L-dopa: disaggregation of brain polysomes and elevation of brain tryptophan

One hour after administration of L-dopa (50 to 300 milligrams per kilogram), there is a marked disaggregation of brain polysomes in immature rats. Adult animals show a similar response, but require larger doses of the amino acid (500 milligrams per kilogram). Single doses of L-dopa significantly elevate amounts of tryptophan in the brain; hence their effect on polysomes does not result from the unavailability of this amino acid.     

Bladder tumors in rats fed cyclohexylamine or high doses of a mixture of cyclamate and saccharin

Papillary transitional cell tumors were found in the urinary bladders in 8 rats out of 80 that received 2600 milligrams per kilogram of body weight per day of a mixture of sodium cyclamate and sodium saccharin (10:1) for up to 105 weeks. From week 79 on, several of these rats received cyclohexylamine hydrochloride (125 milligrams per kilogram per day, the molecular equivalent of the conversion of about 10 percent of the cyclamate dosage to cyclohexylamine) in addition to the sodium cyclamate and sodium saccharin. In another study in which 50 rats were fed daily 15 milligrams of cyclohexylamine sulfate per kilogram of body weight for 2 years, eight males and nine females survived. One of the eight males had a tumor of the urinary bladder. In neither study were bladder tumors found in the control rats or in rats treated with lower doses of the compounds.     

L-dihydroxyphenylalanine: effect on S-adenosylmethionine in brain

Forty-five minutes after intraperitoneal injection of a single dose (100 milligrams per kilogram) of L-dihydroxyphenylalanine, the concentration of S-adenosylmethionine in rat brain was lowered by 76 percent. As little as 10 milligrams of L-dihydroxyphenylalanine per kilogram decreased content of S-adenosylmethionine in the adrenal medulla by 51 percent, whereas 100 milligrams per kilogram did not significantly depress concentration of S-adenosylmethionine in the liver in this time interval. Concentration of S-adenosylmethionine in the brain varied diurnally; L-dihydroxyphenylalanine lowered this concentration whether administered at the daily peak or at the nadir.     

Ascorbic acid and the behavioral response to haloperidol: implications for the action of antipsychotic drugs

Haloperidol, a widely used antipsychotic drug, was tested for its ability to block the behavioral response to amphetamine and to elicit catalepsy in rats treated with saline or ascorbic acid (1000 milligrams per kilogram of body weight). By itself, ascorbic acid failed to exert significant behavioral effects, but it enhanced the antiamphetamine and cataleptogenic effects of haloperidol (0.1 or 0.5 milligrams per kilogram). These results, combined with a growing body of biochemical evidence, suggest that ascorbic acid plays an important role in modulating the behavioral effects of haloperidol and related antipsychotic drugs.     

Cyclophosphamide: effect on experimental allergic encephalomyelitis in Lewis rats

Lewis rats sensitized to spinal cord in adjuvant and exhibiting advanced clinical paralytic signs of experimental allergic encephalomyelitis were treated with cyclophosphamide (5 milligrams per kilogram) daily. Of 30 treated animals, 21 recovered rapidly and appeared clinically well within 7 to 12 days. This immunosuppressive agent may prove therapeutically useful in the treatment of autoimmune diseases.     

Growth retardation in young mice treated with d1-methadone

Newborn mice injected daily for 6 weeks with dl-methadone in dosages of 2 to 8 milligrams per kilogram grew significantly more slowly than their saline-treated littermates. Litters given d-methadone, 4 milligrams per kilogram, grew normally. Concomitant treatment with naloxone, 10 milligrams per kilogram, prevented growth inhibition. A weight deficit persisted in mice observed 6 weeks after cessation of methadone treatment.     

Phenobarbital: effects of long-term administration on behavior and brain of artificially reared rats

Two doses of phenobarbital were given daily for 2 weeks to infant rats fed by intragastric cannulas. The larger dose (60 milligrams per kilogram of body weight) resulted in decreased spontaneous activity and increased responses to novel stimuli. The smaller dose (15 milligrams per kilogram) resulted in increased spontaneous activity and also an increase of responses to novel stimuli. The larger dose produced a 12 percent reduction in brain growth, while the smaller dose was associated with a 3 percent reduction in brain growth.     

