Over the past 60 years, a large number of selective neurotoxins were discovered and developed, making it possible to animal-model a broad range of human neuropsychiatric and neurodevelopmental disorders. In this paper, we highlight those neurotoxins that are most commonly used as neuroteratologic agents, to either produce lifelong destruction of neurons of a particular phenotype, or a group of neurons linked by a specific class of transporter proteins (i.e., dopamine transporter) or body of receptors for a specific neurotransmitter (i.e., NMDA class of glutamate receptors). Actions of a range of neurotoxins are described: 6-hydroxydopamine (6-OHDA), 6-hydroxydopa, DSP-4, MPTP, methamphetamine, IgG-saporin, domoate, NMDA receptor antagonists, and valproate. Their neuroteratologic features are outlined, as well as those of nerve growth factor, epidermal growth factor, and that of stress. The value of each of these neurotoxins in animal modeling of human neurologic, neurodegenerative, and neuropsychiatric disorders is discussed in terms of the respective value as well as limitations of the derived animal model. Neuroteratologic agents have proven to be of immense importance for understanding how associated neural systems in human neural disorders may be better targeted by new therapeutic agents.

Tardive dyskinesia (TD), marked by abnormal involuntary movements and frequently expressed as perioral activity, represents an adverse outcome of prolonged antipsychotic therapy, occurring in approximately 5 % of patients per treatment year. Although neuronal mechanisms underlying TD are largely unknown, more recent experimental studies in animal models of TD are providing insight into the neuronal mechanisms associated with TD and implicating newer treatment approaches. It is now evident that a predominance in the ratio of dopamine (DA) D1:D2 receptor (R) activation accounts for induction of perioral movements in rodent models of TD, in nonhuman primate models of TD, and in humans with TD. Experimentally, TD is produced in animal models of TD, in a manner analogous to that by which TD is produced in humans - by continuous and prolonged administration of a DA D2R antagonist (i.e., an antipsychotic drug). More recently, in a rodent model of TD, it has been shown that a lesion of dopaminergic - mainly nigroneostriatal - neurons reduces the time latency for occurrence of TD, also increases the severity of perioral activity, and results in permanence of TD after complete removal of D2R antagonist treatment. The induction of perioral activity is related to DAR supersensitivity but unrelated to numbers of D2R and D2R in the neostriatum, a brain region associated with perioral activity. More apropos, serotoninergic systems are now recognized as having a greater role in effecting perioral activity, and it appears that 5-HT2C receptor antagonists are most effective in abating perioral activity in a rodent model of TD. These processes and mechanisms, topics addressed in this chapter, highlight a newer understanding of mechanisms underlying TD and provide insight into new approaches towards treatment of TD in humans.

Neurotoxlns represent unique chemical tools, providing a means to 1) gain insight into cellular mechanisms of apopotosis and necrosis, 2) achieve a morphological template for studies otherwise unattainable, 3) specifically produce a singular phenotype of denervation, and 4) provide the starting point to delve into processes and mechanisms of nerve regeneration and sprouting. There are many other notable uses of neurotoxins in neuroscience research, and ever more being discovered each year. The objective of this review paper is to highlight the broad areas of neuroscience in which neurotoxins and neurotoxicity mechanism come into play. This shifts the focus away from neurotoxins per se, and onto the major problems under study today. Neurotoxins broadly defined are used to explore neurodegenerative disorders, psychiatric disorders and substance use disorders. Neurotoxic mechanisms relating to protein aggregates are indigenous to Alzheimer disease, Parkinson's disease. NeuroAIDS is a disorder in which microglia and macrophages have enormous import. The gap between the immune system and nervous system has been bridged, as neuroinflammation is now considered to be part of the neurodegenerative process. Related mechanisms now arise in the process of neurogenesis. Accordingly, the entire spectrum of neuroscience is within the purview of neurotoxins and neurotoxicity mechanisms. Highlights on discoveries in the areas noted, and on selective neurotoxins, are included, mainly from the past 2 to 3 years.

