 protected guinea pigs from allergy-induced asthma provoked by an antigen challenge with aerosolized egg albumin and here the potency was 4 times greater than that of aminophylline. Ascaris antigen-induced asthma in dogs was completely inhibited by the oral administration of BB-1502 in a dose of 1 mg/kg with significant protection seen at 0.3 and 0.1 mg/kg. No complete protection was obtained with aminophylline in the dog asthma model. Cardiovascular effects observed with guinea pigs and dogs following the oral administration of BB-1502 were considerably less than those seen with aminophylline. CNS side effects were nil in rats when BB-1502 was given at 3 times the dose that produced significant stimulation by aminophylline. Acute lethal toxicity determined in mice by the oral route was similar for BB-1502 and aminophylline.
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  • Katsuo KAMATA, Kunihiko OGAWA, Tsutomu KAMEYAMA
    1981 Volume 31 Issue 3 Pages 347-353
    Published: 1981
    Released on J-STAGE: November 07, 2006
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    As a model, we used struggling induced by a repetitive stimulation of the tail or abdomen and two types of pseudoaffective responses were evoked in rats. The effects of narcotic and non-narcotic analgesics on these responses were alternately assessed. Narcotics were markedly effective in inhibiting struggling elicited by tail stimulation and slightly less effective in suppressing the abdominal stimulation-induced struggling. These effects on two types of struggling differed quantitatively but not qualitatively. On the other hand, non-narcotics such as aspirin (200 mg/ kg, i.p.), aminopyrine (160 mg/kg, i.p.) and indomethacin (20 mg/kg, i.p.) had an inhibitory action on the struggling elicited by the tail stimulation but showed equivocal and far less inhibition on the abdominal stimulationinduced response. These two effects were quantitatively and qualitatively different because the slope of the dose-response curves were not in parallel. The action of baclofen appears to be ambiguous since it had distinctive inhibitory actions on both types of struggling. However, baclofen can be classified into the latter group in that it exerted an inhibitory action on two types of struggling, in a quantitatively different manner. These results suggest that two types of struggling in rats provide a convenient means to assess the potency of analgesics.
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  • Yasuharu SASAKI, Sachiko IKUKAWA, Hiroyoshi HIDAKA
    1981 Volume 31 Issue 3 Pages 355-359
    Published: 1981
    Released on J-STAGE: November 07, 2006
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    Inhibitory effect of 8-alkyl cyclic AMP derivatives on the soluble guanylate cyclase activity from human platelets was investigated. Cyclic AMP derivatives with alkyl chains of 6 or less carbons at 8-position of the purine base were not inhibitory, but the derivatives with alkyl chains of 7 or more carbons produced significant inhibition of the soluble guanylate cyclase activity. The extent of inhibitory effect increased when a longer alkyl chain was introduced at the 8-position of cyclic AMP. In contrast, 8-alkyl adenosine derivatives did not inhibit the cyclase activity. These results suggest that the platelet guanylate cyclase has an affinity for cyclic AMP derivatives with hydrophobic property as well as for several guanine nucleotides such as GTP or cyclic GMP.
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  • Tadao SHOJI
    1981 Volume 31 Issue 3 Pages 361-368
    Published: 1981
    Released on J-STAGE: November 07, 2006
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    Effectiveness of E-643, a newly developed α-blocker, and four α-antagonists in blocking pre- and postsynaptic α-adrenoceptors were compared in the isolated rat vas deferens. The inhibitory effect of clonidine on the field-stimulated twitch response was antagonized in the presence of the α-antagonists. The order of affinity (pA2) for presynaptic α-receptors, as assessed from parallel shift of the dose-response curve to clonidine, was: phentolamine>yohimbine>tolazoline>E-643≥prazosin. At concentrations from 10-8 to 10-6 M, neither E-643 nor prazosin had any effect on the twitch which had been depressed by the treatment with clonidine, whereas phentolamine, yohimbine and tolazoline partially reversed it. Contractile effects of cumulative concentrations of noradrenaline were also antagonized by α-antagonists. The order of affinity (pA2) for postsynaptic α-receptors was: E-643≥prazosin>phentolamine>yohimbine>tolazoline. Selectivity for pre- versus postsynaptic α-receptors was assessed by comparing KB values for pre- and postsynaptic α-receptors. The order of selectivity for the presynaptic α-receptors was: yohimbine>tolazoline>phentolamine >> prazosin≥E-643. It is concluded that E-643 is a potent and highly selective postsynaptic α-blocker.
