Developmental toxicity of N-methylaniline following prenatal oral administration in rats.

OBJECTIVES: The objective of the study was to assess prenatal toxicity of N-methylaniline (NMA) administered by gavage to pregnant female rats. MATERIAL AND METHODS: Pregnant female rats were administered N-methylaniline in corn oil by gavage at daily doses of 0.8 mg/kg of body weight (b.w.), 4 mg/kg b.w., 20 mg/kg b.w. and 100 mg/kg b.w. from implantation (the 5th day post mating) to the day prior to the scheduled caesarean section (the 20th day of pregnancy). General behavior, body weight, food and water consumption, hematological, biochemical analyses and pathomorphological changes of the dams were recorded. RESULTS: All the females survived until the end of the study. The test substance was toxic to pregnant females, even at the lowest of the used doses, i.e., 0.8 mg/kg b.w./day. Lower weight gain during pregnancy and significantly higher NMA-dose-dependent absolute weight of the organs were noted in the exposed females. The females from the groups exposed at doses of 20 mg/kg b.w./day and 100 mg/kg b.w./day developed anemia and showed higher concentrations of free thyroxine (FT3) and free triiodothyronine (FT4) thyroid hormones. Total protein concentration exhibited an increase in all the exposed groups of females. In the prenatal toxicity study, administration of N-methylaniline throughout the embryonic and fetal periods produced embryotoxic effects at doses ranging 4-100 mg/kg b.w./day. CONCLUSIONS: Considering the data obtained in this study, it is reasonable to assume that N-methylaniline administered orally to pregnant rats is toxic for mothers even at a low dose of 0.8 mg/kg b.w./day. However, this dose was not associated with any significant effects to their offspring. This prenatal exposure level may be considered as no-observed-adverse-effect level (NOAEL) for the progeny and a dose of 4 mg/kg b.w./day as the lowest-observed-adverse-effect level (LOAEL) for the progeny.

Partial protection from organophosphate-induced cholinesterase inhibition by metyrapone treatment.

BACKGROUND: Organophosphates are cholinesterase (ChE) inhibitors with worldwide use as insecticides. Stress response, evidenced by a dramatic and relatively long-lasting (several hours) rise in the plasma glucocorticoid concentration is an integral element of the organophosphate (OP) poisoning symptomatology. In rodents, corticosterone (CORT) is the main glucocorticoid. There are several reports suggesting a relationship between the stressor-induced rise in CORT concentration (the CORT response) and the activity of the cerebral and peripheral ChE. Thus, it seems reasonable to presume that, in OP intoxication, the rise in plasma CORT concentration may somehow affect the magnitude of the OP-induced ChE inhibition. Metyrapone (MET) [2-methyl-1,2-di(pyridin-3-yl)propan-1-one] blocks CORT synthesis by inhibiting steroid 11ß-hydroxylase, thereby preventing the CORT response. Chlorfenvinphos (CVP) [2-chloro-1-(2,4-dichlorophenyl) ethenyl diethyl phosphate] is an organophosphate insecticide still in use in some countries. MATERIAL AND METHODS: The purpose of the present work was to compare the CVP-induced effects - the rise of the plasma CORT concentration and the reduction in ChE activity - in MET-treated and MET-untreated rats. Chlorfenvinphos was administered once at 0.0, 0.5, 1.0 and 3.0 mg/kg i.p. Metyrapone, at 100 mg/kg i.p., was administered five times, at 24-h intervals. The first MET dose was given two hours before CVP. CONCLUSION: The following was observed in the MET-treated rats: i) no rise in plasma CORT concentration after the CVP administration, ii) a reduced inhibition and a faster restitution of blood and brain ChE activities. The results suggest that MET treatment may confer significant protection against at least some effects of OP poisoning. The likely mechanism of the protective MET action has been discussed.

Comparison of neurobehavioral and biochemical effects in rats exposed to dusts from copper smelter plant at different locations.

