Shusaku Tsujimaru

Attenuating effect of diazepam on stress-induced increases in noradrenaline turnover in specific brain regions of rats: antagonism by Ro 15-1788

One-hour immobilization stress increased levels of the major metabolite of brain noradrenaline (NA), 3-methoxy-4-hydroxyphenyl-ethyleneglycol sulfate (MHPG-SO4), in nine brain regions of rats. Diazepam at 5 mg/kg attenuated the stress-induced increases in MHPG-SO4 levels in the hypothalamus, amygdala, hippocampus, cerebral cortex and locus coeruleus (LC) region, but not in the thalamus, pons plus medulla oblongata excluding the LC region and basal ganglia. The attenuating effects of the drug on stress-induced increases in metabolite levels in the above regions were completely antagonized by pretreatment with Ro 15-1788 at 5 or 10 mg/kg, a potent and specific benzodiazepine (BDZ) receptor antagonist. When given alone, Ro 15-1788 did not affect the increases in MHPG-SO4 levels. Behavioral changes observed during immobilization stress such as vocalization and defecation, were also attenuated by diazepam at 5 mg/kg and this action of diazepam was antagonized by Ro 15-1788 at 10 mg/kg, which by itself had no effects on these behavioral measurements. These findings suggest: (1) that diazepam acts via BDZ receptors to attenuate stress-induced increases in NA turnover selectively in the hypothalamus, amygdala, hippocampus, cerebral cortex and LC region and (2) that this decreased noradrenergic activity might be closely related to relief of distress-evoked hyperemotionality, i.e., fear and/or anxiety in animals.

Effects of acute and repeated alcohol ingestion on hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal functioning in normal males

We investigated the effects of acute and repeated alcohol ingestion on plasma levels of hormones associated with the functioning of the hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-adrenal (HPA) systems in normal males. In the first experiment, 7 normal male subjects were given ethanol (1.3 g/kg) in the form of a 43% alcohol solution of whiskey and water over a 30-min period (from 19:00 h to 19:30 h); blood samples were collected 30 min and immediately before the beginning of alcohol ingestion and then at intervals of 30 min for 180 min. Blood ethanol levels rose sharply and reached their maximum at 60 min, remaining above 1.0 mg/ml until 180 min. Prolactin levels increased, reaching a peak at 60 min, gradually returning to the initial value at 180 min. Decreased testosterone levels were observed only at 30 min. Luteinizing hormone (LH), adrenocorticotrophic hormone (ACTH) and cortisol levels did not show any increases. In the second experiment, 9 normal males were given the same dose of alcohol, but this was given on 7 consecutive evenings and the hormonal changes were examined on the 1st and 7th days, only at 30 and 60 min after alcohol ingestion began (during the period that blood ethanol levels were ascending to their peak). The results on the 1st day reconfirmed the findings in the first experiment and on the 7th day, the last alcohol ingestion produced increases in prolactin levels and decreases in testosterone levels at 30 and 60 min, but did not change other hormone levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of preshock experience on enhancement of rat brain noradrenaline turnover induced by psychological stress

The present study examined alterations of brain noradrenaline (NA) turnover as a function of preshock and psychological stress treatments, by measuring contents of NA metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4), in discrete brain regions of male Wistar rats. Psychological stress induced by exposing to the sight, sound and odor of other rats being shocked produced higher levels of MHPG-SO4 in the hypothalamus, amygdala and locus coeruleus (LC) region, as well as higher levels of plasma corticosterone. Preshock experienced rats also showed marked increases of MHPG-SO4 levels in the same regions described above and elevated plasma corticosterone levels when placed but not shocked in the same environment in which the rats had previously received shocks. The effects of psychological stress on brain NA turnover were affected by the animals shock history preferentially in the hypothalamus and amygdala. These results suggest that: a purely psychological stressor caused acutely enhanced NA turnover in specific brain regions; regional NA activity appeared to be reinstated simply by reexposure to the environment previously associated with shock; preshock experience further intensified the enhancement of amygdaloid NA turnover evoked by psychological stress. An additional experiment, studying the aftereffects of preshock experience, clearly showed that these findings result from sensitization or conditioning to the environment previously paired with shock, and not merely from the aftereffects of the shock per se.

Stressor predictability and rat brain noradrenaline metabolism

This study examined the effects of stressor predictability on regional rat brain noradrenaline (NA) turnover, by measuring levels of a principal metabolite of NA (3-methoxy-4-hydroxyphenylethyleneglycol sulfate, MHPG-SO4). Male Wistar rats were exposed to one of three shock conditions for 19 hr: nonshock, signalled, and unsignalled shocks. Rats in the shock conditions received shock (1.2 mA intensity, 2 sec duration) on a 2.5 min variable time (VT) either preceded by a 12-sec, 10-W light signal (signal-shock interval of 10 sec) or not preceded by this signal. The tail electrodes for these rats were in series, so that the shock received by all rats was of exactly the same number and duration. After 19 hr in a VT-2.5 min shock session, the rats exposed to unsignalled shock (unpredictable group) showed significantly greater increases in MHPG-SO4 levels in the hypothalamus, amygdala, midbrain, cerebral cortex, thalamus and locus coeruleus, as well as in plasma corticosterone levels. Rats exposed to signalled shock (predictable group) showed significant increases in MHPG-SO4 levels in the first four of these regions, as compared to the nonshocked rats. Moreover, the unpredictably shocked rats exhibited greater elevations in MHPG-SO4 levels in the hypothalamus, amygdala, and thalamus, as well as in plasma corticosterone levels, when compared to the predictably shocked rats. These results are consistent with previous reports showing that unsignalled shock induced extensive somatic effects in comparison to signalled shock. The present study suggests that the presence of a signal attenuates the extent of NA release in some brain regions resulting from irregular inescapable shock stress.

