harmine and Body-Weight

beta-Carboline alkaloids are normal body constituents but are also potent tremor-producing chemicals that are naturally present in the food chain.. To explore the hypothesis that high concentrations of beta-carboline alkaloids are associated with essential tremor (ET).. One hundred cases and 100 controls were frequency matched on age, sex, and ethnicity. Blood concentrations of harmane and harmine were quantified by high-performance liquid chromatography, blinded to clinical information.. The mean log blood concentration of harmane was higher in cases than controls (0.72 +/- 0.53 vs 0.51 +/- 0.64 g(-10)/mL; p = 0.01). A nonparametric test on nontransformed data (median harmane = 5.21 g(-10)/mL in cases and 2.28 g(-10)/mL in controls) confirmed this difference (p = 0.005). The mean log blood concentration of harmine was 0.20 +/- 0.48 g(-10)/mL in cases and 0.10 +/- 0.65 g (-10)/mL in controls (p = 0.20). Log harmane concentrations were stratified based on the median value; 62% of cases vs 39% of controls had a high log harmane concentration (p = 0.001). Mean log harmane concentration was similar in the cases with (0.74 +/- 0.58 g(-10)/mL) and without (0.71 +/- 0.50 g(-10)/mL) an affected relative (p = 0.83).. Blood concentrations of harmane were measured in ET cases compared with controls. Concentrations were elevated in cases with and without a family history of ET.

Topics: Aged; Alkaloids; Body Height; Body Weight; Carbolines; Chromatography, High Pressure Liquid; Diet; Essential Tremor; Female; Harmine; Humans; Logistic Models; Male; Middle Aged; Spectrometry, Fluorescence

9-(4'-Aminophenyl)-9H-pyrido[3,4-b]indole [aminophenylnorharman (APNH)] is a novel mutagenic heterocyclic amine, produced by the reaction of norharman with aniline in the presence of S9 mix. In the present study, the acute toxicity of this compound was investigated in male F344 rats. Ten-week-old animals were treated with a single intragastric injection of APNH at doses of 45 or 90 mg/kg body wt and euthanized 1, 3, or 6 days afterward. When APNH was administered at a dose of 90 mg/kg, vacuolation of Sertoli cells in the testis was seen at 1 day after treatment. The testicular damage had markedly progressed by day 6, with multinucleated giant cells and loss of round spermatids in the seminiferous tubules observed in groups 1 and 2 of the four histological categories of spermatogenesis. Numbers of spermatogonia were also decreased by APNH treatment. No toxic changes were observed in Leydig cells under these conditions and serum follicle-stimulating hormone and luteinizing hormone concentrations were also unchanged from control values. Such severe testicular damage was not observed at any time point at the 45 mg/kg dose level of APNH. Moreover, neither norharman nor aniline alone exerted acute testicular toxicity at doses equivalent to 90 mg/kg of APNH. In addition to the testicular lesions, erosive changes of urinary bladder, thymic atrophy, and panmyelophthisis were evident in rats given APNH at 90 mg/kg.

Topics: Administration, Oral; Aniline Compounds; Animals; Body Weight; Carbolines; Carcinogens; Follicle Stimulating Hormone; Harmine; Indoles; Luteinizing Hormone; Male; Mutagens; Organ Size; Pyridines; Rats; Rats, Inbred F344; Seminiferous Tubules; Testis

Harman (1-methyl-beta-carboline) has been shown to induce volitional drinking of ethyl alcohol in the rat. The purpose of this study was to examine the long-term effect of sustained delivery of harman into the dorsal hippocampus on the subsequent preference for alcohol in the genetically bred low alcohol drinking (LAD) rat. The individual pattern of preference for alcohol was first determined following a standard 3-30% alcohol self-selection test for 10 days. Thereafter, a cerebral cannula for constant infusion was implanted stereotaxically into the dorsal hippocampus. The cannula was attached to an osmotic minipump implanted subcutaneously, which was filled with either an artificial cerebrospinal fluid (CSF) vehicle or harman. Harman was delivered at a rate of 1.0 or 3.0 micrograms/h (i.e., 5.5 or 16.5 nmol/h, respectively) for a period of 14 days. Four days after surgery, the rats underwent a second 3-30% alcohol preference test for 10 days. Both doses of harman induced a threefold increase in the voluntary consumption of alcohol, expressed as g/kg per day. This effect of the beta-carboline seems to be specific for ethanol because its intake by the LAD rats was increased significantly only when concentrations from 11% to 30% were presented. Harman also enhanced the daily intake of food in a dose-dependent manner, but did not affect body weights or the volumes of water and total fluid consumed. These results, thus, demonstrate that the long-term exposure of hippocampal neurons to harman induces a preference for high concentrations of alcohol even in a line of rats lacking such a genetic predisposition.

