Behavioral Measures of Neurotoxicity (1990) / Chapter Skim
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Neurobehavioral Time Bombs: Their Nature and Their Mechanisms
Neurobehavioral Time Bombs: Their Nature and Their Mechanisms
Pages 206-225
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From page 206... ...
The events may be viewed as progressing from the molecular level through morphological sites synapses, neurons, nerve networks, nuclei, and systems eventually to exert an effect on 206
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From page 207... ...
The sequence of the neurochemical events taking place in these sites is shown diagrammatically in Figure 2. Events al to an preceding the formation of the chemical-receptor complex, AR, are involved in the processes by which the chemical, A, reaches its site of action.
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From page 208... ...
Very low levels of exposure produce no effects. As exposure increases, a level is reached where behavioral effects begin to appear, the "basal threshold." Further increases induce proportional changes in behavior until a level is reached, the "terminal threshold," at which behavioral malfunctions begin to occur.
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From page 209... ...
J ~ ~ ~ Acetate Choline FIGURE 3 Metabolic pathways involved in the normal biosynthesis and hydrolysis of the neurotransmitter acetylcholine.
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From page 210... ...
Meanwhile, it is relevant to the development of the present theme to summarize briefly the nature of behavioral effects when available antiChEs are employed as pharmacological tools. Early experiments using animal models concluded that exposure to antiChEs produced differential effects on behavior, some behavior patterns being affected and others not.
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From page 211... ...
Relatively selective loss of cholinergic neurons occurs in certain regions of the brain, particularly the projections from large cholinergic cell bodies in the basal forebrain (nucleus basalis of Meynert) to the neocortex and projections from the medial septum to the hippocampus.
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From page 212... ...
The relevance of the early studies to PDD was recognized when it became apparent that the lack of natural precursor chemicals in the diet or the presence of a false precursor could significantly alter normal functioning of the cholinergic system and thus affect behavior (lender et al., 1987~. A major difficulty faced in the earlier studies was to demonstrate that chronic dietary administration of a choline analogue did in fact result in functionally significant replacement of choline in the synthesis of an endogenous analogue of ACh.
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From page 213... ...
The hypothesis states that when there exists a deficiency in the normal supply of choline for use in the two biochemical pathways involved, cholinergic neurons may break down membrane phosphatidylcholine to maintain the choline concentration required for ACh synthesis. This could lead to what has been imaginatively termed "autocannibalism" of the neuron (Wurtman et al., 1985~.
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From page 214... ...
There were no significant effects on total caloric intake, on the maintenance of body fluid balance, or on core body temperature, results which strongly suggest that the behavioral effects described below are unlikely to be attributable to imbalances in basic homeostatic mechanisms. The behavioral changes concomitant with increasing replacement of choline by NADe may be summarized in three major categories.
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From page 215... ...
Furthermore, these effects increased progressively as the available supplies of choline decreased. Earlier in this chapter the hypothesis of autocannibalism was introduced as a possible mechanism underlying behavioral disorders associated with hypofunctioning of the cholinergic system, a condition that might be a consequence of competition for available choline supplies between the needs for it to maintain the membrane integrity of cholinergic neurons and to synthesize ACh.
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From page 216... ...
More specifically, in DAT the failure would be in the production of nerve growth factor (NGF) by hippocampal and cortical cells, resulting in a gradual deterioration of septal and basal nuclei and associated decreases in ChAT activity and ACh synthesis (Appel et al., 1986; Hefti, 1983~.
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From page 217... ...
Behavioral adjustments (including cognitive processes) to ever-chang~ng physical and psychosocial environments require a multitude of dynamic biochemical events that take place in defined morphological sites within the CNS.
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From page 218... ...
had suggested the possibility that interactions might occur between behavior and biochemical events involved in the synthesis or release of nerve growth factors. "It seems a reasonable hypothesis that there may exist a mechanism by which during the coding of new behavioral patterns, the effects of information input on protein synthesis increase the production of protein molecules capable of modifying the structure of nerve or glial cells.
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From page 219... ...
The use of immunohistochemical techniques has made it possible to examine the morphological effects of NGF on axotomized septal neurons (Gage et al., 1988~: infusion of NGF protected most of the immunoreactive neurons from degeneration and prevented the appearance of plaque-like neurons. Findings that suggest the occurrence of neuronal death following brain lesions are based primarily on the detectability of neurotransmitter-related enzymes.
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From page 220... ...
Bilateral lesions in the striatum followed by bilateral fetal striatal implants reversed the spontaneous motor abnormalities induced by the lesions. Severe striatal neuronal cell loss and shrinkage following ibotenic acid lesions of the caudate-putamen produced hyperactivity that was completely compensated by "neural grafting," i.e., implantation of a dissociated cell suspension from fetal rat striatum into the lesioned sites.
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From page 221... ...
Greater success has been reported by other investigators: "Our results suggest that grafting chromaffin cells in direct contact with both the cerebrospinal fluid and the caudate nucleus produced excellent amelioration of most of the clinical signs of Parkinson's disease in our two patients" (Madrazo et al., 1987~. Results of research on animal models had indicated greater success with transplants of fetal tissue than with tissue taken later in development.
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From page 222... ...
1981. A unifying hypothesis for the cause of amyotrophic lateral sclerosis, Parkinsonism and Alzheimer disease.
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1988. Delayed treatment with nerve growth factor reverses the apparent loss of cholinergic neurons after acute brain damage.
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From page 224... ...
1986. Nerve growth factor mRNA in brain: Localization by in situ hybridization.
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From page 225... ...
NEUROBEHAVIORAL TIME BOMBS 225 U.S. National Institutes of Health.
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