Behavioral Measures of Neurotoxicity (1990) / Chapter Skim
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Exposure to Neurotoxins Throughout the Life Span: Animal Models for Linking Neurochemical Effects to Behavioral Consequences
Exposure to Neurotoxins Throughout the Life Span: Animal Models for Linking Neurochemical Effects to Behavioral Consequences
Pages 101-123
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From page 101... ...
The discussion begins with consideration of normally occurring changes in neurochemical events during early development and later aging. NEUROCHEMICAL CHANGES DURING DEVELOPMENT AND AGING Chemical substances entering the body, toxic or nontoxic, produce their effects by altering biochemical events already underway.
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From page 102... ...
Because of its key roles in behavior, the cholinergic system provides examples of how neurochemical changes during the life span influence behavioral effects of neurotoxic agents. A considerable number of compounds exist that have specific cholinergic effects, some widely used throughout the world as pesticides (Koelle, 1975)
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From page 103... ...
In recent years a decrease in the density of muscarinic and nicotinic receptor sites has been recognized as one of the main adaptive mechanisms to overstimulation by acetylcholine in adult animals (Costa et al., 1982; Russell, 1982; Russell and Overstreet, 1987~. It is clear from these brief comments that the neurobehavioral effects of even one class of potentially neurotoxic substances involve complex interactions among the chemical processes it initiates upon entry into the body and the outcome it produces in physiological and behavioral functions.
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From page 104... ...
The postnatal pattern of gain in brain weight is not modified by DFP treatment. Data on brain ChE and mAChRs are presented in Table 2.
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From page 105... ...
Receptor Binding Sites During Postnatal Development Brain ChE (nmol AcThCh hydrolyzed/min/mg protein)
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From page 106... ...
Prenatal exposure of mice to dicrotophos did not alter the postnatal development of brain ChE and ChAT (Bus and Gibson, 1974~. What processes may be involved in these differences between effects of OF on ChE activity in fetal and maternal brain?
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From page 107... ...
107 Ct U ._ Cal Ct Ct o Fat ~ ~ o cn I= Ct ~ ~ X o In o U X ·= o ~ ._ U ~ 7 O ol cn `0, `~_ o -U.
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From page 108... ...
. A major feature of information now available about prenatal exposure to OPs is the finding of a fetal reduction of mAChRs and a postnatal delay in their development well after the complete recovery of brain ChE inhibition.
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From page 109... ...
Each column represents mean + SEM from eight animals (two from each litter)
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From page 110... ...
The information discussed above points to some important analogies in mechanisms underlying the effects of DFP on functioning of the cholinergic system. The analogies hold despite the considerable differences in age-related effects of OPs on brain ChE activity.
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From page 111... ...
. The only significant strain x age interaction occurs in the cortical ChAT activity, where decreases (approximately 15 percent)
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From page 112... ...
Only in the cerebral cortex is there a significant strain x age interaction. Data in Table 5 indicate that the significance may be attributed to a decline of approximately 30 percent in aging Fischer, but not Wistar, animals.
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From page 114... ...
Such results clearly indicate that the outcomes of studies in neurobehavioral toxicology are likely to be affected significantly by genetic or aging variables, both of which have effects on neurochemical processes that are involved in behavior. The results also suggest hypotheses about the mechanisms by which such effects are mediated.
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From page 115... ...
Body weight is a general measure of capability to maintain caloric intake and water balance. Effects of the subchronic DFP treatment on enzyme activities in three brain areas are presented in Figure 3: ANOVA (2 ages x 2 treatments)
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From page 116... ...
'' '' . '' ,,, 1 CEREBRAL HIPPOCAMPUS STRIATUM CORTEX FIGURE 3 Effects of subchronic intoxication by DFP on brain ChE and ChAT of young and senescent Fischer 344 rats (for treatment see Table 6)
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From page 117... ...
It is also clearly apparent that mAChR levels in the brains of the senescent animals are significantly lower than in the brains of young rats. Despite this difference, percentage decreases in mAChR receptor binding induced by the DFP treatment were very similar for both age groups, as reflected in the lack of significant interaction for any of the three brain areas.
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From page 118... ...
Time-Course Recovery of mAChRs Following Down-Regulation in Brain of Senescent Rats It is well established that following termination of repeated treatment with an antiChE agent in newborn and young animals, downregulation of mAChRs gives way to almost complete recovery, requiring about two weeks in early postnatal life (Michalek et al., 1985) and three weeks in adulthood (Costa et al., 1981~.
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From page 119... ...
However, the influence of age on the rate of recovery is evident: both brain ChE activity and mAChR density reach pretreatment values in young rats within two weeks, compared to almost five weeks in senescent rats. These results indicate that the synthesis of both ChE and mAChR molecules is impaired in brain tissues as a consequence of aging.
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From page 120... ...
It is filled with a multitude of events that are involved whenever toxic exposures induce behavioral malfunctions. In assessing the roles of animal models In neurobehavioral toxicology, it is apparent that they have been, and will continue to be, essential to our understanding of the nature of these events.
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From page 121... ...
1981. The effect of cholinesterase inhibition on the ontogenesis of central muscarinic receptors.
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From page 122... ...
1985. Reduced muscarinic receptor plasticity in frontal cortex of aged rats after chronic administration of Cholinergic drugs.
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From page 123... ...
1977. Central cholinergic mechanisms underlying adaptation to reduced cholinesterase activity.
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