Pentylenetetrazol enhances memory function

Pentylenetetrazol, in oral doses of 1 to 30 milligrams per kilogram of body weight, significantly facilitated one-trial learning and memory retention in CF1 mice, whether administered before or immediately after the initial trial. The effects appeared significantly greater than those observed in earlier studies with oral administration of strychnine or picrotoxin at 0.2 to 0.8 and 2.4 milligrams per kilogram, respectively.     

Lack of tolerance to 9 -tetrahydrocannabinol in chimpanzees

Five chimpanzees were given Delta(9)-tetrahydrocannabinol (Delta(9)THC): 1.0 milligram per kilogram of body weight for 21 days and 4.0 milligrams per kilogram of body weight for 42 days. Although accuracy and speed of performance on a delayed matching-to-sample task were significantly affected by both doses, tolerance to Delta(9)THC did not develop. No long-term behavioral effects of Delta(9)THC were observed after termination of the drug regimens.     

Reversal by L-dopa of impaired learning due to destruction of the dopaminergic nigro-neostriatal projection

Rats receiving bilateral stereotaxic injections of 6-hydroxydopamine into the zona compacta of the substantia nigra failed to learn a one-way active avoidance response. Small doses of L-dopa (1.5 milligrams per kilogram of body weight) in combination with a peripheral decarboxylase inhibitor reversed this impairment. Animals with lesions which acquired the avoidance response during L-dopa administration retained this response when drug treatment was discontinued. These experiments suggest that the dopaminergic nigro-neostriatal projection serves a critical function in the acquisition of learned instrumental responses.     

Parathyroid hormone effects in rats treated with diphosphonate

The ability of disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP; 40 milligrams per kilogram of body weight per day) to reduce the hypercalcemic effect of parathyroid hormone in thyroparathyroidectomized rats was confirmed. However, treatment with this large dose of EHDP enhanced the hypophosphatemic effect of a low dose of parathyroid hormone (10 international units per100 grams of body weight), apparently by promoting the renal excretion of phosphate. The data suggest that EHDP may have a direct effect on the renal action of parathyroid hormone and, in this way, may also affect vitamin D metabolism by the kidney.     

Lead exposure during infancy permanently increases lithium-induced polydipsia

Lead (200 milligrams per kilogram) was administered daily by intubation to Long-Evans rats on days 3 through 30 of life. Thirty to 180 days after cessation of lead administration, the lead-treated rats were consistently more polydipsic after lithium administration (2 millimoles per kilogram per day) than were pair-treated controls. Lithium increased the plasma renin activity equally in both the lead treated and the control groups. These data are evidence that there may be permanent neural changes induced by postnatal exposure to lead that are manifested by pharmacological challenge with lithium.     

Intragastric self-infusion of ethanol by ethanol-preferring and -nonpreferring lines of rats

An ethanol-preferring line of rats, developed by selective breeding, consumed as much as 9.4 +/- 1.7 grams of ethanol per kilogram of body weight per day through intragastric self-infusions, yielding blood ethanol concentrations of 92 to 415 milligrams per 100 milliliters. By contrast, the ethanol- nonpreferring line self-administered only 0.7 +/- 0.2 gram per kilogram per day. These findings indicate that the reinforcing effect of ethanol is postabsorptive and is not mediated by the drug's smell or taste. Hence the ethanol-preferring line of rats may be suitable animal model of alcoholism.     

Occurrence of peptide and clavine ergot alkaloids in tall fescue grass

Evidence is presented that ergot alkaloids are ubiquitous in tall fescue pastures infected with the clavicipitaceous fungal endophyte Sphacelia typhina (or Acremonium coenophialum). Ergopeptide alkaloids, predominantly ergovaline, constituted 10 to 50 percent of the total ergot alkaloid concentration, which was as high as 14 milligrams per kilogram in sheaths and 1.5 milligrams per kilogram in blades. Ergot alkaloid concentrations were substantially increased by application of large amounts (10 millimoles per liter) of potassium nitrate or ammonium chloride to infected plants in the greenhouse. The results indicate that ergot alkaloids are probably responsible for the toxicity to cattle of this common pasture and lawn grass and that ergotism-like toxicoses may be caused by clavicipitaceous fungi other than Claviceps.     

