GABA agonists differentially modify blood glucose levels of diabetic rats.

This study described the effects of GABA agonists on glucose plasma concentrations of streptozotocin-induced diabetic rats. Low doses of an indirect GABA agonist, AOAA (aminooxyacetic acid); a GABA(A) and a GABA(B) agent, THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridone) and baclofen, respectively; and a benzodiazepine were administered to non-diabetic and to diabetic rats. Plasma glucose concentrations were estimated during fasting and after an oral glucose load. Diazepam (1 mg/kg), baclofen (1 mg/kg) and AOAA (30 mg/kg), significantly decreased glycemia after oral glucose overload of streptozotocin-induced diabetes. None of the GABA-acting agents tested changed fasting or glucose overload glycemia of normal rats. Diazepam was the only drug to increase the fasting blood glucose concentration of diabetic rats. Treatment with AOAA or diazepam was accompanied by increased insulin plasma concentrations in diabetic rats to levels similar to the ones of non-diabetic animals. These results demonstrate that benzodiazepines and other GABA drugs act the endocrine pancreas in vivo, ultimately increasing plasma insulin and decreasing high blood glucose levels of diabetic rats. The acute and prolonged effects of the multitude of drugs acting on the GABA(A)-benzodiazepine-chloride ionophore complex remain to be broadly investigated as a therapeutic tool in diabetes.

Behavioral changes and cholinesterase activity of rats acutely treated with propoxur.

Early assessment of neurological and behavioral effects is extremely valuable for early identification of intoxications because preventive measures can be taken against more severe or chronic toxic consequences. The time course of the effects of an oral dose of the anticholinesterase agent propoxur (8.3 mg/kg) was determined on behaviors displayed in the open-field and during an active avoidance task by rats and on blood and brain cholinesterase activity. Maximum inhibition of blood cholinesterase was observed within 30 min after administration of propoxur. The half-life of enzyme-activity recovery was estimated to be 208.6 min. Peak brain cholinesterase inhibition was also detected between 5 and 30 min of the pesticide administration, but the half-life for enzyme activity recovery was much shorter, in the range of 85 min. Within this same time interval of the enzyme effects, diminished motor and exploratory activities and decreased performance of animals in the active avoidance task were observed. Likewise, behavioral normalization after propoxur followed a time frame similar to that of brain cholinesterase. These data indicate that behavioral changes that occur during intoxication with low oral doses of propoxur may be dissociated from signs characteristic of cholinergic over-stimulation but accompany brain cholinesterase activity inhibition.

Hematological alterations in rats from xylene and benzene.

Benzene and xylene are used by the chemical industry as raw materials for the manufacturing of paints, insecticides, gums, resins and other compounds. Through its myelotoxic actions, benzene produces hematologic changes ranging from pancytopenia to total bone marrow aplasia. The present investigation studied the possible effects of xylene on rat peripheral blood and compared these effects to those produced by benzene. Thirty-six male Wistar rats were injected s.c. with 2 ml benzene, xylene or saline/kg body weight 3 times a week at 2-3 d intervals for 5 w. The animals were lightly anesthetized and blood was collected by puncture of the retro-orbital plexus before the first administration of the solvents on d 7, 14, 21 and 35 of dosing, and 14 d after dosing was discontinued. Xylene induced leukocytosis as an increase in absolute neutrophil numbers, whereas benzene caused leukocytopenia due to decreases in absolute lymphocyte number. The 2 solvents reduced erythrocyte counts, hematocrit and hemoglobin. Platelet counts were high throughout the dosing with benzene and xylene. Fourteen d after discontinuation of xylene dosing, the rats recovered their initial hematologic values, whereas the animals dosed with benzene did not fully recover leukocytes and erythrocytes. The intoxications with benzene and xylene were not solely hematologic since there was also growth retardation, as shown by reduced weight gain, which did not recover after dosing ceased.

