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K. Kamak, M.A., M.D., Ph.D.

Clinical Director, University of South Carolina School of Medicine Greenville

Indeed, corn and soy crops have both been shown to accumulate excess shikimate in response to glyphosate exposure [20]. However, a study comparing glyphosate-tolerant and glyphosate-sensitive carrot cell lines identified several pathologies beyond the inhibition of Entropy 2013, 15 1419 aromatic amino acids following glyphosate exposure [21]. It was determined that, in addition to abnormally low levels of tryptophan, phenylalanine and tyrosine, the glyphosate-sensitive cells also had 50 to 65% reduced levels of serine, glycine and methionine. The reduction in methionine can have many adverse consequences, as methionine is an essential sulfur-containing amino acid that has to be supplied from the diet. In addition, there was evidence of excess ammonia in the glyphosate-sensitive but not the glyphosate-adapted cells. Both cell types readily absorbed glyphosate from the medium, with a rapid linear uptake observed during the first eight hours following exposure. This demonstrates that glyphosate would be present in food sources derived from glyphosate-exposed plants. The growth disruption could be due either to toxicity of the derived phenolic compounds [25] or to direct toxicity of the ammonia. Under stress-inducing environments, the secondary metabolites derived from certain protein synthesis pathways become disproportionately important, and enzyme regulation induces dramatic shifts in the production of the amino acids versus the secondary metabolites. A study comparing glyphosate exposure with aromatic protein deprivation in plants found several effects in common, but there was a striking anomaly for glyphosate in that it caused a 20-fold increase in the synthesis of the rate-limiting enzyme for a pathway leading to flavonoid synthesis, as a side branch of the tryptophan synthesis pathway [29]. More generally, there is substantial evidence that glyphosate induces the synthesis of monophenolic compounds as well as the polyphenolic flavonoids, in both plants [30] and microbes [31], with concurrent depletion of aromatic amino acid supplies. When carrots are exposed to high doses of glyphosate, they produce significant amounts of various phenolic compounds as well as shikimic acid [32]. The significance of this will become apparent later on in Section 4 on sulfate transport. Elevated amounts of shikimate-derived benzoic acids such as protocatechuate and gallate are also found in plants exposed to glyphosate [29]. Strains of nitrogen-fixing bacteria in the soil produce hydroxybenzoic acids in the presence of glyphosate [31]. This digression towards the competing pathways to produce phenolic and benzoic acid compounds may well explain the suppression of aromatic amino acid synthesis by glyphosate. In early work, glyphosate was shown to interfere with the uptake of the divalent cations, calcium and magnesium, through soybean roots [33]. Glyphosate severely reduced calcium content in the mitochondria of both root and leaf cells. Since magnesium was also affected, but potassium was not, the authors Entropy 2013, 15 1420 suggested that this property might hold for all divalent cations. More recent greenhouse experiments demonstrated that glyphosate application to the root system decreased the levels of calcium, magnesium, iron and manganese in the seeds of the plants [34]. It was proposed that glyphosate binds to and immobilizes all of these divalent micronutrients, impairing their uptake by the plant. These glyphosate-induced deficiencies would carry over to the food supply, leading to deficiencies in these nutrients in humans who consume foods derived from glyphosate-exposed crops. Evidence of disruption of gut bacteria by glyphosate is available for both cattle and poultry. It has recently been proposed that glyphosate may be a significant factor in the observed increased risk to Clostridium botulinum infection in cattle in Germany over the past ten to fifteen years [35]. Glyphosate has been shown to have remarkable adverse effects on the gut biota in poultry [36], by reducing the number of beneficial bacteria and increasing the number of pathogenic bacteria in the gut. Highly pathogenic strains of Salmonella and Clostridium were found to be highly resistant to glyphosate, whereas beneficial bacteria such as Enterococcus, Bacillus and Lactobacillus were found to be especially susceptible. Due to the antagonistic effect of the common beneficial bacterium Enterococcus spp. At the same time, genes involved in importing sugars were upregulated, which suggests a switch to anaerobic fermentation, producing pyruvate (a much less efficient solution) rather than oxidizing glucose for full breakdown to carbon dioxide and water. A switch to anaerobic metabolism is also suggested from a study showing that, in soil treated with glyphosate, the total count of fungi was significantly increased, while oxygen consumption was significantly inhibited [40]. Research conducted by exposing an outdoor aquatic mesocosm (approximating natural conditions) to two pesticides and two herbicides revealed a unique effect (among the four toxins studied) of the herbicide, glyphosate, to destroy tadpoles.

