Cholinergic neurotransmitters lead effects

One of the major concerns aroused by exposures to chemicals that affect the nervous system is their potential to adversely impact cognitive functions such as learning and memory. Such a concern certainly has precedent. Lead exposure at high levels can leave children with permanent mental retardation. Recently, it has been demonstrated that even very low levels of lead exposure (i.e., environmental exposures) can produce subtle changes in cognitive processes. Pesticides are known to exert pronounced effects on cholinergic neurotransmitter systems, the very system that has been repeatedly implicated as a causative factor in Alzheimer s disease. 

Perhaps the most prominent and well-studied class of synthetic poisons are so-called cholinesterase inhibitors. Cholinesterases are important enzymes that act on compounds involved in nerve impulse transmission - the neurotransmitters (see the later section on neurotoxicity for more details). A compound called acetylcholine is one such neurotransmitter, and its concentration at certain junctions in the nervous system, and between the nervous system and the muscles, is controlled by the enzyme acetylcholinesterase the enzyme causes its conversion, by hydrolysis, to inactive products. Any chemical that can interact with acetylcholinesterase and inhibit its enzymatic activity can cause the level of acetylcholine at these critical junctions to increase, and lead to excessive neurological stimulation at these cholinergic junctions. Typical early symptoms of cholinergic poisoning are bradycardia (slowing of heart rate), diarrhea, excessive urination, lacrimation, and salivation (all symptoms of an effect on the parasympathetic nervous system). When overstimulation occurs at the so-called neuromuscular junctions the results are tremors and, at sufficiently high doses, paralysis and death. 

Receptor-dependent vasodilation may also take place in a more indirect manner through the presynaptic modulation of the release of neurotransmitters, such as norepinephrine and acetylcholine. In addition to its effects on postsynaptic receptors, norepinephrine stimulates the presynaptic a2-receptor, thereby inhibiting further transmitter release. Moreover, the activation of other presynaptic receptors such as the muscarinic cholinergic, dopaminergic, purinergic, serotoninergic, and histaminergic receptors leads to diminished norepinephrine release and subsequent vasodilation. 

Patients with the Lambert-Eaton syndrome do not usually respond well to anticholinesterases. The drug 3,4-diaminopyridine (3,4-DAP) increases neurotransmitter release and also the action potential (by blocking potassium conductance) these actions lead to a nonspecific excitatory effect on the cholinergic system, and provide benefit. It should be taken orally, 4-5 times per day. Adverse effects... 

The reported neurochemical effects of lead are, as has been seen, enormous. They can be broadly summarized by neurotransmitter system cholinergic impairment at relatively high levels (usually in the presence of non-specific effects), dopaminergic effects at low levels, and impairment at higher levels (in the presence of obvious non-specific effects), GABAergic effects at levels where a complication from the interaction with D-amino laevulinic acid also occurs. There is also a mixed bag of effects on enkephalin, adenyl cyclase, 5-hydroxytrypamine and other putative aminergic neurotransmitters. 

Other channel and receptor systems in neuronal tissues have been proposed to play a role in the generation of compound-specific clinical symptoms in mammals. The complex nature of the effects of pyrethroids on the central nervous system (CNS) has led various workers to suggest that they also act via modulation of nicotinic cholinergic transmission, reduce peripheral presynaptic adrenoceptor sensitivity [23] which leads to an enhancement of noradrenaline release [24], and affect the serotonin neurotransmission [25]. However, because neurotransmitter-specific pharmacological agents offer only poor or partial protection against poisoning, it is unlikely that any one of these effects represents an alternative primary mechanism of action of the pyrethroids. 

---