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  • Motoki KOBAYASHI, Katsuya OHATA
    1981 Volume 31 Issue 3 Pages 369-373
    Published: 1981
    Released on J-STAGE: November 07, 2006
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    The effects of inhibitors on the kinin-forming enzyme (KFE) activity in the rat stomach were investigated at pH 4.8. The KFE activity was unaffected by trasylol (200 KIU/ml), soybean trypsin inhibitor (100μg/ ml) and p-tosyl-L-lysine-chloromethyl ketone (10-3 M), but was inhibited by pepstatin A (10-6 M) and chymostatin (1.5×10-4 M). Each product from the rat plasma kininogen by the rat stomach KFE and the bovine spleen cathepsin D was eluated at the same retention time on the equilibrium chromatography on the SP-Sephadex C-25 column. The KFE activity in the rat stomach was considerably high compared with that in various regions of the intestine. These results suggest that the KFE is characteristically similar to cathepsin D, and the enzyme is probably relevant to the function of the stomach.
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  • Eijiro TAGASHIRA, Tomoko URANO, Ken-ichi YASUKOUCHI, Tameo HIRAMORI, S ...
    1981 Volume 31 Issue 3 Pages 375-382
    Published: 1981
    Released on J-STAGE: November 07, 2006
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    The experimental results on tolerance to and dependence on phenobarbital (PhB) in male, ICR mice were compared with results previously reported in the case of rats. When food admixed with 1 and 2 mg PhB/g food was administered daily for 13 consecutive days, the mice began to acquire tolerance to PhB from the 4th day or so (rotarod performance test), with little suppression being observed on days 6 or 7. These results indicate that tolerance to PhB is acquired earlier in mice than in rats. The blood and brain concentrations of PhB during the dosing period were reduced abruptly on the 3rd or 4th day, corresponding well with the time course changes in the development of tolerance shown by rotarod performance. The mice were given daily doses of PhB increasing stepwise from 0.5 and 1 mg PhB/g food to 4 mg PhB/g food, over 39 consecutive days. With this gradually increasing dose regimen, the animals maintained moderate to severe depression of CNS throughout the dosing period. The blood and brain halflife of PhB after withdrawal were 16 and 8 hr respectively. From 17 to 24 hours after withdrawal of PhB, the animals showed signs of systemic tremors, Straub-tail, hyperkinesia, wild running “rum fits” and clonic-tonic convulsions. Contrary to the findings in rats, in which there was a frequent incidence of convulsion from 17 to 48 hours after withdrawal, the duration of the characteristic signs after barbiturate withdrawal was obviously shortterm. These results suggest that it may be more reasonable to use rats in preference to mice as a preclinical model of dependence, especially in cross-physical dependence tests for sedative-hypnotic drugs.
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  • Fumiaki HATA, Kunio TAKEYASU, Yoshio MORIKAWA, Ron-Tsan LAI, Hajime IS ...