Lithium and valproate combined administration: acute behavioural effects and drug plasma levels.

Drug plasma concentrations and behavioural effects of acute combined administration of lithium and valproic acid were studied in normonatraemic and hyponatraemic rats. Hyponatraemia was induced two hours before drug administration and behavioural observations lasted for two additional hours. Blood was collected by the end of the behavioural observation. The higher doses of valproic acid (360 mg/kg) or lithium (2 mEq/kg) induced more head-shakes and higher plasma concentration than 180 mg/kg of valproic acid or lithium 1 mEq/kg, respectively. Valproic acid and lithium administered separately induced more head shakes and higher drug plasma levels in hyponatraemic rats than in normonatraemic animals. Combined administration of valproic acid (180 mg/kg) and lithium (2 mEq/kg) produced a supra-aditive effect in head-shakes. The drug interaction between lithium and valproic acid induced a decrease in valproic acid plasma level and an increase in lithium plasma levels.

The effects of GABAergic drugs on grooming behaviour in the open field.

In a previous study it was demonstrated that sodium valproate, a drug that increases GABA cerebral concentrations, decreases grooming in the open field. This effect was not modified by morphine or naloxone. To provide evidence for the participation of the GABA system in the expression of grooming, other GABAergic drugs were acutely administered to rats before the test in the open field. The drugs, in the doses tested, did not modify locomotion, rearing, freezing or defaecation. Aminooxiacetic acid 10 mg/kg, barbital 60 mg/kg, baclofen 1.5 mg/kg, clonazepam 0.1 mg/kg, sodium valproate 150 mg/kg and 4,5,6,7-tetrahydroxi-azolo-5,4c-pyridine-3-ol (THIP) 0.75 mg/kg were the lowest doses to decrease the frequencies of grooming. The estimated ED50 to suppress grooming behaviour in the open field were 1.75 mg/kg baclofen, 52 mg/kg barbital, 0.86 mg/kg clonazepam and 1.0 mg/kg THIP. The decrease in grooming produced by the lowest effective doses of aminooxiacetic acid, clonazepam, sodium valproate and THIP was antagonized by concomitant administration of picrotoxin 1 mg/kg or bicuculline 1 mg/kg. The effects of baclofen and barbital on grooming were not modified by the antagonists. It is concluded that the GABA system, through GABA A and GABA B receptors may play a role in the expression of novelty-induced grooming behaviour.

[Toxicology of toluene: aspects related to its abuse]. / Toxicologia do tolueno: aspectos relacionados ao abuso.

Toluene, present in many industrial and domestic products, is the main solvent involved in solvent abuse and occupational exposure. The main problem in studying toluene-related pathologies is the fact that it is frequently combined with other substances. This review focuses on its potential toxicity. The following subjects are discussed: pharmacologic parameters; physico-chemical features; exposure; clinical trials; experimental research; diagnosis; tolerance and dependence; acute and chronic effects; neurotoxicity; teratogenicity; psychiatric disorders; carcinogenicity; and treatment. It is concluded that is important more research on larger population samples with a view to better definition of the consequences of chronic use should be undertaken.

Serviço de informaçoes sobre substâncias psicoativas. Caraterísticas da informaçao sobre drogas / Psychoactive substances information service. Characteristics of the provision of drug information

Este trabalho apresenta a an lise das consultas realizadas a um serviço de informaçöes sobre substâncias psicoativas, em 42 meses de funcionamento. As 1.284 consultas foram feitas através de uma linha telef"nica, havendo contato direto com um plantonista, com manutençäo do anonimato, caso houvesse interesse do usu rio. Constatou-se que, apesar de ampla variaçäo no número de consultas por período, dependendo da divulgaçäo da existência do serviço, a média é de 1,5 consultas ao dia. Näo h preferência entre os sexos e o uso é näo profissional na maioria das perguntas. Questöes sobre drogas de abuso (inalantes e maconha) säo mais frequentes, havendo interesse na obtençäo de mais informaçöes sobre medicamentos prescritos (benzodiazepínicos e antidepressivos), tanto de açäo central como de outros tipos (drogas cardiovasculares e antimicrobianos). É pequeno o número de perguntas sobre cafeína, nicotina e alucinógenos

