Differential behavioral outcomes of 3,4-methylenedioxymethamphetamine (MDMA-ecstasy) in anxiety-like responses in mice

Anxiolytic and anxiogenic-like behavioral outcomes have been reported for methylenedioxymethamphetamine (MDMA or ecstasy) in rodents. In the present experiment, we attempted to identify behavioral, hormonal and neurochemical outcomes of MDMA treatment to clarify its effects on anxiety-related responses in 2-month-old Balb/c male mice (25-35 g; N = 7-10 mice/group). The behavioral tests used were open field, elevated plus maze, hole board, and defensive behavior against predator odor. Moreover, we also determined striatal dopamine and dopamine turnover, and serum corticosterone levels. MDMA was injected ip at 0.2, 1.0, 5.0, 8.0, 10, or 20 mg/kg. MDMA at 10 mg/kg induced the following significant (P < 0.05) effects: a) a dose-dependent increase in the distance traveled and in the time spent moving in the open field; b) decreased exploratory activity in the hole board as measured by number of head dips and time spent in head dipping; c) increased number of open arm entries and increased time spent in open arm exploration in the elevated plus maze; d) increased time spent away from an aversive stimulus and decreased number of risk assessments in an aversive odor chamber; e) increased serum corticosterone levels, and f) increased striatal dopamine level and turnover. Taken together, these data suggest an anxiogenic-like effect of acute MDMA treatment, despite the fact that behavioral anxiety expression was impaired in some of the behavioral tests used as a consequence of the motor stimulating effects of MDMA.

Effect of cyhalothrin on Ehrlich tumor growth and macrophage activity in mice

Cyhalothrin, a pyrethroid insecticide, induces stress-like symptoms, increases c-fos immunoreactivity in the paraventricular nucleus of the hypothalamus, and decreases innate immune responses in laboratory animals. Macrophages are key elements in cellular immune responses and operate at the tumor-host interface. This study investigated the relationship among cyhalothrin effects on Ehrlich tumor growth, serum corticosterone levels and peritoneal macrophage activity in mice. Three experiments were done with 10 experimental (single gavage administration of 3.0 mg/kg cyhalothrin daily for 7 days) and 10 control (single gavage administration of 1.0 mL/kg vehicle of cyhalothrin preparation daily for 7 days) isogenic BALB/c mice in each experiment. Cyhalothrin i) increased Ehrlich ascitic tumor growth after ip administration of 5.0 x 106 tumor cells, i.e., ascitic fluid volume (control = 1.97 ± 0.39 mL and experimental = 2.71 ± 0.92 mL; P < 0.05), concentration of tumor cells/mL in the ascitic fluid (control = 111.95 ± 16.73 x 106 and experimental = 144.60 ± 33.18 x 106; P < 0.05), and total number of tumor cells in the ascitic fluid (control = 226.91 ± 43.22 x 106 and experimental = 349.40 ± 106.38 x 106; P < 0.05); ii) increased serum corticosterone levels (control = 200.0 ± 48.3 ng/mL and experimental = 420.0 ± 75.5 ng/mL; P < 0.05), and iii) decreased the intensity of macrophage phagocytosis (control = 132.3 ± 19.7 and experimental = 116.2 ± 4.6; P < 0.05) and oxidative burst (control = 173.7 ± 40.8 and experimental= 99.58 ± 41.7; P < 0.05) in vitro in the presence of Staphylococcus aureus. These data provide evidence that cyhalothrin simultaneously alters host resistance to Ehrlich tumor growth, hypothalamic-pituitary-adrenocortical (HPA) axis function, and peritoneal macrophage activity. The results are discussed in terms of data suggesting a link between stress, HPA axis activation and resistance to tumor growth.