Glyphosate acts as a catalyst for the development of antibiotic resistance genes in pathogens. Since both poultry and cow manure are used as natural fertilizers in crops, it can be expected that a vector for microbial resistance to multiple drugs is through contamination of fruits and vegetables. Indeed, multiple resistance genes have been identified from diverse phyla found in cow manure, including Proteobacteria, Firmicutes, Bacteroidetes, and Actinobacteria, that is, in phylogenetically diverse organisms. Several cofactors containing a structurally complex tetrapyrrole-derived framework chelating a metal ion (cobalt (Co), magnesium (Mg), iron (Fe), or nickel (Ni)) are synthesized by gut bacteria and supplied to the host organism, including heme and corrin. Pseudomonas normally thrives in the small bowel and produces abundant cobalamin that may be a significant source for the human host. A generic mechanism of upregulated efflux through membrane pores offers broad-domain resistance to multiple antibiotics. Pseudomonas aeruginosa can use glyphosate as a sole source of Surgical Neurology International 2015, 6:45. The implications of impaired heme and cobalamin synthesis will be further addressed in a future paper. Glyphosate forms strong complexes with the transition metals via the amino, the carboxylic, and the phosphonic moieties in the molecule. Each of these can coordinate separately to metal ions or in combination as bidentate or tridentate ligands. Considering these observations regarding aluminum and arsenic, it is reasonable to expect that something similar might happen with Mn. Unlike these other two, however, Mn plays many essential roles in the body, and so its chelation by glyphosate would interfere with its bioavailability in the general circulation. Mn is a transition metal, and therefore it can catalyze oxidative reactions in neurons via the Fenton reaction. Glyoxylate and Mn3+ would both cause significant arterial damage in association with the inflammatory response. We suggest that another route for Mn transport is the vagus nerve, which delivers Mn from the liver to the brainstem nuclei. The authors, who focused their studies on affected workers in rice paddies in Sri Lanka, identified a synergistic effect of arsenic, which contaminated the soil in the affected regions. This paper is highly significant, because it proposes a mechanism whereby glyphosate greatly increases the toxicity of arsenic through chelation, which promotes uptake by the gut. Glyphosate also chelates aluminum,[230] and it has been reasoned that this enables aluminum to get past the gut barrier more readily through direct analogy with the situation with arsenic, which is also a 3+ cation. Anxiety disorder is also correlated with glyphosate usage on corn and soy, as illustrated in [Figure 5]. Glyphosate has been shown to severely deplete Mn uptake by plants, both by the roots and by the shoots. Certain species of gut bacteria, such as members of the Lactobacillus family, utilize Mn in novel ways for protection from oxidation damage, and, as a consequence, their requirements for Mn are much higher than those of other species. An experiment on a mouse model of colitis demonstrated that Lactobacilus gasseri treatment alleviated inflammation in the colon of Il-10 deficient mice. In another study, cells from children with autism exhibited higher oxidative stress than control cells, including a 1. Recent experiments on goldfish involved exposing them for 96 h to Roundup at concentrations ranging from 2. As noted by Monsanto, "Promotion of stomatal infiltration of glyphosate by an organosilicone surfactant reduces the critical rainfall period," hence the rain-fastness of Roundup WeatherMax with Transorb 2 Technology. Additional adjuvants, well known in the paper-making industry, were used to quickly break down cell walls and collapse the plant. These chemicals originally included sodium sulfite with a later change to oxalic acid (oxalate) as patented in 2006. A study comparing children with autism with controls found a 3-fold increase in serum oxalate levels in the children with autism,[152] and it was suggested that this might be due to excess absorption through the gut barrier, and that oxalate crystals in the brain could potentially disrupt brain function.

By way of merely indicating the diversity of research in this area, some of the techniques and endpoints used in studying the neuropharmacology of drugs of abuse appear in table 1. The necessity of having so many approaches available to us has become more apparent as we have gradually moved away from the notion of a single, global mechanism of tolerance and dependence. Only a short time ago, for example, the view that there must be one discrete locus in the brain responsible for opiate dependence was generally accepted. With the recognition of the multiplicity of both chemical and anatanical systems that are involved in tolerance and dependence to drugs of even a single class, the value of examining a variety of drug-induced responses is readily understood. Furthermore, in light of the broad spectrum of drug classes to which tolerance and/or dependence may develop, the need for such an array of techniques and endpoints becomes even more obvious. Tolerance can be defined either as the reduced effect of the same dose of a drug on subsequent administrations, or as a need to increase the dosage in order to maintain the same level of effect. This simple definition allows for a variety of pharmacokinetic, pharmacodynamic, and other mechanisms to be implicated in the tolerant state. Although our definition of tolerance has not changed, many of our concepts relating to it have. For example, a belief held by most workers in this field until recently was that "tolerance to the depressant but not to the excitant effects of narcotics develops at the spinal cord level, just as elsewhere in the cerebrospinal axis" (Goodman and Gilman 1955). It is now known that tolerance can be demonstarted to the classical excitant effects, namely, pupillary response and gastrointestinal tract activity. Similarly, tolerance has been found to the effects of morphine on intestinal motility in dogs (Weisbrodt et al. Although the degree of tolerance may not be equivalent for all of the actions of an opioid, at least a partial tolerance is demonstrable for most effects. One exception may be found in the effect of morphine on lowering reward threshold. Not only does no tolerance develop on repeated administration, but an increased effect has been reported (Kornetsky and Bain 1982). Another commonly accepted idea in the recent past was that tolerance develops to all of the effects of amphetamine. While it is true that one sees marked tolerance to some of the actions of this drug. Interestingly, no tolerance to its effect against narcolepsy seems to occur Weiner 1980). Marijuana, on the other hand, is an example of a drug to which no tolerance was thought to develop. In fact, it was felt by many that increased sensitivity occurred with repeated administration. While it was once believed that tolerance development requires repeated administrations of a drug, in recent years the occurrence of single-dose tolerance to morphine has been reported. In some cases, tolerance can be demonstrated within hours of a single priming dose; in other instances intervals of days are necessary. The examples cited above serve to illustrate how a more detailed look at tolerance has resulted in a recognition of new elements involved in that phenomenon. Examination of these factors has yielded important insights into the mechanisms behind tolerance. Although the terms tolerance and dependence are inextricably woven into the fabric of our thinking about several classes of drugs, there is recent in vivo evidence with opiates, for instance, that the two phenomena, though linked, are not inseparable (Cochin and Mushlin 1976; Dafny 1982). One must be careful, however, to consider other explanations, such as differences in dose or duration of drug administration, that may be required for the demonstration of each. Furthermore, if a drug acts on a particular receptor type to produce a relatively irreversible or slowly reversible canplex, tolerance may become apparent without concomitant signs of physical dependence. Only careful evaluation can determine if the tolerance exists without physical dependence. As our knowledge about dependence has grown, acceptance of such a simple definition has waned. Although the term may be used in an operational sense to denote the entire series of events associated with chronic abuse of a drug, dependence really comprises two components: the abuse liability of a drug (potential for abuse) and its dependence potential (potential for behavioral and/or physical signs of abstinence). The "abstinence syndrome"can be reversed by readministering the drug or another one with which it is crossdependent. Each class of drugs, however, has its own dependence 29 characteristics, and thus it may be better to describe dependence in term of a particular class. In fact, newer developments in pharmacology have even produced drugs of the same class which show different dependence characteristics.

