Phencyclidine (PCP) is a non-competitive NMDA receptor antagonist that has been shown to induce schizophrenia-like psychotic symptoms that are clinically indistinguishable from schizophrenia in patients. When administered to rodents, PCP produces an array of behaviours that are characteristic of schizophrenia. Schizophrenia is associated with continual and treatment resistant cognitive deficits which are now recognised as a core feature of the disease. The aim of the studies reported in chapter 3 were to establish a set of objects with equal preference in the NOR (novel object recognition) test. Furthermore, the inter-trial-interval (ITI) of the NOR test was investigated in an attempt to elucidate the effects of time and location of the rats during the ITI on the cognitive impairments following sub-chronic PCP treatment. The experiments in chapter 4 were designed to compare the performance of male and female rats in the NOR test following treatment with acute d-amphetamine (d-amph), PCP and sub-chronic PCP treatment. In chapter 5, validation of the cognitive deficits induced by sub-chronic PCP treatment was assessed using carefully selected pharmacological agents. The aim of the studies in chapter 6 was to determine the effects of isolation rearing on cognitive performance in the NOR test following increasing ITIs. Additionally, the sensitivity of isolation reared rats compared to social controls following acute administration of PCP and d-amph was assessed using the NOR test. Studies in chapter 8 utilised the 16-holeboard maze to determine the effects of acute treatment with d-amphetamine, PCP and scopolamine on working memory in the rat. NOR is a visual learning and memory test that measures recognition memory which is impaired in patients with schizophrenia. Studies presented in this thesis demonstrate the importance of careful pilot studies when selecting objects for use in the NOR test. Initial studies in sub-chronic PCP (2 mg/kg for 7 days followed by 7 days drug free) treated female hooded-Lister rats revealed a preference of the rats for the wooden cone object; subsequently this object was eliminated from further NOR experiments. Sub-chronic PCP treated rats were found to be highly susceptible to the disruptive influence of distraction during the short 1 min inter-trial-interval (ITI) in the NOR test. These results are consistent with clinical findings of the effects of distraction on cognition in schizophrenia patients. Following the initial validation experiments, a 1 min ITI in the home cage was selected for all subsequent NOR studies. Further experiments provided evidence to confirm that information presented in the acquisition trial is encoded but not retained in the retention trial of the NOR test by IV PCP-treated rats. Male rats were less sensitive to the recognition memory deficits induced by acute treatment with PCP and d-amphetamine compared with females. Following sub-chronic PCP treatment, both males and females showed object recognition deficits, however, the impairments were more robust in female rats. Female rats were therefore selected for all subsequent experiments. Pharmacological validation was carried out using carefully selected agents which were assessed for their ability to restore the sub-chronic PCP induced cognitive deficit in the object recognition test. It was found that the classical antipsychotic agents haloperidol and fluphenazine, the benzodiazepine anxiolytic chlordiazepoxide and the SSRI antidepressant fluoxetine were ineffective. Further studies showed that the atypical antipsychotic agents, clozapine and risperidone, the analeptic agent modafinil, the nAChR full agonist nicotine, and full agonist and positive allosteric modulator of the α7 nAChR (PNU-282987 and PNU120596 respectively) reversed the recognition memory deficit induced by sub-chronic PCP treatment in the NOR test. Isolation rearing of rats at weaning is an environmental stressor that has relevance for modelling the symptomatology and pathology of schizophrenia. Isolates had a significantly increased locomotor activity (LMA) response to a novel environment and enhanced sensitivity to time delay-induced recognition memory deficits, compared with their socially reared counterparts. Isolates were less sensitive to an acute PCP-induced recognition memory deficit but more sensitive to an acute d-amphetamine induced recognition memory deficit in the NOR test compared to social controls. Preliminary results from the 16-holeboard maze experiments reveal that acute administration of the mAChR antagonist scopolamine, d-amphetamine, PCP and sub-chronic PCP treatment reduced working memory scores compared to vehicle treated controls. Taken together, these findings suggest that sub-chronic treatment with PCP induces cognitive deficits in behavioural tests of relevance to cognition associated with schizophrenia. This may allow the detection of novel pharmacotherapies to alleviate these cognitive deficits and exploration of the nature of cognitive disturbances in these patients.

