Saburo Otsuki

Leukocytosis During Lithium Treatment and Its Correlation to Serum Lithium Level

Mayfield et al., OConnell,6 and Murphy et aL4 have reported that lithium administration for the treatment of affective psychosis induces leukocytosis. According to them, many of the cases receiving lithium salt show transient or persistent leukocytosis, but on the withdrawal of lithium the leukocyte count rapidly settles to the normal level. It is said that the extent of such leukocytosis ranges between 10,000-20,000, and that it is actually neutrophilic leukocytosis and lymphopenia. They attribute the causative factor to changes in steroid metabolism due to the effect of lithium on bone marrow. However, Johnson et aZ.l have not encountered any persistent leukocytosis. Having encountered cases of transient or persistent leukocytosis during the lithium therapy, we have studied the correlation between leukocytosis induced by lithium and lithium level in serum and the results will be presented.

Voluntary Intake of Alcohol Is Attenuated by Ipsapirone in Mice and Role of 5–HT1A Receptor

Abstract: Emerging evidences have suggested that the brain serotonin (5‐hydroxy‐tryptamine, 5‐HT) neurotransmitter system is involved in the compulsive alcohol‐seeking behaviors in humans and animal models. The aim of this study is to examine the effect of ipsapirone, which is a specific 5‐HT1A, agonist with a pyrimidinylpiperazine structure, on alcohol consumption in mice (C57BL/6J) by a voluntary alcohol intake paradigm. When the consumed 8, kohol was expressed as g/kg B.W., the total 12‐day amount was significmtly lower in the ipsapirone‐treated mice than in the saline‐treated mice. However, 5‐HT1A receptor binding sites labeled with [3H]8‐OH‐DPAT in hippocampal membranes did not differ significantly in either the total number of binding sites (Bmax) or dissociation constant (Kd) between the two groups. The possible mechanism regarding the role of ipsapirone that attenuated the alcohol consumption, and its relationship to the subtyping 5‐HT receptors are further discussed.

Localization of the mRNAs for Two Dopamine D2 Receptor Isoforms in the Rat Brain

Abstract: Two molecular forms of the dopamine D., receptor were generated by alternative RNA splicing. To investigate the relative distributions of the two mRNAs encoding the D2 receptor isoforms, D2(415) and D2(444), we performed in situ hybridization histochemistry in the rat brain with the two oligonucleotide probes. An insert probe complementary to an additional fragment of the D, receptor mRNA cloned from the rat brain, and a spanning probe complementary to its contiguous sequence were used. These 48 base probes were 3′‐end labeled with [35S]dATP. The brains were dissected from male SD rats and frozen in dry ice and acetone. Cryostat sections (16 um) were collected on gelatin coated slides and stored at – 20oC. In situ hybridization studies were conducted with a probe concentration of 1 × 10e dpm/100 ^1 of buffer per brain slice at 37oC for 18–20 h in a humid chamber. The slides were washed, dried and exposed to tritium sensitive film for one week. The autoradiograph showed that both mRNA were present at high levels in the corpus striatum, accumbens nucleus and substantia nigra (pars compacta). Identical patterns of labeling were obtained in the rat brain using both the insert and spanning probes, although the optical densities detected with the insert probe were higher than those with the spanning probe in the corpus striatum. This suggests that both D2 receptor mRNAs are expressed similarly in each region of the rat brain and D2(14) expressed dominantly in the corpus striatum.

“Sleep Apnoea” and Sleep Regulating Mechanism –A case effectively treated with monochlorimipramine–

The patient was a 69‐year old male, with apnoea‐tonic convulsion in sleep as the chief complaint. Over the period of 17 years prior to his admission to our clinic he had been treated as a case of night epilepsy, without improvement but aggravation. Satisfactory results of our treatment are briefly summarized as follows.

MELAS without Ragged Red Fibers or Lactic Acidosis Diagnosed by Mitochondrial DNA Testing

Abstract: A case of mitochondrial encephalomyopathy with lactic acidosis, a stroke‐like episode (MELAS) without ragged red fiber, diagnosed by mitochondrial DNA testing, is reported. A 37‐year‐old woman experienced a sudden and recurrent headache with vomiting and stroke‐like episodes. Brain CT and MRI showed multiple infarction in the temporal lobes, not corresponding to artery distribution. However, the plasma levels of lactate and pyruvate were normal, and showed no increase after aerobic exercise. Biopsied muscle showed no evidence of ragged red fibers and deficient activity of mitochondrial enzymes in the respiratory chain. The final diagnosis was made by mitochondrial DNA testing. A southern blot analysis after Apa I digestion revealed the A‐to‐G mutation in the tRNALeu(UUR), which is specific to MELAS.