Servico de informacoes sobre substancias psicoativas. Caracteristicas da informacao sobre drogas

Este trabalho apresenta a analise das consultas realizadas a um servico de informacoes sobre substancias psicoativas, em 42 meses de funcionamento. As 1.284 consultas foram feitas atraves de uma linha telefonica, havendo contato direto com um plantonista, com manutencao do anonimato, caso houvesse interesse do usuario. Constatou-se que, apesar de ampla variacao do numero de consultas por periodo, dependendo da divulgacao da existencia do servico, a media e de 1,5 consultas ao dia. Nao ha preferencia entre os sexos e o uso e nao profissional na maioria das perguntas. Questoes sobre drogas de abuso (inalantes e maconha) sao mais frequentes, havendo interesse na obtencao de mais informacoes sobre medicamentos prescritos (benzodiazepinicos e antidepressivos), tanto de acao central como de outros tipos (drogas vardiovasculares e antimicrobianos). E pequeno o numero de perguntas sobre cafeina, nicotina e alucinogenos.

Effect of sodium valproate on the open-field behavior of rats.

1. It has been reported that sodium valproate induces a morphine-like withdrawal syndrome in rats. The effects of acute or chronic treatment with sodium valproate on rat behavior was studied in the open-field test. 2. Acute sodium valproate (320 mg/kg, intraperitoneally) decreases the frequency of, and the time spent in grooming even when not modifying locomotion, rearing or defecation (N = 15), either 15 or 60 min after an acute treatment. This effect was not modified (N = 10) by concomitant administration of morphine (2 mg/kg) or naloxone (1 mg/kg). 3. Interruption of prolonged (30 days) valproate treatment with increasing doses of 40 to 320 mg/kg, by gavage, twice daily (N = 10) did not modify rat behavior in the open-field, from the first to the fourteenth day of the test. 4. We conclude that the decreased novelty-induced grooming does not depend on the opioid system and may be related to an anti-anxiety effect of valproate.

Effect of sodium valproate on the open-field behavior of rats

It has been reported that sodium valproate induces a morphine-like withdrawal syndrome in rats. The effects of acute or chronic treatment with sodium valproate on rat behavior was studied in the open-field test. Acute sodium valproate (320 mg/kg, intraperitoneally) decreases the freuqncy of, and the time spent in grooming even when not modifying locomotion, rearing or defecation (N=15), either 15 or 60 min after an acute treatment. This effect was not modified (n+10) by concomitant administration of morphine (2 mg/kg) or naloxone (1 mg/kg). Interruption of prolonged (30 days) valproate treatment with increasing doses of 40 to 320 mg/kg, by gavage, twice daily (N=10) did not modify raty behavior in the open-field, from the first to the fourtheenth day of th test. We conclude that the decreased novely-induced grooming does not depend on the opioid system and may be related to anti-anxiety effect of valproate

Enhanced detection of hyperactivity after drug withdrawal with a simple modification of the open-field apparatus.

The open-field apparatus has been used to study withdrawal reactions from chronic treatments with central nervous system depressant drugs. To study the behavior of the same animal after drug withdrawal, the rats are introduced into the open field on consecutive days. Because the open field is a novel environment, the repetition could lead to false-negative results with regard to drug withdrawal. To overcome this problem, we sought a modification of the open field, using different floor-painting patterns every time the animal is observed. The most frequently observed withdrawal manifestation was hyperactivity. We verified that long-term treatment withdrawal reactions from barbital, clonazepam, and ethanol were seen more often if the rats were introduced in the modified open field. In addition, fewer animals were used here than in other trials and hyperactivity was detected more frequently in the modified open field than was sound-induced convulsions. We propose that the modified open field is more useful than the classic one for screening of drug withdrawal reactions.