Dose-response effects of systemic anandamide administration in mice sequentially submitted to the open field and elevated plus-maze tests

The endocannabinoid system is involved in the control of many physiological functions, including the control of emotional states. In rodents, previous exposure to an open field increases the anxiety-like behavior in the elevated plus-maze. Anxiolytic-like effects of pharmacological compounds that increase endocannabinoid levels have been well documented. However, these effects are more evident in animals with high anxiety levels. Several studies have described characteristic inverted U-shaped dose-response effects of drugs that modulate the endocannabinoid levels. However, there are no studies showing the effects of different doses of exogenous anandamide, an endocannabinoid, in animal models of anxiety. Thus, in the present study, we determined the dose-response effects of exogenous anandamide at doses of 0.01, 0.1, and 1.0 mg/kg in C57BL/6 mice (N = 10/group) sequentially submitted to the open field and elevated plus-maze. Anandamide was diluted in 0.9 percent saline, ethyl alcohol, Emulphor® (18:1:1) and administered ip (0.1 mL/10 g body weight); control animals received the same volume of anandamide vehicle. Anandamide at the dose of 0.1 mg/kg (but not of 0.01 or 1 mg/kg) increased (P < 0.05) the time spent and the distance covered in the central zone of the open field, as well as the exploration of the open arms of the elevated plus-maze. Thus, exogenous anandamide, like pharmacological compounds that increase endocannabinoid levels, promoted a characteristic inverted U-shaped dose-response effect in animal models of anxiety. Furthermore, anandamide (0.1 mg/kg) induced an anxiolytic-like effect in the elevated plus-maze (P < 0.05) after exposing the animals to the open field test.

Effects of diazepam on Mycobacterium bovis-induced infection in hamsters

The in utero exposure of hamsters to low doses of diazepam results in impaired host defense against Mycobacterium bovis during adulthood. Delayed developmental immunotoxicity, however, represents a specific situation that might not be general. The present experiment was undertaken to investigate the effects of diazepam on hamster resistance to M. bovis using adult animals. The effects of diazepam treatment on serum cortisol levels were also studied. Adult hamsters (N = 10 for each group) were treated with diazepam (E1 = 1.0, E2 = 2.0 or E3 = 3.0 mg kg-1 day-1 subcutaneously) or with control solution (C) for 30 days. Seven days after the beginning of the treatment, the animals received identical inoculum concentrations of M. bovis. Hamsters treated with the higher (2.0 and 3.0 mg kg-1 day-1) doses of diazepam exhibited: 1) increased granuloma areas in the liver (C = 1.81 + or - 1.39, E2 = 10.29 + or - 4.64 and E3 = 15.80 + or - 4.82) and lung (C = 0.54 + or - 0.55, E2 = 6.28 + or - 3.85 and E3 = 6.31 + + or - 3.56) and 2) increased scores of M. bovis colony-forming units isolated from liver (C = 2.0, E2 = 3.0 and E3 = 3.5), lung (C = 1.0, E2 = 3.0 and E3 = 3.5) and spleen (C = 1.0, E2 = 2.5 and E3 = 4.0). These effects were dose dependent, and were not detected or were less severe in animals treated with the lowest (1.0 mg/kg) dose of diazepam as well as in those of the control group. Furthermore, diazepam treatment (3.0 mg kg-1 day-1 for 30 days) increased (E3 = 71.32 + or - 2.99; N = 10) the serum levels of cortisol compared to control hamsters (C = 22.61 + or - 2.75; N = 10). The present data, that demonstrate an impaired defense against M. bovis in adult hamsters treated with diazepam, were tentatively explained on the basis of a direct and/or indirect action of diazepam on the cytokine network. The effects may be related to stimulation of peripheral benzodiazepine receptor binding sites (PBR) by macrophages and/or lymphocytes, or they may be mediated by PBR stimulation of the adrenals