In animals which had spontaneous seizures, 4-6 Hz bursts occurred also in the motor cortex; this motor cortex abnormality did not occur in animals which did not have spontaneous generalized seizures. Animals displayed bizarre behaviors suggestive of hallucinations during these periods of prolonged discharges, especially during prolonged bursts from the hippocampus and the visual cortex (Hinman and Okamoto 1984). After 5 weeks of treatment with our standard chronic "high" dose pentobarbital regimen (Rosenberg and Okamoto 1974; Okamoto et al. Measured in 12 control and 14 withdrawing animals 48 hours after the last dose of chronic pentobarbital treatment. Measured in 14 control and 14 withdrawing animals 48 hours after the last dose of chronic pentobarbital. All of these results indicate generalized augmentation of neuronal activity during withdrawal. Further electrophysiological studies of inhibitory function at the spinal reflex level (Rosenberg and Okamoto 1978) indicate that recurrent inhibition disappeared almost totally during barbiturate withdrawal (figure 9). Loss of inhibition during withdrawal may be causally related to the enhancement of inhibition by the presence of the 344 barbiturate, as has been demonstrated in the hippocampus (Nicoll et al. The neurochemical basis of this drug enhancement of inhibition and reduced inhibition during withdrawal is of great interest. Glycine is the proposed transmitter for both the Renshaw cell and also for neurons which mediate Ia inhibition (Werman et al. However, our findings do not specifically implicate glycinergic mechanisms either. Although recurrent inhibition, involving the Renshaw cell, was nearly abolished during withdrawal, direct inhibition involving the Ia inhibitory interneuron was not changed. The results of these studies support the hypothesis of a nonspecific adaptation of the nervous system during chronic barbiturate treatment, i. A major part of this adaptation is a decreased activity in certain inhibitory pathways. This view, if correct, means that the adaptation is a response to chronic depression of the nervous system rather than a specific response to the particular drug. Further studies should be forthcoming to elucidate the underlying mechanisms which contribute to a development of cellular tolerance and physical dependence. The influence of aminobutyric acid on semicarbazide-induced depletion of presynaptic inhibition. Gamma-aminobutyric acid antagonism and presynaptic inhibition in the frog spinal cord. Convulsive and sham rage behaviors in decorticate dogs during barbiturate withdrawal. Some effects of pentobarbital and strychnine on transmission through the ventrobasal complex of the cat thalamus. The effects of anesthetics on synaptic excitation and inhibition in the olfactory bulb. Effects of individual variations in drug elimination kinetics for production of pentobarbital physical dependence. Physical dependence produced by long duration, low dose chronic barbital treatment. Characteristics of functional tolerance during barbiturate physical dependency production. Tolerance characteristics produced during the maximally tolerable chronic pentobarbital dosing in the cat. A method for producing maximal pentobarbital dependence in cats: Dependence characteristics. Pharmacological studies on the primary afferent depolarization of the toad spinal cord. The barbiturate withdrawal syndrome; a clinical and electro-encephalographic study. Although tolerance is a requirement for a dependence producing drug, tolerance occurs with a wide variety of psychotropic drugs not producing dependence and can involve behavioral mechanisms as well as alterations in drug disposition and pharmacodynamic responsiveness (Jaffe 1980). A review of the literature on the effect of chronic administration of agonists or antagonists on various neurotransmitter receptors reveals findings which are often conflicting and difficult to interpret.