Mixed exposure to metals (including arsenic and lead) associated with the neurological and respiratory effects constitute one of the major health problems of copper smelting. Chemical composition of the dust, and the expected health effect of inhalation can be very diverse at different parts of the smelter plant. The aims of this study were to compare lung responses and behavioral effects in female Wistar rats after instillation of dust collected from different production processes at the same smelter department. Dusts collected at two different locations of furnace hall were sifted through 25-µm-mesh sieve. Obtained dust fractions, P-25(I) collected near stove, rich in heavy metals and arsenic, and P-25(II) collected near anode residue storage site, rich in aluminium, were instilled to rats. At 1, 7 and 30 days after dusts instillation, lung injury and inflammation were measured by analyzing sings of lung permeability in the bronchoalveolar lavage fluid (BALF), cell differentiation in BALF sediment and lung morphology. The behavioral studies were done 30 days after exposure. Results of biochemical tests showed a strong pro-inflammatory effect of P-25(I) fractions. Mostly characteristic effects after instillation of P-25(I) samples were 10× increased protein leakages in BALF. Both P-25(I) and P-25(II) fractions caused a reduction of Clara-cell 16 protein concentration (CC16) in BALF and activation of serum butyrylcholinesterase (BChE) at all time points. The morphological studies after exposure to P-25(I) fractions showed multi-focal infiltrations in the alveoli. The behavioral results, especially P-25(II) group rats (in open filed, passive avoidance and hot plate tests), indicated adverse effects in the nervous system, which may be related to changes in the dopaminergic and cholinergic pathway. The symptoms were noted in the form of persistent neurobehavioral changes which might be associated with the content of neurotoxic metals. e.g. Al, Mn and/or As. Decrease of CC16 concentration that occurred immediately after instillation of both dust samples, point out impaired anti-inflammatory potential, resulted in early harmful effect not only to the respiratory tract but also to the whole body, including the nervous system.

Fertility and developmental toxicity studies of diethylene glycol monobutyl ether (DGBE) in rats.

OBJECTIVES: The solvent, dimethylene glycol monobutyl ether (DGBE), is a component of latex paints, inks; it is used as a degreasing agent, industrial detergent. The aim of the study was evaluating the effects of DGBE administered by gavage on the estrous cycle and given with drinking water on fertility in rats and early development of their progeny. MATERIALS AND METHODS: Female rats were exposed to DGBE by gavage during 8 weeks at 250, 500 or 1000 mg/kg/day. Vaginal smears were collected during the exposure and 4 weeks after its cessation. Fertility studies were performed in male and female animals exposed to in drinking water. Males were exposed for 10 weeks and then mated with females exposed before mating, during pregnancy and lactation. Young animals were observed during 3 weeks after birth. RESULTS: DGBE does not cause disturbances of the menstrual cycle in females. Parameters used to assess the general toxicity indicate that males receiving DGBE in drinking water are more sensitive to this compound than females: significantly greater, dose-dependent relative spleen weight, significant decrease in hematological parameters from 8% to 15% depending on the dose, were observed. Clinical chemistry parameters (HDL-cholesterol, BUN) and some markers of oxidative stress differ between the exposed groups and the control one, but without adverse health effect. The microscopic examination of internal organs did not reveal morphological changes in male and female rats. CONCLUSION: The results of our study on the impact of exposure to DGBE on fertility in rats indicate that the substance administered for 9-10 weeks to females and males at a limit dose of 1000 mg/kg did not impair fertility or viability of their offspring during the first three weeks of life.

[Benzimidazole and its derivatives--from fungicides to designer drugs. A new occupational and environmental hazards]. / Benzimidazol i jego pochodne--od fungicydów do narkotyków zmodyfikowanych. nowe zagrozenia zawodowe i srodowiskowe.

Benzimidazole and benzimidazole derivatives play an important role in controlling various fungal pathogens. The benzimidazoles are also used to treat nematode and trematode infections in humans and animals. It acts by binding to the microtubules and stopping hyphal growth. It also binds to the spindle microtubules and blocks nuclear division. The most popular fungicide is carbendazim. The fungicide is used to control plant diseases in cereals and fruits. Laboratory studies have shown that carbendazim cause infertility and destroy the testicles of laboratory animals. Other benzimidazole derivatives are used as a preservative in paint, textile, papermaking, leather industry, and warehousing practices, as well as a preservative of fruits. Occupational exposure to benzimidazole may occur through inhalation and dermal contact with those compounds at workplaces where benzimidazole is used or produced. Some of the benzimidazoles are common environmental pollutants. They are often found in food and fruit products. Some of the benzimidazoles, like a astemizole or esomeprazole have found applications in diverse therapeutical areas. Despite of the clear advantages afforded by the use of benzimidazole derivatives, they share a danger potential. The most hazardous, however, are new illegally synthesed psychoactive drugs known as designer drugs. Some of them, like nitazene, etonitazene or clonitazene belong to benzimidazole derivatives. Laboratory animal studies revealed that etonitazene produced very similar effects in central nervous system as those observed after morphine administration. Considering etonitazene's properties, it seems reasonable to expected that long-term exposure to other benzimidazole derivatives may result in drug abuse and development of drug dependence.