Developmental and behavioral effects of postnatal amitraz exposure in rats

The effects of postnatal amitraz exposure on physical and behavioral parameters were studied in Wistar rats, whose lactating dams received the pesticide (10 mg/kg) orally on days 1,4,7,10,13,16 and 19 of lactation; control dams received distilled water (1 ml/kg) on the same days. A total of 18 different litters (9 of them control and 9 experimental) born after a 21-day gestation were used. The results showed that the median effective time (ET50) for fur development, eye opening, testis descent an onset of the startle response were increased in rats postnatally exposed to amitraz (2.7, 15.1, 21.6 and 15.3 days, respectively) compared to those of the control pups (1.8, 14.0, 19.9 and 12.9 days, respectively). The ages of incisor eruption, total unfolding of the external ears, vaginal and ear opening and the time taken to perform the grasping hindlimb reflex were not affected by amitraz exposure. Pups from damps treated with amitraz during lactation took more time (in seconds) to perform the surface righting reflex on postnatal days (PND) 3 (25.0 + 2.0), 4 (12.3 + 1.2) and 5 (8.7 + 0.9) in relation to controls (10.6 + 1.2;4.5 + 0.6 and 3.4 + 0.4, respectively); the climbing response was not changed by amitraz. Postnatal amitraz exposure increased spontaneous motor activity of male and female pups in the open-field on PND 16 (140 + 11) and 17 (124 + 12), and 16 (104 + 9), 17 (137 + 9) and 18 (106 + 8), respectively. Data on spontaneous motor activity of the control male and female pups were 59 + 11 and 69 + 10 for days 16 and 17 and 49 + 9, 48 + 7 and 56 + 7 for days 16,17 and 18, respectively. Some qualitative difference were also observed in spontaneous motor behavior; thus, raising the head, shoulder and pelvis matured one or two days later in the amitraz-treated offspring. Postnatal amitraz exposure did not change locomotion and rearing frequencies or immobility time in the open-field on PND 30,60 and 90. The present findings indicate that postnatal exposure to amitraz caused transient development and behavioral changes in the exposed offspring and suggest that further investigation of the potential health risk of amitraz exposure to developing human and animal offsprings may be warranted.

Effects of high doses of diazepam on carrageenin-induced paw edema in rats

Benzodiazepine (BDZ) receptor sites play a relevant role in immune/ inflammatory reactions. Acute BDZ treatments were shown not only to suppress cell proliferation in rat thymus but also to decrease TNF-alpha, IL-1 and IL-6 release from adult mouse macrophages. In the present investigation the effects of acute (l0.0 and 20.0 mg/kg) and long-term (10.0 mg kg(-1) day(-l), for 21 days) diazepam treatment on carrageenin-induced paw edema were studied in rats. The results showed that acute treatment with high doses of diazepam decreased paw edema volume in a dose-dependent manner, and this effect was observed as early as 1 h after the administration of the 20.0 mg/kg dose and continued until the last measurement was performed (8 h). In contrast, long-term diazepam administration did not modify the phlogistic-induced edema. Taken together, these data show that 1) acute diazepam treatment with high doses decreases the volume of the acute inflammatory paw edema developed by the organism as a response to carrageenininduced injury, and 2) long-term diazepam treatment induces tolerance to this effect. These results are discussed in the light of a possible effect of diazepam on the components of the rat cellular and humoral immune/inflammatory reaction such as T lymphocytes and/or interleukins.

Chemical and biological demonstration of the presence of monofluoroacetate in the leaves of Palicourea marcgravii St. Hil

Cattle losses in Brazil have been attributed to Palicourea marcgravii St. Hil., a toxic plant for cattle. The crude extract from the leaves of P. marcgravii was successively fractionated using solvents with different polarities to determine whether monofluoroacetic acid and/or some other substance present in the leaves may be responsible for the acute symptoms caused by the plant. Authentic sodium monofluoroacetate (SMFA) was used fopr comparison. The only P. marcgravii fraction which induced seizures and death in intoxicated rats was water soluble. The signs and symptoms induced in the animals by the crude extract and water-soluble fraction were the same as induced by SMFA and included tonic seizures and other actions on the CNS. The dose-lelthality and dose-latency to the 1st seizure curves constructed for the water soluble fraction of the leaf extract (30-100 mg/Kg) and SMFA (0.6-3.0 mg/Kg) were parallel. Five animals per dose were used. The potency ratio of SMFA in relation to the water-soluble fraction of the leaf extract was 53.8 (dose-lethality curve) and 64.1 (dose latency to the 1st seizure curve). The water-soluble fraction contained a substance with hRf = 20 which the same as that of authentic SMFA. The 19F NMR spectra of authentic SMFA and the P. marcgravii water-soluble fraction were identical. These data demosntrate the presence of SMF in the water-soluble fraction of P. marcgravii leaves and show that monofluoroacetate is the active principle repsonsible for the signs and symptoms of acute intoxications

