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.

Assessment of long-term effects of exposure to toluene based on the analysis of selected behavioral responses with particular reference to the ability to trigger behavioral hypersensitivity in rats.

Toluene is a major component of numerous commercial organic solvent formulations. It is often listed among the chemicals capable of producing the organic solvent syndrome and a neurobehavioral hypersensitivity condition. The hypersensitivity condition (continued long-term intensification of some behavioral reactions in response to pharmacological or environmental stressors) is usually associated with the increased tonus of the functional dopaminergic system. The aim of our current research was to determine whether, under conditions of inhalation exposure, toluene can produce long-term behavioral changes or modify the intensity of the behavioral response to apomorphine, a dopaminergic receptor agonist. In our experiment, male rats were exposed to 25, 100 and 250 ppm toluene for 4 weeks (5 days/week, 6h/day). The following behaviors were tested: finding water in a radial maze; open field motor activity, acquiring the conditional response of passive avoidance; sensitivity to a thermal pain stimulus (hot plate test) and changes in this sensitivity caused by stress; and acquiring the conditional response of two-directional active avoidance. The behavioral response to apomorphine, i.e. the increased spontaneous locomotor activity, was assessed on day 10 after the termination of the exposure in the rotary drum test. In the behavioral experiment, significant differences between groups were recorded only for the hot plate test; in the 100 and 250 ppm rats, electric-shock-related anxiety response was stronger than in the control group. In the experiment using pharmacological provocation, the behavioral response to apomorphine in the rats exposed to 100 ppm or 250 ppm toluene was significantly lower. Our results indicate that low concentrations of toluene may produce long-term behavioral changes in rats. However, these changes seem to be linked with reduced rather than increased functional tonus of the dopaminergic system.

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.

Assessment of long-term neurotoxic effects of exposure to mesitylene (1,3,5-trimethylbenzene) based on the analysis of selected behavioral responses.

Trimetylbenzene isomers: pseudocumene, hemimellitene and mesitylene, are major components of numerous commercial solvents and high-grade fuels. In our earlier research on rats we have proved that inhalation exposure to pseudocumene or hemimellitene at concentrations close to the MAC value results in behavioral changes detectable many weeks after cessation of the exposure. The aim of our present study is to determine whether exposure to mesitylene causes effects similar to those observed for pseudocumene and hemimellitene. Male rats were used in the experiment. The animals were exposed in the inhalation chambers to mesitylene vapors at the following concentrations: 0 ppm--group MES0; 25 ppm (125 mg/m3)--group MES25; 100 ppm (500 mg/m3)--group MES100 and 250 ppm (1,250 mg/m3)--group MES250 for 4 weeks (6 h/day, 5 days/week). The following behaviors were tested: 1) ability to find water in a radial maze (14-19 days after the exposure); 2) open field locomotor activity (25 days after the exposure); 3) acquiring the conditioned reaction of active avoidance (35-45 days after the exposure); 4) sensitivity to pain and stress-induced changes of pain sensitivity (50-51 days after the exposure); and 5) acquiring the conditioned reaction of two-way active avoidance (54-60 days after the exposure). Significant between-group differences were noted in passive and active avoidance tests and sensitivity to pain. In the MES25, MES100 and MES250 rats, the persistence of the passive avoidance reaction was shorter, and more trials were required to produce the active avoidance reaction than in controls (group MES0), the MES100 group appeared to be more fearful on the second day of testing on the hot plate. The exposed groups did not differ in the magnitudes of the detected changes (no concentration-effect relationship). These results indicate that inhalation exposure to mesitylene, like that to pseudocumene and hemimellitene, at concentrations close to the current hygiene standard value for trimethylbenzene, may produce long-term functional changes in the rat central nervous system.