Behavioral effects following repeated exposure to hexachloronaphthalene in rats.

Polychlorinated naphthalenes (PCNs), including hexachloronaphthalene (HxCN), are widespread global environmental contaminants. Our experiments were aimed at assessing HxCN effects on motor behavior, long-term memory, pain sensitivity, magnitude of stress-induced analgesia, auditory function and sensorimotor gating, following repeated intragastric administration (28 days) of HxCN at 0.3 and 1.0 mg/kg body weight. Three weeks after the exposure termination, male Wistar rats were subjected to the neurobehavioral tests battery performed in the following order: open-field test, passive avoidance test, hot-plate test and acoustic startle response test. Repeated administration of HxCN induced disorders of motivational processes manifested by: anorectic effect caused by aphagia and adipsia; significantly reduced motor activity (hypokinesia); impaired long-term memory and acquired passive avoidance reaction; reduced pain threshold and shortened duration of anxiety reaction after pain stimulus (sensory neglect). Some of these neurobehavioral effects (impaired long-term memory, reduced pain threshold and stress-induced analgesia) were observed at 0.3 mgHxCN/kg body weight without any signs of overt toxicity. The outcome of our study shows that HxCN, like other compounds of the persistent organic pollutants (POPs) group, creates a potential risk of behavioral changes in the central nervous system in the general population as a result of environmental exposure.

Neuroendocrine and behavioral response to amphetamine challenge after exposure to an organophosphorus pesticide.

OBJECTIVES: Exposure to various stressors is known to result in sensitization to psychostimulants, a state related to the psychostimulant dependence and addiction. It has been shown in some studies that the rise in corticosterone (CORT) concentration is indispensable for both the induction and the expression of behavioral sensitization. Therefore, it might be suspected that behavioral hyposensitivity to amphetamine (AMPH) is somehow related to a reduced CORT response to the psychostimulant subsequent to the chlorphenvinphos (CVP) intoxication. MATERIALS AND METHODS: The male adult Wistar rats received single i.p. injections of CVP at the doses 0.5, 1.0 or 3.0 mg/kg b.w., or pure corn oil. CORT concentration was determined in samples of blood drawn from the tail vein before and then 30, 60, 180 min and 24 h after injection. The other rats were divided into two groups and tested, three weeks after the CVP injection for the effect of AMPH (0.5 mg/kg b.w. i.p.) on the serum CORT concentration. In addition, behavioral sensitivity to AMPH was assessed by measuring locomotor activity of the animals in an open-field. RESULTS: 1) The stressor property of CVP was confirmed. The injection resulted in up to tenfold increase in the serum CORT concentration. The magnitude and duration of this response were dose-related. 2) Three weeks after the CVP exposure, the CORT response to AMPH was significantly increased. 3) The behavioral response to the psychostimulant, i.e. augmented locomotion, was significantly reduced compared to the control. CONCLUSIONS: The results confirm that CVP exposure causes behavioral hyposensitivity to AMPH. This effect, however, could not be ascribed to a diminished CORT response.

Assessment of neurobehavioral and biochemical effects in rats exposed to copper smelter dusts.