Intracerebroventricular administration of cholecystokinin reduces stereotypy in dopamine supersensitive rats

Cholecystokinin (CCK-8) coexists with dopamine in some neurons and modulates dopaminergic neurotransmission. In the present study we determined the effect of CCK-8 on stereotyped behavior in supersensitive dopaminergic system. Adult male Wistar rats, weighing 200-250 g, were used. Dopaminergic supersensitivity was induced by long-term haloperidol (HAL) treatment (30 days: 1.0 mg/kg twice a day). Seventy-two hours after HAL withdrawal animals received CCK-8 (14.5 nmol/5 µl) or saline intracerebroventricularly (icv) before being tested for apomorphine (APO, 0.6 mg/kg, sc)-induced stereotyped behavior. experimental groups were: long-term HAL-treated rats that received saline (HSAL, N = 9) or CCK-8 (HCCK, N = 11) icvand long-term saline-treated rats that received CCK-8(SCCK,N = 9) or saline (SSAL, N = 8) icv. As expected, HSAL rats showed statistically significant higher stereotypy scores than SSAL rats (42 + or - 1.7 vs 31 + or - 1.6; P<0.05) and CCK-8 icv reduces stereotypy in dopaminergic-supersensitive rats, and suggest that the dopamine supersensitivity phenomenon can be modulated by CCK-8

Effect of manipulation of the GABA system on dopamine-related behaviors

The interaction between GABAergic and dopaminergic system within the central nervous system was investigated in rats using the open-field apparatus and apomorphine-induced stereotypy, and in mice using haloperidol-induced catalepsy. The single intraperitoneal adminsitration of baclofen 3.0 mg/kg, 4,5,6,7-tetrahydroisoxasolo-(5,4-c) piridin-3-ol (THIP) 10.0 mg/kg and picrotoxin 2.0 mg/kg decreased both ambulation and rearing frequencies of the rats in the open-field; only the GABA agonists increased the duration of animal immobility. THIP (10.0 mg/kg) increased the duration of haloperidol-induced catalepsy. For apomorphine-induced stereotypy, baclofen 3.0 mg/kg and picrotoxin 1.0 mg/kg induced a significant leftward displacement of the control dose-response curve constructed for apomorphine (0.1-10 mg/kg) in relation to the control. In addition, baclofen, THIP, picrotoxin and 3-mercaptopropionic acid (3-MPA) 10.0 mg/kg decreased both rearing and sniffing behaviors elicited by apomorphine and increased licking and/ or gnawing. Different mechanisms seem to be involved in the similar effects induced by GABA agonists and antagonists. Picrotoxin induced stereotyped movements per se with a dose-dependent effect, but baclofen and THIP did not. The present data suggest that GABA manipulation facilitates the progressive activation of the different dopaminergic pathways involved in stereotyped behaviors, thus increasing those stereotyped components (gnawing and licking) that appear after a high level of activation of dopaminergic pathways

Effects of amitraz on the arterial blood pressure and body rectal temperature of conscious rats

O presente trabalho estuda os efeitos da administraçäo única de amitraz (100 mg/kg) sobre a pressäo sanguínea arterial e a temperatura corporal de ratos Wistar. A administraçäo de amitraz diminuiu a pressäo sanguínea arterial e também produziu hipotermia. A administraçäo de tiramina (100,0 mg/kg) induziu um aumento significativo (p<0,05) na pressäo sanguínea arterial de ratos que receberam previamente amitraz, näo alterando a dos ratos controle. Metade dos ratos que receberam amitraz e tiramina morreram entre 3 e 10 horas após a administraçäo, fato este näo ocorrido com os animais que receberam soluçäo fisiológica e posteriormente tiramina. Os sinais de intoxicaçäo dos animais experimentais incluíram sedaçäo, falta de coordenaçäo motora e coma. A posterior administraçäo de ioimbina (10,0 mg/kg) näo alterou a hipotermia produzida pela administraçäo de amitraz (p<0,05). Apesar de näo poder ser excluída uma possível açäo do amitraz sobre alfa2-noradrenoceptores cerebrais, os resultados indicam uma provável açäo deste praguicida inibindo a enzima monoaminoxidase