Met-enkephalin, injected during the early phase of stress, attenuates stress-induced increases in noradrenaline release in rat brain regions

By measuring levels of 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4), the major metabolite of noradrenaline (NA), we investigated the effects of Met-enkephalin (Met-ENK) ICV injected at three different stages of stress, i.e., 0 min, 5 min, or 10 min after exposure to immobilization stress. Immobilization stress caused significant increases in MHPG-SO4 levels in all brain regions examined, i.e., the hypothalamus, amygdala, thalamus, midbrain, hippocampus and locus coeruleus (LC), which suggests that stress increases NA release in these regions. Met-ENK at a dose of 50 micrograms, injected ICV immediately before stress exposure significantly attenuated stress-induced increases in MHPG-SO4 in the amygdala, thalamus and LC, but did not have such an effect when injected either 5 min or 10 min or 10 min after exposure to stress. Similarly, Met-ENK at 150 micrograms at 0 min significantly attenuated these increases in all brain regions examined, however, it did not do so when given at 5 min or 10 min after stress initiation. The amount of defecation and the weight loss caused by stress were also significantly attenuated by Met-ENK injected but only at 0 min. These results suggest that the attenuating effect of Met-ENK on stress-induced increases in NA release is greatly affected by the time of the peptide administration and that Met-ENK might inhibit stress-induced increases in NA release in these regions by affecting the initial changes induced by stress.

Pentobarbital attenuates stress-induced increasesin noradrenaline release in specific brain regions of rats

To examine whether anxiolytic action of drugs acting at the GABA/BZD-chloride channel complex may be related to the brain noradrenergic system, we investigated the effect of pentobarbital, a typical barbiturate which has potent GABA modulating properties, on increased NA release in nine brain regions of stressed rats. Pentobarbital (10 and 25 mg/kg) was injected IP 65 min before sacrifice (5 min before one-hour immobilization stress). Levels of 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4), the major metabolite of brain noradrenaline (NA), and of plasma corticosterone, were fluorometrically determined. Pentobarbital treatment by itself increased MHPG-SO4 levels in the thalamus, locus coeruleus (LC) region, midbrain and basal ganglia of nonstressed rats. Stress produced increases in MHPG-SO4 levels in all brain regions examined and elevation of plasma corticosterone levels. Pentobarbital attenuated, in a dose-dependent manner, stress-induced increases in MHPG-SO4 levels in the hypothalamus, thalamus, anterior cerebral cortex, LC region and basal ganglia and also attenuated the stress-induced elevation of plasma corticosterone levels. These data suggest that pentobarbital can attenuate both stress-induced increases in NA release in specific brain regions as well as activation of the hypothalamo-pituitary-adrenocortical system. These attenuating effects may be related to the anxiolytic action of barbiturates.

Vitamin B12 accelerates re-entrainment of activity rhythms in rats

The effects of methyl vitamin B12 (5-6 mg/kg, p.o.) on the entrainment of circadian running wheel activity rhythm to a new lighting schedule were measured in rats. After the light-dark (LD) cycle was abruptly reversed, rats given vitamin B12 took less time to entrain their circadian locomotor activity rhythm to the new cycle than did controls. This result indicates that vitamin B12 accelerates the reentrainment of the mammalian circadian activity rhythm following an abrupt change in the environmental LD cycle.

Blocking effects of ethanol on stress-induced activation of rat mesoprefrontal dopamine neurons

We investigated the effects of ethanol on stress-induced activation of the brain dopamine (DA) systems in rats. Ethanol (0.5 and 1.0 g/kg) was injected IP 25 min before sacrifice (5 min before 20-min immobilization stress). Ethanol treatment by itself did not affect the levels of either DA or its major metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), in the mesoprefrontal cortex, cingulate cortex, olfactory tubercle, or caudate putamen. Immobilization stress for 20 min caused increases in DOPAC levels in the prefrontal cortex (160% of control) and cingulate cortex (135% of control), but not in the olfactory tubercle or caudate putamen. The stress had no effects on DA levels in any of the four brain regions studied. Pretreatment with ethanol blocked, in a dose-dependent manner, the stress-induced increases in DOPAC levels in the mesoprefrontal cortex. The present data suggest that ethanol exhibits a blocking effect on stress-induced activation of the mesoprefrontal DA neurons. This blocking effect may be related to the anxiolytic action of ethanol.

Antiepileptic drugs and bone atrophy. A 3-year follow-up study.

われわれは同一精薄施設の長期入所者87例 (うち62例はAED服用群) を対象と, て, 抗てんかん薬 (AED) と骨萎縮性病変の発生状況および, 1α-OH-D3 (VD) の骨萎縮性病変に対する効果について, MD法, MD/MS法を用いて3年間の追跡調査を行い, 以下の結果を得た。初回 (1986年) のMD法で正常であった57例は, VDを投与しなかったところ, 徐々にMD法で異常が出現し悪化した。なかでもAED服用群 (42例) に悪化傾向が強かった。初回のMD法で異常を認めた30例は, VDを投与したところ, 骨皮質の骨塩量 (GS max) の増加を主体に改善傾向を示し, 3年間投与, てもVDの効果の減弱や1副作用は認められなかった。なかでもAED服用群 (20例) の方が未服用群 (10例) よりも平均骨塩量 (ΣGS/D) と断面2次モーメント (I) が増加した。以上のことから, 特にAEDの投与中に認められた骨萎縮性病変には, VDの投与が有効であった。今回の対象とした精薄施設の入所者は全体的に特異なレーダーチャートを示したが, それは主に骨の横径発達の遅滞に関連, ていると思われた。