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SummaryMechanism of central actions of antidepressants were studied in experimental animals.Tests were made on general behavior, anticonvulsant activity in maximal electroshock seizure, antireserpinic action, antagonistic action to methamphetamine‐excitation, anesthesia induced by hexobarbital, hypertension due to noradrenalin, hypotension induced by acetylcholine, anti‐tremorine action and antagonism for physostigmine in unanesthetized mice and rabbits. In these tests, it seemed that the mechanism of antidepressants is related to the changes of biogenic amines in the brain and to the central autonomic functions. Namely, imipramine, amitriptyline and nialamide were related intimately to the changes of biogenic amine and to the inhibitory effects of parasympathetic functions. Diazepam was connected with the tranquilizing effects and the inhibitory effects of parasympathetic functions, and dimethylaminoethanol had no relation to the autonomic functions.

(R)-1-(10,11-Dihydro-dibenzo[b,f]azepin-5-yl)-3-methylamino-propan-2-ol ((R)-OHDMI) and (S,S)-1-cyclopentyl-2-(5-fluoro-2-methoxy-phenyl)-1-morpholin-2-yl-ethanol (CFMME) were synthesized and found to be potent inhibitors of norepinephrine reuptake. Each was labelled efficiently in its methyl group with carbon-11 (t(1/2)=20.4 min) as a prospective radioligand for imaging brain norepinephrine transporters (NET) with positron emission tomography (PET). The uptake and distribution of radioactivity in brain following intravenous injection of each radioligand into cynomolgus monkey was examined in vivo with PET. After injection of (R)-[(11)C]OHDMI, the maximal whole brain uptake of radioactivity was very low (1.1% of injected dose; I.D.). For occipital cortex, thalamus, lower brainstem, mesencephalon and cerebellum, radioactivity ratios to striatum at 93 min after radioligand injection were 1.35, 1.35, 1.2, 1.2 and 1.0, respectively. After injection of [(11)C]CFMME, radioactivity readily entered brain (3.5% I.D.). Ratios of radioactivity to cerebellum at 93 min for thalamus, occipital cortex, region of locus coeruleus, mesencephalon and striatum were 1.35, 1.3, 1.3, 1.2 and 1.2, respectively. Radioactive metabolites in plasma were measured by radio-HPLC. (R)-[(11)C]OHDMI represented 75% of plasma radioactivity at 4 min after injection and 6% at 30 min. After injection of [(11)C]CFMME, 84% of the radioactivity in plasma represented parent at 4 min and 20% at 30 min. Since the two new hydroxylated radioligands provide only modest regional differentiation in brain uptake and form potentially troublesome lipophilic radioactive metabolites, they are concluded to be inferior to existing radioligands, such as (S,S)-[(11)C]MeNER, (S,S)-[(18)F]FMeNER-D(2) and (S,S)-[(18)F]FRB-D(4), for the study of brain NETs with PET in vivo.

11C-labeled (+)-trans-2-[[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]methylsulfanyl]ethanol ([11C]5) and (+)-trans-2-[[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]methylsulfanyl]-1-(piperidin-1-yl)ethanone ([11C]6) were synthesized and evaluated as new imaging agents for the norepinephrine transporter (NET). [11C]5 and [11C]6 display high affinity for the NET in vitro (Ki = 0.94 and 0.68 nM, respectively) and significant selectivity over the dopamine (DAT) and serotonin transporters (SERT). Because of their high affinity and favorable transporter selectivities we speculated that these ligands might serve as useful PET agents for imaging NET in vivo. Contrary to our expectations, both of these ligands provided brain images that were more typical of those shown by agents binding to the DAT.

Dopamine-β-hydroxylase activity in the rat adrenal gland decreases 53% three weeks after hypophysectomy. ACTH administration for 5 days causes the activity to increase. Large doses of dexamethasone do not affect the adrenal activity after hypophysectomy. Total cardiac DBH activity is decreased after pituitary ablation but, when expressed per g of tissue, is higher than in the hearts of sham-operated, agematched animals.(Endocrinology 87: 894, 1970

The purpose of this study was to evaluate the effects of alcohol on hemodynamic changes induced by visual stimulation. Ten healthy human subjects were examined using Optical Topography((R)) (Hitachi Medical Corporation: ETG-100). Each subject gradually drank 0.4 ml/kg alcohol over 10 min. Changes in oxy-hemoglobin (Hb), deoxy-Hb and total-Hb concentration were measured five times: 20 min before alcohol intake, immediately after alcohol intake, and at 20, 40 and 60 min after alcohol intake. A questionnaire was used to assess subjective feelings of alcohol. Blood-alcohol concentration (BAC) was estimated from ethanol concentration in expired air four times: immediately after alcohol intake and at 20, 40 and 60 min after alcohol intake. The visual stimulation tool was a checkerboard. It showed alternations of black and red patterns at a frequency of 8 Hz. The stimulus was displayed for 10 s after a rest of 30 s. The stimulus was repeated 10 times. Oxy-Hb concentration increased and deoxy-Hb concentration decreased during visual stimulation before and after alcohol intake, despite changes in the score of subjective feelings of alcohol and BAC. Alcohol intake does not significantly affect hemodynamic changes caused by visual stimulation in the visual cortex.

