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Behavioral evidence for modified receptor sensitivity in rat brain induced by methyl bromide exposure
T Honma1, M Kanada, M Miyagawa
1National Institute of Industrial Health, Kanagawa, Japan.
Abstract:
To clarify the neurochemical basis of methyl bromide toxicity in rats, we measured changes in the sensitivity of cerebral monoamine, dopamine (DA) and norepinephrine (NE) receptors, using abnormal behavior and locomotor activity as indicators of receptor sensitivity. Apomorphine and clonidine were used as specific agonists of DA (D1 and D2) and NE (alpha 2) receptors, respectively. In the first experiment, rats were exposed to methyl bromide gas at 25-200 ppm for 8hr once or to methyl bromide at 5-50 ppm 8hr a day for 7 days. The intensity of stereotyped oral (STO) behavior produced by an injection of apomorphine, 0.5 mg/kg i.p., was rated over the following 28 days. The STO behavior of rats exposed to methyl bromide (MB rats) was much more intense than in air-exposed (control) rats. This finding strongly suggests that the sensitivity of striatal DA, D1 and D2, receptors to apomorphine was increased by methyl bromide exposure. In the second experiment, rats were exposed to 50 ppm methyl bromide for 8hr once or to 10-50 ppm methyl bromide 8hr a day for 7 days. Seven days after the final exposure, rats were injected with a small dose of apomorphine, 0.3 mg/kg i.p., and the counts of apomorphine-induced locomotor activity (ALA) were recorded. The ALA counts of MB rats were markedly higher than in the control rats. This finding suggests that the DA receptors in the nucleus accumbens of MB rats are more sensitive to apomorphine than those of control rats. In the third experiment, rats were exposed to 50 ppm methyl bromide, 8hr a day for one day or 7 consecutive days, and the degree of attenuation of locomotor activity following clonidine injection (CLA) was rated. CLA counting was performed 7 days after the final exposure. CLA counts in MB rats were not attenuated as much as in the control rats. This indicates that the cerebral NE receptors, i.e., alpha 2-adrenoceptors, of MB rats may be less sensitive to clonidine than those of control rats. Increased behavioral sensitivity to apomorphine was observed in rats even when exposed to 5 ppm (TLV) methyl bromide.
Insights
Methyl bromide exposure increases dopamine receptor sensitivity in rats, leading to heightened behavioral responses. Norepinephrine receptor sensitivity may decrease, indicating neurochemical changes from methyl bromide toxicity.
Area of Science:
- Neuroscience
- Toxicology
- Neurochemistry
Background:
- Methyl bromide is a toxicant with known neurotoxic effects.
- Understanding the neurochemical basis of methyl bromide toxicity is crucial for risk assessment.
- Monoamine receptors, including dopamine and norepinephrine, are key targets for neurotoxicants.
Purpose of the Study:
- To investigate the neurochemical effects of methyl bromide exposure on dopamine (DA) and norepinephrine (NE) receptors in rats.
- To assess changes in receptor sensitivity using behavioral and locomotor activity indicators.
- To determine the lowest effective exposure level of methyl bromide causing neurochemical alterations.
Main Methods:
- Rats were exposed to methyl bromide via inhalation at various concentrations and durations.
- Dopamine receptor sensitivity was assessed using apomorphine to measure stereotyped oral behavior and locomotor activity.
- Norepinephrine receptor sensitivity was evaluated using clonidine to measure the attenuation of locomotor activity.
Main Results:
- Methyl bromide exposure significantly increased the intensity of apomorphine-induced stereotyped oral behavior, suggesting enhanced dopamine D1 and D2 receptor sensitivity.
- Apomorphine-induced locomotor activity was markedly higher in methyl bromide-exposed rats, indicating increased dopamine receptor sensitivity in the nucleus accumbens.
- Methyl bromide exposure resulted in less attenuation of locomotor activity after clonidine injection, suggesting decreased sensitivity of cerebral alpha 2-adrenoceptors.
Conclusions:
- Methyl bromide exposure enhances the sensitivity of cerebral dopamine receptors (D1 and D2) in rats.
- Methyl bromide exposure may decrease the sensitivity of cerebral norepinephrine (alpha 2-adrenoceptors).
- Increased behavioral sensitivity to apomorphine was observed even at the threshold limit value (TLV) of 5 ppm methyl bromide.