There is a growing consensus, based on several converging lines of evidence, which suggests schizophrenia is the product of a developmental insult occurring in the late 2 nd or early 3 rd trimester. Additionally, it has been observed that adults who abuse the noncompetitive NMDA antagonist PCP present with symptoms that mimic schizophrenia, such as hallucinations, formal thought disorder, delusions, unstable or flattened affect, social withdrawal, and impaired cognition. Thus, several labs have attempted to use early postnatal PCP administration in rodents as a drug model of schizophrenia. The current study investigated the cognitive effects of early postnatal PCP administration in C57BL/6 mice. Mouse pups received daily administrations of either 10.0 mg/kg PCP or saline on postnatal (PN) days 5-15. After weaning, pups were assessed in locomotor activity, a reference memory task in the Morris water maze, and a spatial delayed alternation task in the T-maze. Additionally, pups were subjected to a pharmacological challenge with PCP in the delayed alternation task. In males, No significant differences were detected between PCP- and saline-treated animals in locomotor activity. However, in the reference memory task, PCP-treated males had significantly longer path lengths, and displayed a non-significant trend towards increased thigmotaxia. Furthermore, males treated with PCP displayed significantly reduced accuracy in the working memory task without differences in choice latency, and were more sensitive to the acute effects of PCP than saline controls. Finally, these deficits were associated with a 29% increase in NR1 subunit expression in the hippocampus. Interestingly, PCP-treated female mice were not significantly different from saline-treated controls in locomotor activity, reference memory task performance, or delayed alternation performance, did not have a significantly different reaction to pharmacological challenge with PCP in the delayed alternation task, and did not demonstrate any changes in NR1 subunit expression. The present study provided the first evidence that early postnatal PCP administration in C57BL/6 mice can produce selective memory pairments. However, this effect was limited to the male mice, suggesting that the female mice were protected somewhat from these effects.

Ketamine and phencyclidine (PCP) are noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) type of ligand-gated glutamate receptors. Both agents have high abuse liability, and may produce dependence. Tolerance to the reinforcing effects of drugs of abuse is widely regarded as a key component of the dependence process. Therefore, the present study was conducted to examine whether tolerance develops to the reinforcing effects of ketamine, and whether PCP and dizocilpine, a noncompetitive NMDA antagonist with negligible abuse liability, produce cross-tolerance to the reinforcing effects of ketamine. Further, identification of the neural mechanisms that underlie tolerance to the reinforcing effects of drugs may yield information regarding drug dependence.

Selon un point de vue très répandu, l’injection quotidienne et répétée de phencyclidine (PCP)reproduit chez ranimai des symptômes négatifs similaires à ceux observés dans la schizophrénie humaine en créant une hypodopaminergie corticale, notamment dans le cortex préfrontai. Le présent mémoire s’insère dans un programme de recherche qui vise à tester ce point de vue qui, dans les faits, repose sur peu de données empiriques publiées. Plus spécifiquement, l’expérience rapportée dans le mémoire compare la performance de rats traités avec du PCP de façon sous chronique et répétée à celle de rats contrôles injectés avec une solution saline, dans deux tâches introduisant des changements de règles et requérant l’intégrité du cortex préfrontal: une tâche de localisation spatiale à buts variables dans un labyrinthe radial et une variante du test de tri decartes du Wisconsin (WCST) adaptée aux rats. L’absence de différence significative entre les groupes exposé et non exposé à la drogue dans les deux tâches examinées met en doute la capacité réelle de cette drogue à reproduire, chez le rat, un syndrome fronto-cognitif déficitaire apparenté à la schizophrénie.

This thesis consisted of experiments designed to explore the construct of attention and investigate the disruptive effects of psychotomimetics, with a specific focus on NMDA antagonists. Phencyclidine (PCP) was administered through a variety of treatment regimens in order to to determine the ability of inducing cognitive-specific disruptions in attentional functioning. The hypothesis that sub-chronic exposure to PCP would result in persistent attentional impairment was tested, using the 5-choice serial reaction time task (5-CSRTT). The 5-CSRTT assesses not only visuospatial attention, but also components of impulsivity, compulsivity, speed of processing and motivation. It was determined that an additional task-related intervention that increased the attentional load was required to elucidate attentional impairment following sub-chronic PCP treatment. The ability of rats to perform the modified version of the 5-CSRTT, known as the 5-choice continuous performance test (5C-CPT), was investigated. The 5C-CPT was implemented to provide a task that may have greater analogy to the human CPT, than the original 5-CSRTT. The consequence of dopaminergic D1 system activation was investigated. It was revealed that D1 partial agonism improved attentional performance in a baseline-dependent manner. Following successful acquisition of the task, it was shown that repeated PCP treatment induced cognitive disruption that was cognitive-specific, and not confounded by generalised response disruption. Furthermore, a partial attenuation of the PCP-induced performance disruption was achieved following administration of the D1 partial agonist, SKF 38393. Moreover, sub-chronic PCP treatment was shown to impair 5C-CPT performance in the drug-free state. However, an additional challenge that further increased the attentional load was needed to elucidate a performance deficit. This highlighted that sustained attention/vigilance is sensitive to persistent impairment following sub-chronic PCP administration in a manner consistent with deficits observed in schizophrenia patients. This prompted the investigation that tested the hypothesis that sub-chronic PCP treatment could induce enduring structural deficits in regions associated with attentional performance. Magnetic resonance imaging (MRI) was conducted, in conjunction with 5-CSRTT and pre-pulse inhibition (PPI). It was revealed that sub-chronic PCP treatment resulted in morphological brain abnormalities in brain regions associated with 5-CSRTT performance. This was coupled with deficits in sustained attentional performance following an increase in attentional load, yet PPI was unaffected. Taken together, these findings suggested sub-chronic PCP treatment impairs attentional functionality, an effect that dissociates between effortful and passive attentional processes.