Effect of Chronic Administration of Haloperidol (Intermittently) and Haloperidol‐Decanoate (Continuously) on D2 Dopamine and Muscarinic Cholinergic Receptors and on Carbachol‐Stimulated Phosphoinositide Hydrolysis in the Rat Striatum

Abstract: It has been reported that apomorphine‐induced stereotypy is sensitized after a chronic intermittent administration of haloperidol (HPD), but not after a chronic continuous exposure to haloperidol‐decanoate (HPD‐D). The present study was undertaken to investigate changes in the D2 dopamine and muscarinic receptors in the ratstriatum after the administration of HPD intermittently and HPD‐D continuously. The number of striatal [3H] spiperone binding sites increased significantly after HPD‐D, but did not change after HPD. Neither the number of [3H](–)QNB binding sites nor carbachol‐stimulated phosphoinositide hydrolysis changed after either HPD or HPD‐D. These results indicate that the increase in striatal D2 receptors in rats administered HPD‐D represents behavioral and biochemical tolerance, and that neither the D2 dopamine receptor supersensitivity nor muscarinic receptor hyposensitivity underlies sensitization of apomorphine‐induced stereotypy.

GABA Levels in Cerebrospinal Fluid of Patients with Epilepsy

Abstract: The lumbar cerebrospinal fluid (CSF) γ‐aminobutyric acid (GABA) levels were measured in 27 patients with epilepsy, another three epileptic patients with status epilepticus and three epileptic patients with chronic cerebellar ataxia. The mean lumbar CSF GABA levels of the 27 patients with epilepsy were not significantly different from those of normal controls. Six of these 27 patients who had daily partial complex and partial motor seizures showed significantly low CSF GABA levels as did the six other patients, three each with status epilepticus and chronic cerebellar ataxia. These findings suggest that some epileptic patients have impaired brain GABAergic neurons.

Lack of Effect of Haloperidol or Methamphetamine Treatment on the mRNA Levels of Two Dopamine D, Receptor Isoforms in Rat Brain

Abstract: In order to investigate whether changes of the two mRNAs encoding the D2 receptor isoforms were induced by chronic haloperidol or methamphetamine treatment in rats, we measured the brain mRNA levels using in situ hybridization histochemistry (ISHH). We used two oligonucleotide probes, an “insert” probe to hybridize with the longer D, receptor, D2(444), mRNA, and a “spanning” probe to hybridize with the shorter D2 receptor, D2(415), mRNA. Both D2 mRNAs were detected by ISHH in the caudate putamen, nucleus accumbens, substantia nigra, pars compacta and ventral tegmental men. The distributions and the amounts of the mRNAs for the two D2 isoforms did not change after chronic administration of haloperidol (1 mg/kg/day for 14 days, ip) or methamphetamine (4 mg/kg/day for 14 days, ip). These results suggest that the changes of D2 receptor density induced by chronic neuroleptic and psychostimulant treatment are not due primarily to receptor expression.

Possible Relationship between Antimanic Effect and Activity of Zotepine to 5HT1 Receptor

Abstract: Zotepine (ZTP), synthesized by Fujisawa Pharmaceutical Co., Ltd. for possible use as an antipsychotic drug, clinically features a very rapid and potent antimanic effect. To elucidate the psychopharmacological mechanisms of zotepine, we have attempted to measure the potency of ZTP compared with other neuroleptic drugs in competing for binding sites in the brain associated with dopamine, serotonin (5–HT1, 5–HT2), noradrenaline (NA) and acetyl‐choline. Zotepine was found to have the most potent activity to the 5HT1 receptor among the test drugs. Chlorpromazine and thioridazine, which belong to phenothiazines and clinically have less potent antimanic effect, shared ZTPs potent activity to the NA receptor, while they were less potent than ZTP in activity to the 5HT1 receptor. These results show that the activity of the drugs to the 5HT1 receptor may be associated with the antimanic effect.

Organ Distribution and Metabolism of Radioactive Iodochlorohydroxyquinoline (Clioquinol, Chinoform) in Animals

:311-clioquinol used was synthesized by the method of Das and Mukherji.2 A radiothin-layer chromatography proved the substance used to be 99% pure. Clioquinol -2,3,4,-14C was purchased from Daiichi Pure Chemicals Co., Ltd. Purity analysis by radio-thin-layer chromatography on silica gel in methanol : benzene : acetone : acetic acid (4 : 14 : 1 : 1) and benzene : methanol : acetic acid (45 : 8 : 9) showed that radioactive 14C-clioquinol has 99 % purity. The radioactive clioquinol was emulsified in carboxyl-methyl cellulose (CMC) suspension and served as materials for oral administration, intraperitoneal and intramuscular injections. For intravenous injection, the substance was dissolved in 0.1N NaOH.