Effects of amitraz on isolation-induced aggression in mice

Estudaram-se os efeitos do amitraz, um derivado farmacomidínico, no comportamento agressivo induzido pelo isolamento social em camundongos. Os resultados mostraram que o Amitraz aumentou a latência para o primeiro ataque e diminuiu näo somente a duraçäo de briga como as frequências de ataques entre esses animais. Estes resultados sugeriram que os efeitos do praguicida sobre o comportamento agressivo dos camundongos foram consequência de um efeito inibitório do mesmo sobre a atividade da enzima monoamina oxidase no Sistema Nervoso Central, e, consequentemente, de um aumento dos níveis cerebrais de serotonina

Behavioral and biochemical effects of Xylazine: possible interactions between central noradrenergic-dopaminergic systems

Alguns efeitos comportamentais e bioquímicos da xilazina foram estudados em ratos e camundongos. Os resultados mostraram que a xilazina: a)diminuiu a atividade geral de ratos e camundongos observados em campo-aberto; b) foi incapaz de produzir catatonia e suprimiu este comportamento induzido pelo haloperidol em camundongos; c) potencializou o comportamento estereotipado induzido pela apomorfina em ratos; d) aumentou os nívei cerebrais de noradrenalina, porém näo alterou aqueles de dopamina. Estes resultados foram discutidos considerando-se açäo da xilazina em sistemas noradrenérgicos centrais e da interaçäo entre sistemas noradrenérgicos e dopaminérgicos centrais

Effects of age and isolation on the evolution of catalepsy during chronic haloperidol treatment

Sixteen young (5 months) and 16 old (20-24 months) male Wistar rats, housed together or in individual cages were observed for cataleptic behavior 10, 20 and 30 days after the beginning of chronic haloperidol treatment (1.0 mg/kg, twice daily, for 30 days). Catalepsy was measured by the bar test. Age increased the duration of haloperidol-induced catalepsy of isolated and group-housed rats in the three observation sessions (old-isolated = 7.4 ñ 0.2; old-group housed = 7.5 ñ 0.1; young-isolated =6.3 ñ 0.2; young-group housed = 6.8 ñ 0.2 In seconds in session 1, for example). Conversely, isolation did not modify the sensitivity to the sensitivity to the cataleptic effect of haloperidol. Even more important, no differences in duration of haloperidol-induced catalepsy were observed among the three sessions for each group. The resultss indicate that under the experimental conditions employed the animals did not develop tolerance nor sensitization to haloperidol-induced catalepsy. In addition, neither age nor isolation modified the absence of effects of repeated haloperidol treatment on the catalepsy behavior of rats

Effects of acute 2,4-dichlorophenoxyacetic acid intoxication on some rat serum components and enzyme activities

The present study was undertaken to investigate the effects of acute 2,4-dichlorophenoxacetic acid (2,4-D) intoxication (0.6 g/kg, po) on lactate dehydrogenase, alkaline phosphatase, aspartate amino-transferase, alanine aminotransferase, amylase, creatinine, glucose, total protein and albumin levels in rats. Serum levels of lactate dehydrogenase, alkaline phosphatase and creatinine increased from 1-to 4-fold at 5,8 and 24 h after 2,4-D administration, whereas serum levels of aspartate and alanine aminotransferase were higher only at 8 and 24 h. Amylase levels were only increased 8 h after administration of 2,4-D and then returned to normal levels. In contrast, 2,4-D reduced the serum levels of glucose and total protein 5,8 and 24 h and serum albumin levels 5 h after herbicide intoxication. Thus, acute intoxication with 2,4-D disrupts serum levels of several enzymes and components which are considered to be indicators of tissue injury. Most likely these alterations mainly reflect hepatic and muscle tissue damage induced by the herbicide, but significant pancreatic and kidney toxicity may also have occurred

Effects of single and long-term administration of sulpiride on open-field and stereotyped behavior of rats