Cognitive deficits are the single strongest predictor of the functional outcome in patients with schizophrenia. Current treatments are largely ineffective in improving cognitive impairments and promising pre-clinical research has mostly failed to translate clinically. Despite the advances provided by rodent models, the neurobiological basis of cognitive deficits in schizophrenia is poorly understood. Therefore, this thesis proposes a zebrafish model for studying cognitive impairments of schizophrenia. Although more evolutionarily distant to humans compared to the rat, the zebrafish has emerged as a popular vertebrate model of human disorders due to its genetic tractability, complex nervous system and elaborate behavioural repertoire. We investigated the effects of genetic alterations and neurodevelopmental disruption on behaviour and learning in zebrafish. Using both disc1 mutant lines and sub-chronic phencyclidine (PCP) on larvae from 6-10 dpf, we were able to assess behavioural changes as a function of developmental age. In particular, this thesis aimed to develop appropriate behavioural assays to assess zebrafish learning and executive function relevant to disorders seen in human patients with schizophrenia. It was possible to demonstrate robust learning across several domains, namely, reversal, classical avoidance and non-associative learning, alongside locomotor and anxiety-related behaviours. There were varied deficits associated with each of the two – genetic (disc1 gene mutation) and environmental (sub-chronic PCP) – manipulations, consistent with observations in rat research. Together, the research in this thesis demonstrates that a zebrafish model exhibits behaviour resembling that of mammalian models of schizophrenia and provides a foundation for the utility of zebrafish in examining cognitive impairments associated with schizophrenia.

A selective neurotoxin takes many forms: as an antibody to a neurotrophin, as an alkylator, as an excitotoxin, as a blocker of requisite neuronal excitation during ontogenetic development, as a generator of oxidative stress, as an inhibitor of vital intraneuronal processes, and as an agent adversely affecting a host of multiple sites in neurons. Neurotoxins have been invaluable for elucidating cellular mechanisms attending or preventing neuronal necrosis and apoptosis, and for modeling and thereby discerning mechanisms invoked in neurological and psychiatric disorders. Neuroprotectants, endogenous and exogenous, are being explored as potentially useful agents to ward off diseases. Finally, hypothesized as posing a risk to humans as environmental constituents, neurotoxins are now being remodeled as adjuncts for therapeutic intervention in a variety of human medical disorders.

This thesis consisted of experiments designed to explore the construct of attention and investigate the disruptive effects of psychotomimetics, with a specific focus on NMDA antagonists. Phencyclidine (PCP) was administered through a variety of treatment regimens in order to to determine the ability of inducing cognitive-specific disruptions in attentional functioning. The hypothesis that sub-chronic exposure to PCP would result in persistent attentional impairment was tested, using the 5-choice serial reaction time task (5-CSRTT). The 5-CSRTT assesses not only visuospatial attention, but also components of impulsivity, compulsivity, speed of processing and motivation. It was determined that an additional task-related intervention that increased the attentional load was required to elucidate attentional impairment following sub-chronic PCP treatment. The ability of rats to perform the modified version of the 5-CSRTT, known as the 5-choice continuous performance test (5C-CPT), was investigated. The 5C-CPT was implemented to provide a task that may have greater analogy to the human CPT, than the original 5-CSRTT. The consequence of dopaminergic D1 system activation was investigated. It was revealed that D1 partial agonism improved attentional performance in a baseline-dependent manner. Following successful acquisition of the task, it was shown that repeated PCP treatment induced cognitive disruption that was cognitive-specific, and not confounded by generalised response disruption. Furthermore, a partial attenuation of the PCP-induced performance disruption was achieved following administration of the D1 partial agonist, SKF 38393. Moreover, sub-chronic PCP treatment was shown to impair 5C-CPT performance in the drug-free state. However, an additional challenge that further increased the attentional load was needed to elucidate a performance deficit. This highlighted that sustained attention/vigilance is sensitive to persistent impairment following sub-chronic PCP administration in a manner consistent with deficits observed in schizophrenia patients. This prompted the investigation that tested the hypothesis that sub-chronic PCP treatment could induce enduring structural deficits in regions associated with attentional performance. Magnetic resonance imaging (MRI) was conducted, in conjunction with 5-CSRTT and pre-pulse inhibition (PPI). It was revealed that sub-chronic PCP treatment resulted in morphological brain abnormalities in brain regions associated with 5-CSRTT performance. This was coupled with deficits in sustained attentional performance following an increase in attentional load, yet PPI was unaffected. Taken together, these findings suggested sub-chronic PCP treatment impairs attentional functionality, an effect that dissociates between effortful and passive attentional processes.