Female Wistar rats were instilled per os by gavage with different copper dust samples: P-25 obtained by passing the test material through a 25 µmsieve, and P-0.1 containing soluble matter and ultra-fine, non-soluble<100 nm particulate matter (PM) fraction. The control group received sterile saline. The effects were studied at day 1, 7, and 30 post-exposure, focusing on bronchoalveolar lavage fluid (BALF) analysis (including biochemistry, cell morphology, cell viability, and Clara cell 16 protein concentration) and pathomorphology of lung. Results of biochemical tests showed a strong pro-inflammatory effect of both particulate fractions. The morphological studies after exposure to P-25 and P-0.1 fractions showed multi-focal infiltrations in the alveoli. Changes in behavioral (radial maze and passive avoidance tests) have shown that memory in groups exposed to dust was impaired. Our findings indicate that both samples of dust from Copper Smelter cause greater and lesser intensity (P-25 > P-0.1) of the symptoms of acute inflammatory reaction immediately 24 h after instillation to rats. Exposure results in dropping CC16 protein level in serum of rats. After one month, previous acute inflammation was resolved and transformed in persistent low-grade inflammation. The low-grade inflammation resulted in induction of neurobehavioral effects probably by changes in "cholinergic anti-inflammatory pathway" in which acetylcholine modulates neurotransmission.

Effects of stress pretreatment on the dynamics of blood cholinesterase activity after exposure to an organophosphorus pesticide in the rat.

A single i.p. administration of 1.0 mg/kg of chlorphenvinphos (CVP), an organophosphorus pesticide, results in an acute stress response, evidenced by a marked (6-7 fold) rise in plasma corticosterone (CORT) concentration, and a diminished behavioural sensitivity to amphetamine (AMPH) three weeks postexposure. Surprisingly, in rats subjected to a single series of inescapable electric footshocks (60 10 msec triplets of 3.0 mA, 2 msec, square pulses during 20 min - IF ) two weeks prior to the CVP exposure, these effects are not observed. It has been assumed that the reduced effectiveness of CVP might be related to some persisting alterations in the functional state of the cholinergic system. The aim of the present work was to discover whether and in what way the IF pretreatment affects i) the cholinesterase activity in blood, and ii) the dynamics of the alterations in the cholinesterase (ChE) activity following the CVP exposure. The experiments were performed on 3 mo. old, male Wistar rats. In the first experiment, the blood samples were taken from the tail vein 15, 60 and 180 min after the IF. In the second experiment, the rats were pretreated with IF and 14 days later given 1.0 mg/kg of CVP i.p. Blood samples were taken 15 min, 60 min, 180 min, 24 h, 7 days, and 14 days after the CVP exposure. In the first experiment no differences in the ChE activity in plasma (pChE) and erythrocytes (rbcChE) were found between the shocked and control rats. In the second experiment, however, in rats pretreated with IF the rbcChE activity of was reduced by CVP less and pChE activity returned to normal faster than in rats not pretreated with IF. The results confirm that exposure to IF, a nonchemical stressor, induces some long-lasting adaptive changes which render the cholinergic system less susceptible to the harmful action of ChE inhibitors. It has been hypothesized that the changes consist in an increase of the antioxidant potential in blood and possibly other tissues.

Contrasting effects of 4-week inhalation exposure to pseudocumene or hemimellitene on sensitivity to amphetamine and propensity to amphetamine sensitization in the rat.

OBJECTIVES: Some data suggest that increased behavioural sensitivity to psychostimulants may develop after exposure to volatile chemicals in common use. The purpose of the present experiment was to find out whether and in what way inhalation exposure to pseudocumene (PS) or hemimellitene (HM) at low concentrations alters behavioural sensitivity to the psychostimulant amphetamine (AMPH), and propensity to develop behavioural sensitization to AMPH. MATERIAL AND METHODS: Adult male Wistar rats were exposed 6 h/day, 5 days a week for 4 weeks to PS or HEM at 0, 25, 100 or 250 ppm. Behavioural sensitivity to AMPH was assessed by measuring locomotor activity of the animals in an open-field. Behavioural sensitization to AMPH was induced by a repeated AMPH treatment. RESULTS: In rats exposed to HEM, the behavioural sensitivity to AMPH was increased, but remained unchanged in rats exposed to PS. The second testing revealed an augmented behavioural response to AMPH in control rats. In the HM exposed rats this augmenting was significantly more evident and in the PS exposed rats significantly less evident than in controls. For each of the two solvents, the concentration-effect relationship was nonlinear; out of the three concentrations used, 100 ppm was the most effective. CONCLUSIONS: The results confirm that low-level inhalation exposure to trimethylbenzene isomers may induce behavioural sensitisation and/or increase the susceptibility of the animals to develop this state upon repeated psychostimulant treatment. They show, however, that HM and PS differ markedly in their ability to induce such alterations.