Les neurones dopaminergiques de la substance noire (SNc) sont les plus vulnérables à la dégénérescence dans la maladie de Parkinson et ses modèles animaux. Suite à des travaux antérieurs et à des résultats préliminaires du laboratoire Trudeau, notre hypothèse actuelle suggère que la très grande taille de l'arborisation axonale des neurones de la SNc soit un facteur clé à l'origine de leur vulnérabilité, puisque cet état devrait être associé à un taux élevé de phosphorylation oxydative et de production de radicaux libres. En accord avec cette hypothèse, les autres populations dopaminergiques, dotées d'arborisations de moindre taille, résistent mieux aux lésions expérimentales et à la maladie chez l'humain. L'objectif du présent projet était de développer un modèle murin dans lequel les neurones de la SNc présentent une taille d'arborisation axonale plus grande, se rapprochant davantage de celle observée chez l'humain et en reproduisant la vulnérabilité, ce qui pourrait représenter une percée importante dans l'identification de nouvelles approches thérapeutiques. Basée sur le bourgeonnement axonal compensatoire des neurones dopaminergiques suite à des lésions partielles, la méthode utilisée fut l'injection unilatérale intranigrale de la toxine 6-hydroxydopamine (6-OHDA) à quelques jours de vie (P5), en visant l'élimination de 50% des neurones de la SNc. Un immunomarquage contre la tyrosine hydroxylase (TH), enzyme de synthèse de la dopamine, ainsi qu'une quantification du signal TH dans le striatum et des comptes neuronaux stéréologiques ont permis de quantifier la lésion partielle et de mettre en évidence la présence d'une croissance axonale compensatoire des neurones dopaminergiques survivants, à 10 et 90 jours post-lésion, suggérant une compensation précoce. Afin de mettre en évidence l'origine du bourgeonnement axonal, nous avons injecté un vecteur viral de type AAV encodant une protéine fluorescente (EYFP) dans la SNc ou la VTA des animaux adultes. Nos résultats confirment la présence de neurones nigrostriés à plus grande arborisation suivant une lésion unilatérale précoce à la 6-OHDA, dont la vulnérabilité accrue pourra être évaluée dans des expériences à venir par des protocoles lésionnels au MPTP, une toxine permettant de modéliser la maladie de Parkinson chez la souris. / Dopaminergic neurons of the substantia nigra (SNc) are amongst the most vulnerable to neurodegeneration in Parkinson's disease and its animal models. According to previous work and preliminary results in our laboratory, our present hypothesis postulates that the large axonal arborisation size of SNc neurons is a key driving factor in their vulnerability, since this characteristic is associated with increased oxidative phosphorylation levels and free radicals production. In agreement with this hypothesis, other dopaminergic populations with smaller axonal arbors better resist to experimental lesions and to the disease process in humans. The current project aims to develop a mouse model in which SNc neurons present an axonal arborisation of increased size, closer to what is encountered in humans, thus reproducing their vulnerability, which could represent an important breakthrough in the identification of new therapeutic approaches. Based on compensatory axonal sprouting of dopaminergic neurons following partial lesions, the method used was the unilateral intranigral injection of the toxin 6-hydroxydopamine (6-OHDA) at an early age (P5), to induce the loss of approximately 50% of SNc neurons. Immunostaining against tyrosine hydroxylase (TH), an enzyme required for the synthesis of dopamine, TH signal quantification in the striatum and stereological counting of neurons allowed for the quantification of the partial lesion and demonstrated compensatory axonal sprouting at 10 and 90 days post-lesion, with our results suggesting an early compensation. To better characterize the origin of axonal sprouting, we injected an AAV viral vector encoding a fluorescent protein (EYFP) in either the SNc or the VTA of adult animals. Our results confirm the presence of nigrostriatal neurons with increased arborisation sizes following early unilateral lesion using 6-OHDA, whose increased vulnerability will be evaluated in future experiments through lesion protocols using MPTP, a toxin used to model Parkinson's disease in mice.