La schizophrénie est un trouble neuropsychiatrique sévère dont les manifestations cliniques sont complexes et hétérogènes. L'administration de phencyclidine (PCP) chez le rat est couramment employée pour reproduire des comportements dysfonctionnels analogues aux symptômes de la schizophrénie. Les données comportementales recueillies au moyen du modèle PCP sont toutefois disparates et difficiles à intégrer: la sélection limitée des paradigmes expérimentaux et la nature élémentaire des indices comportementaux utilisés pour mesurer les effets du PCP expliquent en partie ce problème. La présente thèse se propose de préciser les symptômes schizophréniques pouvant être reproduits au moyen du PCP chez le rat en utilisant des paradigmes moins conventionnels et introduisant des conditions expérimentales plus discriminantes au sein des tests standards. Le premier article vérifie chez le rat les effets d'une exposition quotidienne à 10 mg/kg de PCP pendant 15 jours sur l'expression et l'organisation du toilettage dans deux conditions stressantes, l'exposition à des jets d'eau ou à un son fort, et une condition appétitive, la consommation de nourriture. Dans le deuxième article, les effets d'un traitement identique sont examinés sur la locomotion en l'absence ou en présence d'un son fort, la coordination motrice sur le retard et la motivation à compléter une variété de tâches encadrées, menant ou non à un renforcement. Un troisième article tente de cibler les effets du PCP sur les fonctions émotionnelles dans la cage clarté/noirceur et pendant l'exposition à une odeur de prédateur. Environ 20 h après l'exposition au PCP, le toilettage est augmenté dans toutes les conditions mais il est désorganisé seulement en réponse aux jets d'eau stressants. Au même moment, la locomotion est diminuée peu importe la présence d'un son fort dans l'environnement mais la coordination motrice et la motivation à se déplacer en présence et en l'absence d'une récompense sont intactes. Sept jours après la fin d'un traitement répété, l'évitement de situations anxiogènes est amplifié. L'administration sous-chronique répétée de PCP engendre donc des anomalies dans les fonctions émotionnelles et dans la motivation à compléter un comportement dirigé vers un but en l'absence d'encadrement adéquat. Ces dysfonctions sont compatibles avec certains symptômes positifs, négatifs, désorganisés et émotionnels du syndrome schizophrénique humain. / Schizophrenia is a severe neuropsychiatric disorder that encompasses complex and heterogeneous symptoms. Phencyclidine (PCP) administration in rats is commonly used to reproduce abnormal behaviors reminiscent of human schizophrenia. However, behavioral data collected with the PCP model are inconsistent and difficult to understand: paucity of available experimental paradigms and rudimentary behavioral tools used to assess PCP outcomes likely account for this problem. The aim of this thesis was to circumscribe reproducible schizophrenic-like symptoms in the PCP rat model by using less conventional paradigms and by introducing precise, more discriminating conditions in classical tests. The first paper verified in the rat the effects of a daily exposure to 10 mg/kg PCP for 15 days on grooming expression and organization in two stressful conditions, water spray or loud sound exposure, and one appetitive condition, food consumption. In the second paper, the effects of identical PCP treatment were examined on locomotion in the absence or in the presence of a loud sound, on motor coordination, and on extrinsic motivation. A third paper tried to better define PCP effects on emotional functions in the light/dark apparatus and during exposure to a predator odor. Around 20 h after PCP exposure, grooming was enhanced in ail stressful and appetitive conditions but was disorganized only in the stressful, water condition. Locomotion was reduced whether or not a sound was introduced in the environment but motor coordination and motivation to achieve rewarded and non rewarded goal-directed behaviors were unaffected. Seven days after a repeated treatment, avoidance of anxiogenic stimuli was increased. Repeated subchronic PCP administration thus provokes emotional dysfunctions and an inability to self-generate behaviors in the absence of adequate support. These dysfunctions are compatible with positive, negative, disorganized, and emotional symptoms of human schizophrenia.

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.