Neurobehavioural functions in adult progeny of rat mothers exposed to methylmercury or 2,2', 4,4', 5,5'-hexachlorobiphenyl (PCB 153) alone or their combination during gestation and lactation.

OBJECTIVES: Methylmercury (MeHg) and polychlorinated biphenyls (PCBs) are ubiquitous environmental pollutants. Both are neurotoxic, especially for the developing brain. The main source of human exposure to MeHg and PCBs is seafood. The aim of the present work was to find out whether and how separate or combined perinatal exposure to these neurotoxicants affects neurobehavioural functions in maturity. MATERIALS AND METHODS: The study was performed on adult Wistar rats, the progeny of rat mothers exposed to MeHg (0.5 mg/kg/day or 2.0 mg/kg/day), PCB 153 (1.0 mg/kg/day or 5.0 mg/kg/day), or to MeHg 0.5 mg/kg/day + PCB 153 5.0 mg/kg/day, from day 7 of pregnancy to day 21 post partum. The following functions were assessed: spontaneous locomotor activity (open field test), spatial short-term memory (radial maze test), long-term memory (passive avoidance test), sensitivity to pain and vulnerability to stress (hot plate test), efficiency of the sensorimotor gating (startle response test), and sensorimotor coordination (the rotarod test). RESULTS: The results obtained in the MeHg part of the study showed a reduced locomotor activity in the female progeny of both exposed groups, an impaired passive avoidance in the male progeny of the high and low exposure group and a faster recovery from the effects of the stressful experience (hot plate test) in the male progeny of the high dose group. Results obtained in the PCB part showed an increased locomotor activity in the female progeny of both exposure groups and impairment in rotarod performance in males of the high dose group. Neurobehavioural alterations were not found in either the females or males exposed jointly to MeHg and PCB 153. CONCLUSIONS: The results suggest that in condition of the combined exposure, MeHg may protect against the effects of PCB 153 and vice versa.

Exposure to chlorphenvinphos, an organophosphate insecticide, prevents from behavioral sensitization to amphetamine.

OBJECTIVES: Exposure to organophosphorus (OP) pesticides, irreversible inhibitors of acetylcholinesterase (AChE), may result in long-lasting alterations in the functional state of the central nervous system. In earlier studies, we found that a single exposure of the rat to chlorphenvinphos (CVP), an OP pesticide, made the animal hyposensitive to amphetamine (AMPH) three weeks posttreatment. A repeated administration of AMPH is known to result in a progressive increase in the behavioral sensitivity to the psychostimulant. It makes it likely that treatment with AMPH after the CVP exposure may result in amelioration of the CVP-induced hyposensitivity to the psychostymulant. The purpose of the present experiment was to check out this supposition. MATERIALS AND METHODS: At the first stage, the relationship between the CVP dose and the effect on sensitivity to AMPH was tested. The rats were given CVP once intraperitoneally (i.p.) at a dose of 0.0, 1.0 or 3.0 mg/kg. Three weeks later their open field behavior was assessed before and after i.p. administration of 0.25, 0.5 or 1.0 mg/kg of AMPH. At the subsequent stage, the susceptibility of the CVP-treated rats to AMPH sensitization by repeated AMPH treatment was investigated. For this purpose each of the rats was repeatedly treated with AMPH in its home cage (one injection/day for five days). At stage two, the daily AMPH dose received by each animal was of the same magnitude as that received at stage one. Two weeks after the last AMPH treatment dose, the motor response to a test AMPH dose (0.5 mg/kg) was measured in all rats. RESULTS: The results of stage one confirmed a significant reduction of behavioral sensitivity to AMPH in the CVP-treated rats. The results of stage two indicated that the CVP-induced decrease in sensitivity to AMPH was not ameliorated by a repeated treatment with AMPH at any of the used doses. In fact, in the rats exposed to the high CVP dose, repeated treatment with AMPH resulted, dose dependently, in augmenting of the depressive effect of the pesticide. CONCLUSIONS: It appears then that treatment to an OP pesticide reduces the rat's sensitivity to AMPH and makes the animal resistant to sensitization by repeated treatment with the psychostimulant.

Amphetamine- and scopolamine-induced locomotor activity following treatment with chlorphenvinphos or chlorphyriphos in rats.

