A dose-response study of anticholinesterase drugs on contractile and phosphatidylinositol responses of rat trachea.

UNLABELLED: We investigated whether anticholinesterase drugs in large doses inhibit muscarinic receptors of airway smooth muscle. In vitro measurements of isometric tension and [(3)H]inositol monophosphate (IP(1)) that formed were conducted by using rat tracheal rings or slices. Neostigmine and pyridostigmine caused muscular contraction and IP(1) accumulation in small doses (10 microM and < or = 100 microM, respectively), but they attenuated muscular contraction and IP(1) accumulation in larger doses (1000 microM). Edrophonium did not affect the smooth muscle tone and IP(1) levels. Neostigmine, pyridostigmine, and edrophonium attenuated the carbachol (5.5 microM)-induced smooth muscle contraction and IP(1) accumulation, when administered in large doses (1000 microM). The attenuation of contraction by neostigmine at large doses was not affected by methoctramine, an M(2) muscarinic receptor antagonist, but was reversed by washing with fresh Krebs-Henseleit solution. The results suggest that anticholinesterase drugs have dual effects on the tension and phosphatidylinositol responses of rat trachea. Large doses of anticholinesterase drugs cause airway smooth muscle relaxation, which may be seen in patients with myasthenia gravis who have received excessive anticholinesterase therapy. IMPLICATIONS: Neostigmine and pyridostigmine, but not edrophonium, have dual effects on the tension and phosphatidylinositol responses of rat trachea. Large doses of anticholinesterase drugs cause airway smooth muscle relaxation, which may be seen in patients with myasthenia gravis who have received excessive anticholinesterase therapy.

Tempo of background sound and performance speed.

24 undergraduates performed a self-paced line tracing task. Fast music accelerated performance compared with slow music whereas the tempo of metronome tones did not affect performance.

Steroidal muscle relaxants attenuate the contractile and phosphatidylinositol responses of rat trachea.

Interaction of the steroidal muscle relaxants, pancuronium, vecuronium and rocuronium with airway muscarinic receptors of rat trachea was investigated in vitro concerning the contractile and phosphatidylinositol (PI) responses. Pancuronium and vecuronium attenuated, while rocuronium did not affect carbachol (CCh)-induced contraction and CCh-induced IP1 accumulation. Pancuronium could inhibit completely CCh-induced contraction at a dose of 30 microM, while it could not inhibit completely CCh-induced IP1 accumulation at the same dose. These drugs attenuated KCl-induced contraction. These results suggest that pancuronium and vecuronium would attenuate airway smooth muscle contraction through the inhibition of muscarinic receptor-mediated PI response, and that the inhibition of voltage-operated Ca++ channel might be involved, in part, in the attenuation by pancuronium of the contraction.

Involvement of the endogenous opioid system in the drinking behavior of schizophrenic patients displaying self-induced water intoxication: a double-blind controlled study with naloxone.

Previously we found significant suppression of polydipsia in a schizophrenic patient with PIP syndrome (psychosis, intermittent hyponatremia, and polydipsia). Suppression was obtained with a small dose of naloxone injected once every 2 weeks in long-term repeated studies. We attempted to confirm the effect of naloxone on PIP syndrome by using a double-blind controlled study. The body weights of eight schizophrenic inpatients with PIP syndrome were checked five times daily, and the maximum weight gain during 1 day was chosen as an index of their polydipsia. Naloxone (0.6 mg in three divided doses) or placebo (saline) injection was given once every 2 weeks three times. Assignment to either the naloxone or placebo series was done randomly in a double-blind, crossover design. Naloxone decreased the maximum weight gain per day significantly in five cases. However, naloxone also increased weight gain significantly in three cases. There was no correlation of the weight-increasing effect of naloxone with the duration and intensity of excessive drinking. Our findings showed that the endogenous opioid system might be related to compulsive drinking behavior in the PIP syndrome and that opioid antagonists such as naloxone or naltrexone could be useful in the therapy of PIP syndrome.

Naloxone attenuates drinking behavior in psychiatric patients displaying self-induced water intoxication.

1. The present study was performed to examine the effect of naloxone on drinking behavior in three schizophrenic inpatients with psychosis, intermittent hyponatremia, and polydipsia. 2. Their body weight were checked five times daily and the maximum weight gain during a day was chosen as an index of their polydipsia. 3. After control recording for six weeks, a daily naloxone (0.6 mg) injection series was performed once every two weeks for three series (six weeks). Withdrawal of this drug for six weeks resulted in weight gain recovering to control level. 4. The present study showed that naloxone seems to be a potential treatment for psychiatric patients displaying self-induced water intoxication and that endogenous opioid systems are involved in the compulsive drinking behavior of this syndrome.