    1981 Volume 31 Issue 3 Pages 383-390
    Published: 1981
    Released on J-STAGE: November 07, 2006
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    Contractile responses of rat vas deferens were studied with particular attention directed to the role of receptors and neuronal control. Marked contraction of the vas deferens was observed with α-adrenergic agonists, depending on their concentrations. This tissue had a low sensitivity to ACh. Four days after denervation, this tissue showed a supersensitivity to α-adrenergic agonists and a high K+ concentration, but not to ACh. The increase in sensitivity to α-agonists resulted in an enhancement of the maximal response and a shift of the concentration response curve to lower concentrations of these reagents. Alterations were seen in the α-adrenergic receptors in the rat vas deferens, assayed by measuring the binding of [3H]WB4101. The maximal binding sites decreased significantly to 86 from 142 fmoles per mg protein. The affinity of the receptors for α-agonist, determined by measuring the ability of agonists to displace bound [3H] WB4101, increased significantly, while the affinity to a-antagonists remained unchanged. Studies on [3H]QNB binding indicated no significant change in muscarinic ACh receptors after denervation. Thus, supersensitivity of the α-adrenergic mechanism mediated by a specific change in affinity of α-receptors occurs after denervation of rat vas deferens. These changes in sensitivity and in receptors are discussed in relation to the characteristics and roles of α-receptors in the rat vas deferens.
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  • Yukiko SUZUKI, Yukihiko HAGIWARA, Kyoji TAGUCHI, Kazuyo KAJIYAMA, Taka ...
    1981 Volume 31 Issue 3 Pages 391-400
    Published: 1981
    Released on J-STAGE: November 07, 2006
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    The effects of desoxynupharidine hydrochloride (DN) as the extractive component of the Nuphar japonicum DC on the central nervous system were studied. In the acute cats, DN (1-3 mg/kg, i.v.) produced 8-10 Hz waves in the hypothalamus lateralis and amygdala, and the hippocampal arousal wave gave way to the irregular high amplitude slow waves. In the midbrain reticular formation, nucl. reticularis and cortex, 12-13 Hz waves and high amplitude slow waves increased. A sleep-like pattern with spindle burst-like waves formed the general pattern of all EEGs. These spontaneous EEG activities were significantly inhibited by epinephrine hydrochloride and were potentiated by tolazoline hydrochloride and dibenamine hydrochloride etc. The above EEG changes were obtained even in the spinal cats. DN depressed the EEG arousal response produced by high frequency stimulation of the sciatic nerve and increased the threshold of stimulation. In the chronic cats, DN (1 mg/kg, i.v.) produced spindle burst-like waves of 12-14 Hz in the cortex and sedation concomitantly. These findings suggest that DN has an inhibitory effect on the central nervous system and that adrenergic neurons are probably involved.
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  • Tadamitsu KOMORI, Kenjiro YAMAMOTO
    1981 Volume 31 Issue 3 Pages 401-407
    Published: 1981
    Released on J-STAGE: November 07, 2006
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    The hypotensive effect of YS-980, (4R)-3-[(2S)-3-mercapto-2-methyl propanoyl]-4-thiazolidinecarboxylic acid, was investigated in normotensive and different models of hypertensive rats. Experiments were carried out in both anesthetized rats (1 mg/kg i.v.), and conscious unrestrained rats (10 mg/kg p.o.). YS-980 markedly lowered blood pressure in acute renal hypertensive and two-kidney, one-clip hypertensive rats and moderately lowered the pressure in SHR. Contrary to these hypotensive effects, this agent did not reduce the blood pressure in DOCA hypertensive rats. In normotensive rats, YS-980 had a slight hypotensive action in anesthetized rats but not in the conscious animals. The hypotensive effect of YS-980 is attributed mainly to suppression of the reninangiotensin system.