OBJECTIVES: Effects of acute exposure to organophosphorous pesticides (OPs), chlorphenvinphos (CVP) or chlorphyriphos (CPF) on amphetamine (AMPH)- or scopolamine (SCOP)-induced open-field locomotion were compared in rats. MATERIALS AND METHODS: CVP and CPF were administered intraperitoneally, both at doses resulting in about 50% inhibition of erythrocyte acetylcholinesterase (rbcAChE). The pesticide groups did not differ one from another in the magnitude of the acute behavioral effects. RESULTS: Three weeks after the exposure, i.e. when AChE activity returned to normal level, the behavioral response to AMPH and SCOP was significantly reduced in CVP-, but not in CPF-pretreated rats. CONCLUSIONS: These results confirm that a single exposure to organophosphorous pesticides may result in neurobehavioral effects detectable after restitution of AChE. They also show that CVP and CPF differ in respect of long lasting functional consequences of exposure, which suggests a difference in the mechanism of toxicity.

Behavioral sensitivity to amphetamine or scopolamine after acute administration of nicotine in the rat.

OBJECTIVES: Earlier experiments have revealed that a single pretreatment of the rat with chlorphenvinphos (CVP) at a subtoxic dose (1.0 mg/kg, about 1/10 of DL50) makes the animal hyposensitive to the locomotor stimulating effect of amphetamine (AMPH) or scopolamine (SCOP) given three weeks postexposure. Such a hyposensitivity did not develop after a single or multiple (at short intervals) dosing with oxotremorine (OXO), a direct muscarinic agonist, which suggests that it was not mediated by muscarinic receptors. The purpose of the present experiment was to find out whether activation of nicotinic receptors could induce behavioral hyposensitivity to AMPH. MATERIALS AND METHODS: Male adult Wistar rats were pretreated once with 0.00, 0.5 or 1.0 mg/kg of nicotine (NIC), a nicotinic agonist, and challenged 15 days later with 1.0 mg/kg of AMPH or 0.75 mg/kg of SCOP. The pre- and postdrug open-field behavior of the rats was measured using a computerized set of activity meters. RESULTS: Pretreatment with NIC, like pretreatment with OXO, did not make the animals hyposensitive to AMPH or SCOP. In a preliminary experiment we have also found that rats do not develop hyposensitivity to AMPH and SCOP after pretreatment with physostigmine, a reversible anticholinesterase and a direct nicotinic and possibly muscarinic agonist. CONCLUSIONS: The results suggest that a transient overstimulation of the cholinergic system cannot be the cause or a sufficient condition for the development of the CVP-induced diminution of sensitivity to AMPH and SCOP.

Pretreatment with footshock alters some effects of subsequent organophosphate exposure.

Pre-exposure to non-chemical stressors may alter a subject's vulnerability to chemical stressors. We found recently that rats given a subtoxic dose of chlorfenvinphos (CVP), an organophosphorus pesticide, develop behavioral hyposensitivity to amphetamine (AMPH). The present experiments were performed in order to find out whether pre-exposure to a non-chemical stressor several days prior to CVP exposure could influence this effect of the pesticide. In experiment 1 adult male Wistar rats were subjected once to either a short, 5 min (SFS) or long, 20 min (LFS) series of unavoidable footshocks (FS). Twenty-four hours or 14 days after the FS, their open field behavior was tested before and after a test dose of AMPH (0.5 mg/kg. i.p). In experiment 2, the rats were subjected to LFS and 14 days later they were injected intraperitoneally with CVP (1.0 mg/kg) or vehicle (corn oil). In both experiments, serum corticosterone (CORT) levels were determined in separate groups of rats in order to assess the magnitude of the stress response induced by the applied stressors. It was found that: (i) the rise in serum CORT concentration after SFS or LFS was similar in magnitude, while that following LFS was more persistent; (ii) exposure to LFS, but not to SFS, resulted in a decreased response to AMPH on day 14 after the experience; (iii) in rats not pretreated with LFS, CVP exposure resulted in a profound increase in serum CORT concentration. In LFS pretreated rats, however, this effect was significantly reduced; (iv) three weeks after the exposure to CVP, the psychomotor response to AMPH was diminished in control rats but was normal in LFS pretreated animals. The results indicate that pretreatment with a non-chemical stressor may protect the rat against at least some of the effects of an organophosphate pesticide.

Alteration in behavioral sensitivity to amphetamine after treatment with oxotremorine. Effect of dose and test environment.