Effects of phenylethylamine on rat locomotor behavior and avoidance learning.

1. The effects of beta-phenylethylamine (PEA) alone and in association with caroxazone, a potent inhibitor of monoamine oxidase B (MAO B), on the activity and long-term memory in the wheel-shaped activity monitor and on fixed-interval two-way avoidance acquisition were studied in rats. In a separate study, we determined the effects of PEA and of d-amphetamine on the variable-interval two-way avoidance acquisition. 2. The action of PEA was markedly different from that of amphetamine in several aspects. The stimulating effects of PEA in the wheel-shaped activity monitor were of a more subtle nature than those of amphetamine and in the variable-interval two-way avoidance acquisition PEA had no effect, while amphetamine improved performance. 3. PEA did not induce an increase in path-choice stereotypy, but caroxazone did. The absence of any caroxazone-session interaction effects on the path iteration frequency suggested that there were no long-term memory effects. 4. In the fixed-interval two-way avoidance acquisition experiments, PEA increased the avoidance responses of rats while caroxazone had no effect. The association of the two drugs did not potentiate either.

Effects of phenylethylamine on rat locomotor behavior and avoidance learning

1. The effects of ß-phenylethylamine (PEA) alone and in association with caroxazone, a potent inhibitor of monoamine oxidase B (MAO B), on the activity and long-term memory in the wheel-shaped activity monitor and on fixed-interval two-way avoidance acquisition were studied in rats. In a separate study, we determined the effects of PEA and of d-amphetamine on the variable-internal two-way avoidance acquisition. 2. The action of PEA was markedly different from that of aplhetamine in several aspects. The stimulating effects of PEA in the wheel-shaped activity monitor were of a more subtle nature than those of amphetamine and in the variable-interval two-way avoidance acquisition PEA had no effect, while amphetamine improved performance. 3. PEA did not induce an increase in path-choice stereotypy, but caroxazone did. The absence of any caroxazone-session interaction effects on the path interation frequency suggested that there were no long-term memory effects. 4. In the fixed-interval two-way avoidance acquisition experiments, PEA increased the avoidance responses of tats while caroxazone had no effect. The association of the two drugs did not potenciate either

Effects of carbamazepine or imipramine alone or in association with amphetamine on the fighting time of REM sleep-deprived rats.

The fighting time of REM sleep-deprived rats was measured after both acute and long-term intraperitoneal treatment with carbamazepine (CBZ) or imipramine (IMI) alone or associated with amphetamine. Fighting time was increased by the lower doses of CBZ (5-20 mg/kg) or IMI (0.5-2 mg/kg) administered acutely. At the highest dose tested, CBZ (40 mg/kg) was not significantly different from the control value, and the fighting time observed after 4 mg/kg IMI was less than that observed with 2 mg/kg. Amphetamine (2 mg/kg) alone increased the fighting time and this effect was not modified by association with 5-40 mg/kg CBZ or 0.5-4 mg/kg IMI. Long-term treatment (14 days) with CBZ (20 mg kg-1 day-1) or IMI (2 mg kg-1 day-1) significantly reduced fighting time in contrast to the increase observed with a single acute treatment at the same dose. The fighting time of rats acutely treated with amphetamine (2 mg/kg) was significantly but not completely reduced by previous long-term pretreatment with CBZ, whereas IMI pretreatment had no effect. The differences between the effects of acute and long-term treatment with CBZ cannot be explained by the development of metabolic tolerance, since serum CBZ levels were the same in both situations.

Carbamazepine-induced hyperglycemia in hyponatremic rats.

Hyponatremia was induced by intraperitoneal administration of 5.5% glucose followed by treatment with carbamazepine. Serum determinations of carbamazepine were also performed. Carbamazepine decreased serum Na+ and increased blood glucose concentration in the hyponatremic rats.