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  • Teruyuki YANAGISAWA, Norio TAIRA
    1981 Volume 31 Issue 3 Pages 409-417
    Published: 1981
    Released on J-STAGE: November 07, 2006
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    In canine Purkinje fibers firing spontaneously at a cycle length of about 2.7 sec, 2-nicotinamidethyl nitrate (SG-75) (10-6-10-4 M) increased the cycle length and in high concentrations (10-5-10-4 M) abolished the spontaneous firing. The increase in cycle length was due entirely to that decrease in slope of the diastolic depolarization which was more marked during late diastole than during early diastole. Neither the maximum diastolic potential nor the take-off potential was changed. When the membrane potential failed to reach the take-off potential, it polarized again after the early diastolic depolarization, in some fibers. The depth of the notch was increased and the peak value of the plateau of the action potential was decreased by SG-75, however, the maximum rate of rise of the action potential remained unchanged. Shortening of the action potential duration was evident when Purkinje fibers were stimulated at a cycle length of 2 sec. These fibers remained excitable at 10-4 M SG-75 and when stimulated at a cycle length of 2 sec, the action potential occurred with a duration of less than half of control. These results can be interpreted as being due to an increase in the background K current induced by SG-75.
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  • Seizaburo KANOH, Yoshiyuki OGAWA
    1981 Volume 31 Issue 3 Pages 419-424
    Published: 1981
    Released on J-STAGE: November 07, 2006
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    As proteolipid of the myelin sheath and its parent glial membrane may possibly interact with bacterial pyrogen (lipopolysaccharide, LPS) during penetration into the brain, we investigated the interaction of LPS with proteolipid derived from the cerebrum of rabbits, rats and chickens. Intravenous administration of LPS (1 μg/kg) produced a febrile response in rabbits, but not in rats and chickens. Marked hyperthermia was observed in these three species after intracisternal administration of LPS (0.01-0.1 μg/ kg). Dinitrophenol (30 mg/kg s.c.) induced a high fever in these three species tested, particularly in the chickens. The pyrogenicity of LPS given intravenously to rabbits was inactivated by incubation of LPS with proteolipid in vitro. Inactivation effects of proteolipid extracted from the three species was in the order of: chickens, rats and rabbits. In rats, the inactivation effects of proteolipid from the adult animal were more potent than in the case of newborn animals. The febrile response induced by dinitrophenol and leucocytic pyrogen in rabbits, however, was not suppressed by incubation with proteolipid extracted from the rabbit brain. These results suggest that proteolipids do play an important role in the mechanism of penetration of LPS into the brain.
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  • Yoshiyuki OGAWA, Seizaburo KANOH
    1981 Volume 31 Issue 3 Pages 425-431
    Published: 1981
    Released on J-STAGE: November 07, 2006
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    Our previous finding that the cerebral proteolipid could inactivate the pyrogenicity of lipopolysaccharide (LPS) in vitro was also studied by Sephadex LH-20 column chromatography and the following results were obtained. When rabbit cerebral proteolipid was chromatographed, two main protein peaks were obtained. One appeared in the chloroform (C)/ methanol (M) 6:1 and the other C/M 4:1 effluent, designated as fraction IV and fraction V, respectively. When the incubation mixture of proteolipid and LPS was chromatographed, a new protein peak appeared in the C effluent. The new protein peak was suggested to be a complex of proteolipid protein and LPS, because pyrogenicity could be detected in the protein fractions only after treatment with 2% SDS. Fraction V but not fraction IV inactivated the pyrogenicity of LPS in vitro. By re-chromatography of the incubation mixture of fraction V and LPS, a complex of protein and LPS was also eluted in the C effluent. On the other hand, by rechromatography of the incubation mixture of fraction IV and LPS, such a complex was not detected in the C effluent. The present results suggest that the proteolipid apoprotein eluted in the C/M 4:1 effluent on a Sephadex LH-20 column plays an important role in the inactivation of the pyrogenicity of LPS.
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  • Yasushi YAMAZOE, Hiroaki NUMATA, Tomoji YANAGITA
    1981 Volume 31 Issue 3 Pages 433-442
    Published: 1981
    Released on J-STAGE: November 07, 2006
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    The metabolic fate of thebaine in rhesus monkeys was investigated. Using thin layer chromatography, more than four metabolites were detected in the urine of monkeys given thebaine (8 mg/kg, s.c.). Two of the metabolites isolated by high performance liquid chromatography were not consistent with those reported previously. With the use of gas chromatography-mass spectrometry, the structures were identified as oripavine (3-O-demethylthebaine) and nororipavine (3-O, N-di-demethylthebaine) from the mass spectra of their trimethylsilyl and propionyl derivatives. Further experiments with liver microsomes from rhesus monkeys showed that, in addition to these metabolites, northebaine was also formed from thebaine in the presence of NADPH.