Topics: Alcohol Drinking; Animals; Body Weight; Dose-Response Relationship, Drug; Eating; Harmine; Hippocampus; Infusion Pumps, Implantable; Injections; Male; Rats; Rats, Inbred Strains; Stimulation, Chemical

Livers from fasted (N = 16) and fed (N = 22) rats were perfused with harmol (50 microM) for an initial 30 min with normal oxygen delivery (6-10 mumol/min/g liver), then for 45 min with perfusate equilibrated with O2/N2 mixtures, which reduced hepatic oxygen delivery to 0.9-6 mumol/min/g liver, and finally for a further 30 min period of normal oxygenation. Seventy per cent of the harmol eliminated was accounted for as the glucuronide conjugate and approximately 5% as the sulphate conjugate. During the hypoxia phase with fed preparations, decreasing oxygenation did not reduce harmol clearance or harmol glucuronide formation clearance until oxygen delivery was less than 2.5 mumol/min/g liver, whereas with fasted preparations this hypoxic threshold was much higher (5 mumol/min/g liver). Below the hypoxic threshold, harmol clearance was linearly related to oxygen delivery in both groups. Hepatic tissue concentrations of unchanged harmol at the end of the hypoxia phase were double those after the same period of normal oxygenation, whereas tissue harmol glucuronide concentrations were similar. By establishing a hypoxic threshold for reduced oxygen availability this study shows that harmol glucuronidation is relatively insensitive to hypoxia, but sensitivity increases markedly in fasted animals.

Topics: Animals; Body Weight; Fasting; Glucuronates; Harmine; Humans; Hypoxia; Liver; Male; Oxygen; Oxygen Consumption; Rats; Rats, Sprague-Dawley; Sensitivity and Specificity

The modifying effects of harman or norharman on liver carcinogenesis were investigated in male F344/DuCrj rats initially treated with N-nitrosodiethylamine (DEN). Two weeks after a single dose of DEN (200 mg/kg, intraperitoneally), rats were given harman or norharman at dietary levels of 1000 and 200 parts per million (ppm), or sodium phenobarbital (PB) at 500 ppm as a positive control, for 6 wk. At wk 3 following DEN administration, all animals were subjected to partial hepatectomy. Marked retardation of body weight gain was observed in rats treated with harman or norharman at 1000 ppm, but not at 200 ppm. Increased relative kidney but not liver weights were associated with harman or norharman treatment, especially in the higher dose groups. Although no toxicity-related hepatocyte lesions were found, severe renal toxic tubular lesions and regeneration were evident. Neither harman nor norharman significantly increased the numbers or areas of glutathione S-transferase placental form (GST-P) positive foci observed after DEN initiation, in clear contrast to PB. The results thus demonstrated that harman and norharman are nontoxic for the liver and lack modifying potential for liver carcinogenesis in our medium-term bioassay system.

Topics: Alkaloids; Animals; Body Weight; Carbolines; Cocarcinogenesis; Diethylnitrosamine; Glutathione Transferase; Harmine; Liver; Male; Rats; Rats, Inbred F344

The effects of neonatal exposure of rats to chlordecone, during the major postnatal period of neuroendocrine differentiation were assessed after the animals matured to 90 days of age. On day 4 postpartum, pups received a s.c. injection of either DMSO vehicle or chlordecone (1 mg/pup) dissolved in DMSO. The neonatal exposure produced a significant sex-dependent alteration in adult body weight; chlordecone-exposed males were lighter than vehicle-exposed controls and chlordecone-exposed females were heavier than vehicle-exposed controls. Behavioral tests sensitive to neonatal chlordecone exposure during preweaning development--i.e., spectral analysis of movement, activity, and auditory startle responsiveness--gave no statistically significant evidence for residual effects of the early organochlorine treatment. When challenged with harmine, a known tremorogen with putative effects on olivocerebellar pathways, chlordecone-exposed males were less responsive than vehicle-exposed littermates in a spectral analysis of movement. The movement spectrum of chlordecone-exposed females was not differentially sensitive to the harmine challenge. However, subsequent evaluation of the auditory startle reflex indicated that harmine interacted with the neonatal treatment and sex of the animal; chlordecone-exposed males were less responsive and chlordecone-exposed females more responsive than same sex vehicle-exposed littermates. The responsiveness to a d-amphetamine challenge, expressed as a ratio of baseline activity in a pre- and post-test design, suggested the chlordecone-exposed males gave an exaggerated response to the drug challenge. Collectively, these findings suggest that the neonatal chlordecone exposure had a significant organizational effect on the development of behavioral and/or neural function. These findings also suggest the predictive utility of early behavioral tests; that is, long-term alterations were noted in each component of the toxicological syndrome previously identified during preweaning development.

Topics: Animals; Animals, Newborn; Behavior, Animal; Body Weight; Chlordecone; Dextroamphetamine; Female; Habituation, Psychophysiologic; Harmine; Insecticides; Male; Motor Activity; Movement; Nervous System; Rats; Rats, Inbred F344; Reflex, Startle; Sex Factors; Synaptic Transmission; Time Factors; Tremor