Our earlier experiment revealed that rats pretreated once with an anticholinesterase develop hyposensitivity to amphetamine (AMPH). One of the likely causes of this effect might be a transient hyperexcitation of the central muscarinic receptors. It has appeared, however, that rats pretreated with oxotremorine (OX), a muscarinic agonist, show an augmented behavioral response to AMPH weeks later. The present experiments were performed in order to obtain more information on the relationship between the OX-induced sensitization to AMPH and the OX dose and dosing regime (single or repeated), and to find out whether the environment associated with the acute effects of OX could affect the response to AMPH. In experiment 1, adult male rats were given a single i.p. injection of OX in home cages at a moderate (0.5 mg/kg) or high (1.0 mg/kg) dose. In experiment 2, the rats received eight 1.0 mg/kg doses of OX in the course of three days. After each injection, some animals returned to their home cages, and some were placed in the test cages for 30 min. In both experiments, the response to AMPH was assessed on day 21 after the treatment. The obtained results indicate that: (i) a single i.p. exposure to OX results in an increase of the rat's behavioral sensitivity to AMPH but the moderate dose is more effective in inducing this effect; (ii) repeated exposure to OX at high doses, in a regime enabling development of tolerance to the acute OX effects, does not alter the rat sensitivity to AMPH, and (iii) expression of the AMPH response is suppressed in environment which has been associated with acute effects of OX.

Behavioral sensitivity to amphetamine after repeated exposure to an organophosphorous pesticide in the rat. Effect of coexposure to restraint.

In the work environment, chemical stressors coexists frequently with physical or psychological stressors. The purpose of the present experiment was to find out whether the effects of a repeated exposure to chlorphenvinphos (CVP), an organophosphorus pesticide, could be modified by a concurrent exposure to restraint, a psychological stressor. The experiment was performed on male Wistar rats. CVP was administered ten times (one injection/day) at doses of 0.5 or 1.0 mg/kg i.p. (1/30 and 1/10 of LD50, respectively) within a period of two weeks. A half of the rats from each group were immobilized in restraint chambers for 120 min/day starting 10-15 min after CVP injection. In each rat, the effect of 0.5 mg/kg of amphetamine (AMPH) and 0.75 mg/kg of scopolamine (SCOP) on motor activity in an open-field was tested three weeks or six weeks (in rats exposed to 0.5 mg/kg or 1.0 mg/kg doses of CVP, respectively) after the last exposure day. No clear cut effect on the behavioral responsiveness to AMPH or SCOP were noted in rats subjected to repeated restraint, repeated 0.5 mg/kg doses of CVP, or combination of these two stressors. In rats exposed to CVP at the 1.0 mg/kg doses, the behavioral response to AMPH was augmented and this effect was not apparently altered in rats coexposed to restraint. The above result indicates that the repeated exposure to CVP may lead to functional alterations within the central nervous system and that coexposure to restraint neither facilitates nor prevents these alterations from development.

Behavioural responsiveness to amphetamine or scopolamine following repeated exposure to chlorphenvinphos in rats.

A number of reports indicate that exposure to organophosphates (OPs), inhibitors of acetylcholinesterase (AChE), may result in long-lasting neurobehavioural alterations suggestive of an increased cholinergic tone. It is known that rats with cholinergic hyperreactivity are behaviourally hyposensitive to cholinergic antagonists and dopaminergic agonists. The purpose of the present study was to find out whether a similar trait would develop in rats exposed to chlorphenvinphos (CVP), an OP pesticide, in the past. The rats were given ten daily i.p. injections of CVP at doses of 0.5 mg/kg (group P-0.5) or 1.0 mg/kg (group P-1.0). The locomotion stimulating effect of i.p. injection of 1.0 mg/kg amphetamine (AMPH), or 0.7 mg/kg scopolamine (SCOP), was assessed on postexposure day 21 (group P-0.5) or 42 (group P-1.0), i.e. after a time sufficient for AChE recovery. The assessment revealed that in group P-1.0 the behavioural response to AMPH and SCOP was significantly depressed. In rats of the P-0.5 group, however, the behavioural response to each of the drugs was increased. The results suggest that, depending on the exposure level, contrasting alterations in some neurotransmitter systems may be induced by repeated exposure to CVP.