Pyrazole and induction of fatty liver by a single dose of ethanol

Pyrazole (4 millimoles per kilogram or 272 milligrams per kilogram of body weight), given to fasted rats 10 minutes before gavage with ethanol (4 grams per kilogram), completely prevented both the disappearance of ethanol from the blood over a 16-hour period and the ethanol-induced reduction in the ratio of oxidized to reduced hepatic nicotinamide-adenine dinucleotide. However, it did not affect the accumulation of triglycerides in the liver after the administration of ethanol. These results indicate that metabolism of ethanol is not required for production of fatty liver by a single, large dose of ethanol.     

Diazepam maintenance of alcohol preference during alcohol withdrawal

After forced intragastric intubation of alcohol, rats will show a greatly increased tendency to self-administer alcohol in a free-choice situation. Diazepam (Valium) dosage (5 milligrams per kilogram of body weight) during the period ow withdrawal serves to maintain undiminished such alcohol self-administration. Without such diazepam dosage the tendency to self-administer alcohol returns to control levels.     

p,p'-DDT: effect on calcium metabolism and concentration of estradiol in the blood

Ringdoves given 10 parts per million p,p'-DDT showed a decrease of estradiol in the blood early in the breeding cycle and egg-laying was delayed. There was also a decrease in deposition of medullary calcium and in eggshell weight. Injection of p,p'-DDE (150 milligrams per kilogram of body weight) caused reduction of eggshell weight and inhibition of carbonic anhydrase in the oviduct.     

Fenfluramine: amphetamine congener that fails to maintain drug-taking behavior in the rhesus monkey

Fenfluramine, over a dose range from 0.003 to 3 milligrams per kilogram of body weight, failed to maintain self-injection behavior in rhesus monkeys that had initiated and maintained responding for cocaine or methohexital. This absence of a positive reinforcing effect could not be attributed to a slow onset of drug effect or to the use of behaviorally inactive doses. Fenfluramine, because of its distinctive properties, may produce fewer problems of human abuse than do amphetamine-type agents.     

In vivo activity against HIV and favorable toxicity profile of 2',3'-dideoxyinosine

The purine analog 2',3'-dideoxyinosine (ddI), which has anti-retroviral activity in vitro was administered for up to 42 weeks to 26 patients with acquired immunodeficiency syndrome (AIDS) or severe AIDS-related complex (ARC). Ten of these individuals were AZT-intolerant. Eight dose regimens were studied. The drug was orally bioavailable and penetrated into the cerebrospinal fluid (CSF). Comparatively little evidence of an effect against human immunodeficiency virus (HIV) was seen at the lowest four doses. However, patients in the four highest dose groups (ddI at 1.6 milligrams per kilogram intravenously and then greater than or equal to 3.2 milligrams per kilogram orally at least every 12 hours or higher) had increases in their circulating CD4+ T cells (P less than 0.0005), increased CD4/CD8 T cell ratios (P less than 0.01), and, where evaluable, more than an 80% decrease in serum HIV p24 antigen (P less than 0.05). The patients also had evidence of improved immunologic function, had reduced viremic symptomatology, and gained a mean of 1.6 kilogram with these comparatively infrequent dosing schedules (every 8 or 12 hours). The most notable adverse effects directly attributable to ddI administration at the doses used in this study included increases in serum uric acid (due to hypoxanthine release) and mild headaches and insomnia. These results suggest that serious short-term toxicity at therapeutic doses is not an inherent feature in the profile of agents with clinical anti-HIV activity. Further controlled studies to define the safety and efficacy of this agent may be worth considering.     

Ventricular arrhythmias related to antibiotic usage in dogs

In dogs, pretreatment with the macrolide antibiotic tylosin (5 milligrams per day per kilogram of body weight) increased the incidence of ventricular tachycardia and fibrillation during acute myocardial ischemia. Another group received a dose of acetyl strophanthidin which was nontoxic in controls, but which resulted in a ventricular arrhythmia in six of seven animals on antibiotic treatment. Enhancement of loss of potassium ion from the myocardium by the antibiotic was presumed to be related to the altered cardiac rhythm.