1. The effects of single (3.0 to 180.0 mg/Kg) and long-term (up to 90.1 mg/Kg) administration of sulpiride on open-field and apomorphine-induced stereotyped behavior of rats were studied. 2. when animals were studied 30 min after ip sulpiride administration and rearing frequencies in the open-field or apomorphine effects were not modified in a dose-dependent and consistentway by the single sulpiride administration. 3. In relation to control values, a significant decrease im apomorphine-induced stereotyped behavior was observed when rats were injected with a single sulpiride dose 2.5, 5.0, 7.5 and 10.0 h before the dopaminergic agonist. 4. Withdrawal from long-term ip sulpiride administration (up to 90.0 mg/Kg per injection, twice daily for 57 days) induced a significant increase in all parameters of activity recorded in the open-field, and the responsiveness to apomorphine was also augmented in sulpiride-withdrawn rats. 5. These results suggest that sulpiride, a benzamide drug that differs from classic neuroleptic agents by producing fewer extrapyramidal side effects, also supersensitivity of central dopaminergic receptors

Effects of exposure to a pyrethroid insecticide during lactation on the behavior of infant and adult rats

Cyhalothrin, a pyrethroid insecticide, was administered to female Wistar rats as a 0.02% solution plus 0.04% sucrose (w/v) in drinking water from whelping to pup weaning after 21 days of lactation. The pesticide did not change the maternal behavior of the dams as measured by the scoring system of Sderstein and Eneroth. The body weight of pups exposed to the pesticide and at age 90 days was not different from that of controls, and the motor activity of the pups measured in a simple photocell activity cage was not affected by pesticide treatment. Furthermore, no overt sings of neural toxicity were observed in the offspring. However, the treatment disrupted rat behavior in adulthood when assessed by using an inhibitory avoidance learning task. Thus, inhibitory avoidance tests carried out on rats at 90 days of age were capable of demonstrating neural toxicity of Cyhalothrin (0.02%) present only in the drinking water of dams during 21 days of lactation

Is monofluoracetic acid the active neurotoxic principle in Palicourea marcgravii (St. Hill) leaves?

Acute intoxication of rats with the crude extract of Palicourea marcgravii (PM) and with monofluoraccetic acid (MFA) solutions was comapred since it has been reported that PM leaves contain monofluoreacetates (455 microng/g air-dried material). The neurotoxic signs produce by oral administration of PM and MFA were similar and included tonic-clonic seixures. The dose-reponse curves onstructed for the convulsant effects of PM and MFA were parallel and the CD50s were 630 mg/Kg (508-781) and 0.90 mg/Kg (0.76-1.06), respectively. These data suggest that the neurotixic signs produced by PM are the consequence of MFA presente in the plant leaves

Effect of a specific stress (aldrin) on rat progeny behavior

The effect of dam exposure to aldrin, an organochlorinated compound (1.0 mg/Kg, sc, daily), during pregnancy or lactation was studied in young tat pups (11, 15, 18 and 22 days of age) and in adult animals (90 days of age). Locomotor activity was significantly greater in both young and adult animals when compared to contols. Male rats that received aldrin during lactation also showed reduced plasma corticosterone levels. Maternal behavior was not affected bu treatment during either period. The results sugest that aldrin may act as a perinatal stress factpr

Some behavioral effects of the pesticide amitraz

Acute oral administration of the pesticide amitraz at the doses of 60 and 100 mg/kg (N = 10 per group) significantly decreased the rearing frequency of rats observed in a open field to 8 + or - 8 and 5 + or- 5, respectively, when compared to 28 + or - 5 for control rats treated with vehicle only. The same doses of amitraz (N = 10 per group) increased duration of immobility to 80 + or - 50 and 113 + or - 64 s, respectively, when compared to 113 + or - 64 s for the controls. Acute oral administration of amitraz (20, 60 or 100 mg/kg, N = 10 per group) significantly increased the convulsive threshold dose of rats for strychnine, picrotoxin and pentylenetetrazole. A mitraz administered ip to mice at the doses of 20, 60 and 100 mg/kg (N = 10 per group) significantly increased sleeping time in a dose-dependent manner to 96 + or - 26, 120 + or - 29 and 198 + or - 58 min, respectively, when compared to 45 + or - 15 min for control mice treated with vehicle only. These results indicate that amitraz produces a depressant effect on the central nervous system