The era of selective neurotoxins arose predominately in the 1960s with the discovery of the norepinephrine (NE) isomer 6-hydroxydopamine (6-OHDA), which selectively destroyed noradrenergic sympathetic nerves in rats. A series of similarly selective neurotoxins were later discovered, having high affinity for the transporter site on nerves and thus being accumulated and able to disrupt vital intraneuronal processes, to lead to cell death. The Trojan Horse botulinum neurotoxins (BoNT) and tetanus toxin bind to glycoproteins on the neuronal plasma membrane, then these stealth neurotoxins are taken inside respective cholinergic or glycinergic nerves, producing months-long functional inactivation but without overtly destroying those nerves. The mitochondrial complex I inhibitor rotenone, while lacking total specificity, still destroys dopaminergic nerves with some selectivity; and importantly, results in the neural accumulation of synuclein-to model Parkinson’s disease (PD) in animals. Other neurotoxins target specific subtypes of glutamate receptors and produce excitotoxicity in nerves with that receptor population. The dopamine D2 receptor agonist quinpirole, termed a selective neurotoxin, produces a behavioral state replicating some of the notable features of schizophrenia, but without overtly destroying nerves. These processes, mechanisms or treatment-outcomes account for the means by which neurotoxins are classified as such, and represent some of the means by which neurotoxins as a group are able to destroy or functionally inactivate nerves; or replicate an altered neurological state. Selective neurotoxins have proven to be important in gaining insight into biochemical processes and mechanisms responsible for survival or demise of a nerve. Selective neurotoxins are useful also for animal modeling of human neural disorders such as PD, Alzheimer disease, attention-deficit hyperactivity disorder (ADHD), Lesch-Nyhan disease, tardive dyskinesia, schizophrenia and others. The importance of neurotoxins in neuroscience will continue to be ever more important as even newer neurotoxins are discovered.

There has been an awareness of nerve poisons from ancient times. At the dawn of the twentieth century, the actions and mechanisms of these poisons were uncovered by modern physiological and biochemical experimentation. However, the era of selective neurotoxins began with the pioneering studies of R. Levi-Montalcini through her studies of the neurotrophin "nerve growth factor" (NGF), a protein promoting growth and development of sensory and sympathetic noradrenergic nerves. An antibody to NGF, namely, anti-NGF - developed in the 1950s in a collaboration with S. Cohen - was shown to produce an "immunosympathectomy" and virtual lifelong sympathetic denervation. These Nobel Laureates thus developed and characterized the first identifiable selective neurotoxin. Other selective neurotoxins were soon discovered, and the compendium of selective neurotoxins continues to grow, so that today there are numerous selective neurotoxins, with the potential to destroy or produce dysfunction of a variety of phenotypic nerves. Selective neurotoxins are of value because of their ability to selectively destroy or disable a common group of nerves possessing (1) a particular neural transporter, (2) a unique set of enzymes or vesicular transporter, (3) a specific type of receptor or (4) membranous protein, or (5) other uniqueness. The era of selective neurotoxins has developed to such an extent that the very definition of a "selective" neurotoxin has warped. For example, (1) N-methyl-D- aspartate receptor (NMDA-R) antagonists, considered to be neuroprotectants by virtue of their prevention of excitotoxicity from glutamate receptor agonists, actually lead to the demise of populations of neurons with NMDA receptors, when administered during ontogenetic development. The mere lack of natural excitation of this nerve population, consequent to NMDA-R block, sends a message that these nerves are redundant - and an apoptotic cascade is set in motion to eliminate these nerves. (2) The rodenticide rotenone, a global cytotoxin that acts mainly to inhibit complex I in the respiratory transport chain, is now used in low dose over a period of weeks to months to produce relatively selective destruction of substantia nigra dopaminergic nerves and promote alpha-synuclein deposition in brain to thus model Parkinson's disease. Similarly, (3) glial toxins, affecting oligodendrocytes or other satellite cells, can lead to the damage or dysfunction of identifiable groups of neurons. Consequently, these toxins might also be considered as "selective neurotoxins," despite the fact that the targeted cell is nonneuronal. Likewise, (4) the dopamine D2-receptor agonist quinpirole, administered daily for a week or more, leads to development of D2-receptor supersensitivity - exaggerated responses to the D2-receptor agonist, an effect persisting lifelong. Thus, neuroprotectants can become "selective" neurotoxins; nonspecific cytotoxins can become classified as "selective" neurotoxins; and receptor agonists, under defined dosing conditions, can supersensitize and thus be classified as "selective" neurotoxins. More examples will be uncovered as the area of selective neurotoxins expands. The description and characterization of selective neurotoxins, with unmasking of their mechanisms of action, have led to a level of understanding of neuronal activity and reactivity that could not be understood by conventional physiological observations. This chapter will be useful as an introduction to the scope of the field of selective neurotoxins and provide insight for in-depth analysis in later chapters with full descriptions of selective neurotoxins.