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  • Toshio YOSHIZAKI, Kanya TONDA
    1981 Volume 31 Issue 3 Pages 443-449
    Published: 1981
    Released on J-STAGE: November 07, 2006
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    We studied the effects of tricyclic antidepressants on the tetrabenazine (TB)-induced depletion of brain dopamine (DA) using rats. The test drugs were generally administered orally 3 hours before sacrifice and 2 mg/kg of TB or reserpine (RES) was administered subcutaneously 2 hours before sacrifice. The TB-induced DA depletion was enhanced by pretreatment with desmethylimipramine (DMI, 12.5-100 mg/kg), imipramine (12.5-100 mg/kg), chlorimipramine (25-100 mg/kg), amitriptyrine (100 mg/kg), maprotyrine (50 mg/kg) and chlorpromazine (5-20 mg/kg i.p.), while these drugs did not enhance RES-induced depletion. Observations to elucidate the action mechanism of antidepressant-induced enhancement were as follows. After TB administration, brain DA content was at the minimal level at 30 min after and on the way to recovery at 2 hours, but it approached the minimal level at 2 hours after RES administration. DMI pretreatment did not enhance the DA depletion at 0.5 hours after TB administration. In pargyline-pretreated rats, TB produced a decrease of brain DA with an increase of 3-methoxy-tyramine (3-MT), while RES showed only a slight effect on DA and 3-MT up to 2 hours. Amphetamine sulfate (20 mg/kg i.p.) slightly increased, while combinations with DMI decreased brain DA. These results suggest that tricyclic antidepressants inhibit DA reuptake from the synaptic cleft in vivo.
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  • Tomoko FUJII, Seiji KONDO
    1981 Volume 31 Issue 3 Pages 451-454
    Published: 1981
    Released on J-STAGE: November 07, 2006
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  • Motoki KOBAYASHI, Katsuya OHATA
    1981 Volume 31 Issue 3 Pages 455-458
    Published: 1981
    Released on J-STAGE: November 07, 2006
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  • Sumie KAWANO, Toshiko NAKAO, Kogo HIRAGA
    1981 Volume 31 Issue 3 Pages 459-462
    Published: 1981
    Released on J-STAGE: November 07, 2006
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  • Kaoru IRIE, Teruko NOMOTO
    1981 Volume 31 Issue 3 Pages 463-466
    Published: 1981
    Released on J-STAGE: November 07, 2006
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  • Yohkazu MATSUSHIMA, Munekazu GEMBA
    1981 Volume 31 Issue 3 Pages 467-469
    Published: 1981
    Released on J-STAGE: November 07, 2006
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  • Osamu SUZUKI, Hideki HATTORI, Minoru ASANO
    1981 Volume 31 Issue 3 Pages 470-473
    Published: 1981
    Released on J-STAGE: November 07, 2006
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  • Shigetoshi CHIBA, Hidehiko WATANABE, Akemi KOSHIHARA
    1981 Volume 31 Issue 3 Pages 474-476
    Published: 1981
    Released on J-STAGE: November 07, 2006
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  • Kumeji TAKEUCHI, Hiroshi KOGO, Yoshio AIZAWA
    1981 Volume 31 Issue 3 Pages 477-479
    Published: 1981
    Released on J-STAGE: November 07, 2006
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  • Fumitoshi ASAI, Eiki SATOH, Masakazu NISHIMURA, Norimoto URAKAWA
    1981 Volume 31 Issue 3 Pages 480-483
    Published: 1981
    Released on J-STAGE: November 07, 2006
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