GABA-gated chloride ion influx in brains of tremor rats.

We measured the GABA-gated chloride ion influx and GABA concentrations in the cerebral cortex and the hippocampus of young (5 weeks old) and older (15 weeks old) tremor rats. GABA-gated chloride ion influx in these tremor rats was significantly greater than in the controls of both the 5 week- and 15 week-old groups. GABA concentrations in the cerebral cortex and hippocampus of the tremor rats increased compared with controls of 5 weeks and decreased compared with controls of 15 weeks. These findings suggest that the GABAergic presynaptic neurons in the cortex and hippocampus of the tremor rat are disturbed with aging. This change may be related to the appearance of absence-like seizures in the rats. The increased GABA-gated chloride ion influx in tremor rats may be a compensatory mechanism against the genetically-determined seizure susceptibility of these rats. Furthermore, the increased GABA levels and GABA-gated chloride ion influx found in 5 week-old tremor rats may be related to the tremor movements.

Detecting of the minimal residual disease contaminated in peripheral blood stem cell transplantation in the B-cell malignant lymphoma patients.

For sufficient collection of hemopoietic stem cells from peripheral blood for autologous peripheral blood stem cell transplantation (PBSCT), four patients with B-cell-type non-Hodgkin lymphoma (B-NHL) were examined for the appearance of circulating hemopoietic progenitors in blood (PSC) during the hemopoietic recovery phase following marrow ablative therapy in combination with or without administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF). Each patient received only chemotherapy in the first course, and rhG-CSF (1 microgram/kg/day) was administered for 14 consecutive days from the last day of the second chemotherapy. In the second chemotherapy course with rhG-CSF administration, white blood cell (WBC) counts demonstrated two peaks, and the appearance of granulocyte-macrophage precursor cells (CFU-GM) in blood at the maximum level was coincident with the second peak of WBC elevation. Erythroid precursor cells (BFU-E) were also detectable in blood after chemotherapy but the peak level was not enhanced by the use of rhG-CSF. To determine whether the minimal residual disease (MRD) cells were contaminated in PSC corrected from blood, kappa-lambda imaging (KLI) analysis was performed to detect the malignant B-cell population (mBp) before and after chemotherapy. No mBp was found in two of four patients in blood, although three of them were involved with mBp in bone marrow. The presence of mBp was detected in two patients both before and after chemotherapy, even though these cells were hardly detected morphologically, suggesting the necessity of judging for the incidence of contamination of MRD cells when collecting PSCs.

Naloxone attenuates drinking behavior in a schizophrenic patient displaying self-induced water intoxication.

This study was performed to examine the effect of naloxone on drinking behavior in a schizophrenic inpatient with psychosis, intermittent hyponatremia, and polydipsia (PIP syndrome). His body weight was checked five times daily, and the maximum and minimum weight gains during a day were chosen as an index of polydipsia. Both daily (0.6 mg) and repeated (0.6 mg for 6 days) injections of naloxone suppressed his weight gain significantly for 2 weeks. Withdrawal of the drug for 4 weeks resulted in weight gain recovering to control level. Thereafter, a second trial was performed to examine the long-term effect of this treatment. A daily naloxone (0.6 mg) injection series was performed once every 2 weeks for six series (12 weeks). This drug regimen also suppressed his weight gain in a continuous fashion. The study showed that naloxone seems to be a potential treatment for PIP syndrome and that endogenous opioid systems play a part in the compulsive drinking behavior of the PIP syndrome.

Psychological stress-induced increases in noradrenaline release in rat brain regions are attenuated by diazepam, but not by morphine.

By measuring levels of noradrenaline (NA) and its major metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4) in the hypothalamus, amygdala and locus coeruleus region, we investigated the effects of diazepam 5.0 mg/kg, morphine 6.0 mg/kg, or naloxone at 5.0 or 10 mg/kg injected SC immediately before stress exposure, on increases in NA release caused by psychological stress. Psychological stress, wherein rats were exposed to emotional responses which were displayed by other electrically shocked rats, significantly increased MHPG-SO4 levels in the three brain regions examined and elevated plasma corticosterone levels. Both increases in brain MHPG-SO4 levels and elevations of plasma corticosterone levels induced by stress were attenuated significantly by diazepam but neither by morphine nor by naloxone. MHPG-SO4 levels in the hypothalamus and amygdala in the morphine-stress group were significantly higher than those in the saline-stress group. These findings suggest that psychological stress, in which an emotional factor is predominantly involved, causes increases in NA release in these brain regions examined and that these increases are attenuated only by diazepam, in contrast to the previous report, where increases in brain NA release caused by immobilization stress are attenuated not only by diazepam but also by morphine and are enhanced by naloxone.