Background:Salsolinol, a neuropharmacologically active compound, is formed by the condensation of acetaldehyde (AcH) with dopamine (DA) in the brain. The aim of our study was to examine the effect of a high concentration of AcH on salsolinol formation and to compare the release of DA, serotonin (5‐HT), and salsolinol in the striatum and nucleus accumbens (NAc) in free‐moving rats.Methods:After the insertion of a microdialysis probe, male Wistar rats (250–300 g) were treated with cyanamide (CY, a potent aldehyde dehydrogenase inhibitor) + ethanol (EtOH), CY + 4‐methylpyrazole (4‐MP, a strong alcohol dehydrogenase inhibitor) + EtOH, 4‐MP + EtOH, CY, and 4‐MP. Simultaneous quantitation of DA, 5‐HT, and salsolinol in dialysates was performed by using in vivo microdialysis coupled with high‐performance liquid chromatography with an electrochemical detector and blood EtOH and AcH by using a head‐space gas chromatographic method.Results:Salsolinol was detected only in the CY + EtOH groups in both the striatum and NAc, and we also detected a high AcH concentration in the blood in those groups. A correlation was found between the dialysate levels of salsolinol and blood concentrations of AcH. The striatal levels of DA and 5‐HT were approximately two times higher, whereas salsolinol levels were approximately three times higher compared with the usual level in the NAc. No significant difference of DA and 5‐HT levels in the dialysates was observed in either the control or the other study groups.Conclusion:Our observation suggested that the brain salsolinol formation may depend on the concentrations of DA and AcH in freely moving rats, and there is no effect of a high concentration of AcH on DA and 5‐HT levels in the striatum and NAc.

Background: Acetaldehyde binds to some proteins, which results in Schiff base formation. It is assumed that acetaldehyde binds to the proteins after the consumption of ethanol, to form an adduct. Such acetaldehyde adducts are related to organ disease.Methods: We examined 8‐week‐old male BALB/c mice, which were given a liquid diet for 7 days. The diet consisted of vitamins, minerals, amino acids, and a 5% (v/v) ethanol solution. After the 7 days, we took tissue samples from the brain, liver, and adrenal cortex to investigate the distribution of acetaldehyde adducts. We performed immunohistochemical staining of the cerebral cortex, liver, and adrenal cortex from the mice by using antibodies against acetaldehyde adducts.Results: Our study showed that acetaldehyde adducts formed in the cerebral cortex in the early phase in alcohol‐fed mice.Conclusions: Because acetaldehyde in the liver has been shown to cause liver damage, our study suggests a relationship between acetaldehyde adducts in the brain and brain damage.

The effect of alcohol on variant angina was studied in six patients who had a history of chest pain occurring with alcohol ingestion. On alcohol testing, Holter ECG monitoring was performed and a 12-lead ECG was recorded at the time of chest pain. In five, chest pain with ST elevation occurred 5.5 to 17.5 h after the ingestion of alcohol (100 to 150 ml as ethanol). These showed recurrent ST elevation on Holter ECG, most episodes being asymptomatic. Results of provocation testing were reproducible in all four patients in whom tests were repeated and ST elevation occurred in the same leads. No complications were observed. The Holter ECG revealed a higher heart rate after alcohol ingestion. The plasma level of alcohol was zero when angina occurred and plasma epinephrine, norepinephrine and serotonin were unchanged following alcohol ingestion. Alcohol ingestion may be a useful method of provoking variant angina, particularly in those who have a history of angina related to alcohol ingestion.

Sedentary/inactive lifestyle leads middle-aged and older adults to metabolic syndrome and frailty. Capsinoids from nonpungent chili pepper cultivar have been reported to reduce body fat mass, promote metabolism, and improve unidentified complaints of chills. Additionally, they have an anti-inflammation effect; therefore, we hypothesized that continuous oral ingestion of capsinoids alleviates age-related inflammation in the brain and improves the physical activity (PA) in middle-aged and older adults. In our double-blind human study, 69 participants (17 male, 52 female; mean age: 74.1 ± 7.7 years; range: 52–87 years) were administered either 9 mg of capsinoids which were extracted from pepper fruit variety CH-19 Sweet (Capsicum anuum L.) (CP group), or a placebo (PL group) daily over a 3 month period. In an animal study, PA and inflammation-related mRNA expression in the brain were examined in 5-week (young) and 53-week (old) aged mice fed a diet with or without 0.3% dihydrocapsiate, a type of capsinoids, for 12 weeks. In a human study, capsinoids intake did not increase the amount of light-to-moderate PA less than 6.0 metabolic equivalents (METs) (CP: 103.0 ± 28.2 at baseline to 108.2 ± 28.3 at 12 weeks; PL: 104.6 ± 19.8 at baseline to 115.2 ± 23.6 at 12 weeks, METs × hour/week); however, in participants exhibiting an inactive lifestyle, it showed significant increase (CP: 84.5 ± 17.2 at baseline to 99.2 ± 24.9 at 12 weeks; PL: 99.7 ± 23.3 at baseline to 103.8 ± 21.9 at 12 weeks). The energy expenditure in physical activity also improved in the inactive CP group (CP: 481.2 ± 96.3 at baseline to 562.5 ± 145.5 at 12 weeks; PL: 536.8 ± 112.2 at baseline to 598.6 ± 127.6 at 12 weeks; kcal/day). In all participants, CP showed reduced waist circumference, percent body fat, and visceral fat volume; in addition, chills were eased in subjects aged 80 years and older. The older mice fed capsinoids showed increased locomotion activity, decreased inflammation, and oxidative stress in the brain. The results suggest that the continuous oral ingestion of capsinoids gains PA through anti-inflammation effect in the brain as well as reduces fat accumulation and chills in inactive and older humans.