Direct evidence of conditioned fear-elicited enhancement of noradrenaline release in the rat hypothalamus assessed by intracranial microdialysis.

Inescapable footshock stress produced marked increases in noradrenaline (NA) release, which was assessed by intracranial microdialysis, in the hypothalamus of conscious rats. Emotional stress, without physical stimuli (replacement to the environment where the rats had received footshock previously), also increased hypothalamic NA release. These results suggest that foodshock stress caused increases in NA release and this activation of NA neurons appears to be reinstated simply by re-exposure to the environment previously associated with shock.

Effects of stress, non-stress cyclicity on hypothalamic noradrenaline release in rats.

The effects of continuous stress and intermittent stress at short intervals on rat hypothalamic noradrenaline (NA) release were assessed by measuring the levels of a principal metabolite of NA, 3-methoxy-4-hydroxy-phenylethyleneglycol sulfate (MHPG-SO4) in male Wistar rats. The rats were exposed to one of five restraint stress conditions, unstressed (control), six 15 min intermittent stress periods (interspersed with 18 min non-stress periods), three 30 min intermittent stress periods (interspersed with 45 min non-stress periods), 90 min continuous stress period or 180 min continuous stress period. The 15 min intermittently stressed rats had significantly larger increases in hypothalamic MHPG-SO4 than the single 90 min and 180 min continuously stressed rats, while the 30 min intermittently stressed rats were significantly different from only the 180 min continuously stressed rats. In a comparison of the 15 min and 30 min intermittently stressed rats, which had the same total duration of stress exposure; the 15 min group had larger increases in MHPG-SO4 levels than the 30 min group. This study provides supporting evidence for the role of stress cyclicity in determining the extent of stress-induced NA release from the hypothalamus.

Naloxone enhances stress-induced increases in noradrenaline turnover in specific brain regions in rats.

Male Wistar rats were injected subcutaneously with either saline or naloxone, 1 mg/kg or 5 mg/kg, 10 min before exposure to 1-hour immobilization-stress. Control animals were sacrificed 70 min after respective injections. Levels of noradrenaline (NA) and its major metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-S04) in seven discrete brain regions and plasma corticosterone levels were fluorometrically determined. Immobilization stress caused significant elevations of plasma corticosterone which were not affected by pretreatment with naloxone. In the hypothalamus, amygdala and thalamus, immobilization-stress caused significant elevations of MHPG-S04 levels, and naloxone at 5 mg/kg significantly enhanced these stress-induced elevations virtually without affecting the basal level of the metabolite. In contrast, in the hippocampus, cerebral cortex and pons plus medulla oblongata, MHPG-S04 levels were elevated by stress, but were not affected by naloxone pretreatment. The effect of naloxone on stress-induced reductions of NA levels was unclear, since naloxone by itself (5 mg/kg) significantly decreased the amine levels in 5 of 7 brain regions examined. These results indirectly suggest that endogenous opioid peptides in the hypothalamus, amygdala and thalamus are partly involved in the stress process and attenuate increases in NA turnover induced by stress.

Psychological stress enhances noradrenaline turnover in specific brain regions in rats.

Concentrations of noradrenaline (NA) and 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4) in the hypothalamus, amygdala, cerebral cortex and pons + medulla oblongata were examined in male Wistar rats exposed to foot-shock or to psychological stress for 1 hour. Animals in the psychological stress group were prevented from receiving foot shock, but were exposed to responses of shocked rats. Foot shocked rats exhibited a significant reduction in NA content and a significant elevation in MHPG-SO4 level in all brain regions when compared to control rats which were neither shocked nor exposed to shocked rats. Rats exposed to the psychological stress displayed a significant reduction of NA level in the amygdala, significant elevation of MHPG-SO4 content in the hypothalamus and amygdala, and a moderate elevation of plasma corticosterone level. These results suggest that psychological stress produces mild enhancement of NA release preferentially in the hypothalamus and amygdala; while foot shock stress elicits a more intense response of noradrenergic neurons in more extended brain regions.