Neste estudo avaliamos atividades biológicas pré-clínicas de moléculas obtidas de Mangifera indica e de Valeriana glechomifolia. Mangiferina, isolada de M. indica, estimulou a proliferação celular e induziu um aumento significativo na secreção do fator de crescimento do nervo e do fator de necrose tumoral em células de glioblastoma humano U138-MG in vitro. Uma injeção sistêmica de mangiferina melhorou a consolidação da memória de longa duração (LTM) de reconhecimento de objetos (RO) e prejudicou a retenção da memória aversiva no teste da esquiva inibitória (EI) em ratos. A melhora da LTM no RO promovida pela administração sistêmica de mangiferina também foi observada com a administração intrahipocampal. Já o prejuízo da memória no teste da EI observado sistemicamente não ocorreu com a infusão no hipocampo ou amígdala. Camundongos atáxicos também apresentaram melhora na memória de RO após administração crônica de mangiferina, sem efeito na EI; um extrato comercializado de M. indica não afetou a memória no RO, mas facilitou a memória na EI. Os resultados indicam que mangiferina melhora a LTM no RO com envolvimento do hipocampo por meio de um mecanismo que pode envolver um aumento dos níveis da neurotrofina NGF e da citocina TNF-α. Valepotriatos, isolados de V. glechomifolia, demonstraram inibição da viabilidade de células tumorais U138-MG nas doses de 30 e 100μg/μl; o 8-Br- AMPc, um análogo do AMPc, atenuou à inibição dos valepotriatos na viabilidade celular, sugerindo que os valepotriatos interagem com a rota de sinalização celular do AMPc/PKA na inibição da viabilidade de células cancerosas. A administração sistêmica de valepotriatos, em camundongos 30 minutos antes dos testes, apresentou os seguintes resultados: durante a exploração no campo aberto, a dose 10mg/kg causou redução na locomoção e no comportamento exploratório e diminuição da ansiedade no teste do labirinto em cruz elevado. Não ocorreu diferença entre os tratamentos na memória de EI e na memória RO, exceto no grupo que recebeu 3mg/kg de valepotriatos que apresentou piora na LTM de RO. Os resultados indicam que os valepotriatos causaram atividades ansiolítica e sedativa sem déficits na memória de EI e RO em camundongos tratados com 10mg/kg. As atividades biológicas in vitro e in vivo encontradas nas moléculas estudadas (especialmente mangiferina e valepotriatos) geram interesse de investigações para utilizações terapêuticas na memória e no câncer. / We evaluated the biological activities of molecules obtained from Mangifera indica and Valeriana glechomifolia. Mangiferin, isolated from M. indica, stimulated cell proliferation and induced a significant increase in levels of nerve growth factor and tumor necrosis factor secreted in human glioblastoma cells U138-MG in vitro. A systemic injection of mangiferin improved long term memory (LTM) consolidation of object recognition (NOR) and impaired memory retention in aversive inhibitory avoidance test (IA) in rats. The improvement in NOR memory promoted by systemic administration of mangiferin was also observed with intrahippocampal administration. The memory impairment observed systemically in the IA did not occur with the infusion into the hippocampus or amygdala. Ataxic mice also showed improvement in NOR memory after chronic administration of mangiferin, with no effect on IA; a standardized extract of M. indica had not effect on memory in NOR, but facilitated the memory in IA. The results indicate that mangiferin improvement NOR memory involving the hippocampus through a mechanism that may involve increased levels of neurotrophins and cytokines. Valepotriates isolated from V. glechomifolia showed inhibition of the viability of U138-MG tumor cells at doses of 30 and 100μg/μl; 8-BrcAMP, an analogue of cAMP, reversed the inhibition of valepotriates on cell viability, suggesting that valepotriates interact with the cAMP/PKA signaling route in the inhibition of the viability of cancer cells. Systemic administration of valepotriates in mice, 30 minutes before tests, showed the following results: during the open-field, the dose of 10mg/kg caused a reduction in locomotion and exploratory behavior and decreased anxiety in the test of elevated plus maze. There was no difference between treatments in IA or NOR memories, except from the group receiving valepotriates at 3mg/kg, which worsened in the NOR. The results indicated that valepotriates at 10mg/kg caused anxiolytic and sedative activities without inducing memory deficits in IA and NOR. The biological activities in vitro and in vivo found with the studied molecules (notable mangiferin and valepotriates) support further research for potential therapeutic uses in cancer and in memory.

Neste estudo avaliamos atividades biológicas pré-clínicas de moléculas obtidas de Mangifera indica e de Valeriana glechomifolia. Mangiferina, isolada de M. indica, estimulou a proliferação celular e induziu um aumento significativo na secreção do fator de crescimento do nervo e do fator de necrose tumoral em células de glioblastoma humano U138-MG in vitro. Uma injeção sistêmica de mangiferina melhorou a consolidação da memória de longa duração (LTM) de reconhecimento de objetos (RO) e prejudicou a retenção da memória aversiva no teste da esquiva inibitória (EI) em ratos. A melhora da LTM no RO promovida pela administração sistêmica de mangiferina também foi observada com a administração intrahipocampal. Já o prejuízo da memória no teste da EI observado sistemicamente não ocorreu com a infusão no hipocampo ou amígdala. Camundongos atáxicos também apresentaram melhora na memória de RO após administração crônica de mangiferina, sem efeito na EI; um extrato comercializado de M. indica não afetou a memória no RO, mas facilitou a memória na EI. Os resultados indicam que mangiferina melhora a LTM no RO com envolvimento do hipocampo por meio de um mecanismo que pode envolver um aumento dos níveis da neurotrofina NGF e da citocina TNF-α. Valepotriatos, isolados de V. glechomifolia, demonstraram inibição da viabilidade de células tumorais U138-MG nas doses de 30 e 100μg/μl; o 8-Br- AMPc, um análogo do AMPc, atenuou à inibição dos valepotriatos na viabilidade celular, sugerindo que os valepotriatos interagem com a rota de sinalização celular do AMPc/PKA na inibição da viabilidade de células cancerosas. A administração sistêmica de valepotriatos, em camundongos 30 minutos antes dos testes, apresentou os seguintes resultados: durante a exploração no campo aberto, a dose 10mg/kg causou redução na locomoção e no comportamento exploratório e diminuição da ansiedade no teste do labirinto em cruz elevado. Não ocorreu diferença entre os tratamentos na memória de EI e na memória RO, exceto no grupo que recebeu 3mg/kg de valepotriatos que apresentou piora na LTM de RO. Os resultados indicam que os valepotriatos causaram atividades ansiolítica e sedativa sem déficits na memória de EI e RO em camundongos tratados com 10mg/kg. As atividades biológicas in vitro e in vivo encontradas nas moléculas estudadas (especialmente mangiferina e valepotriatos) geram interesse de investigações para utilizações terapêuticas na memória e no câncer. / We evaluated the biological activities of molecules obtained from Mangifera indica and Valeriana glechomifolia. Mangiferin, isolated from M. indica, stimulated cell proliferation and induced a significant increase in levels of nerve growth factor and tumor necrosis factor secreted in human glioblastoma cells U138-MG in vitro. A systemic injection of mangiferin improved long term memory (LTM) consolidation of object recognition (NOR) and impaired memory retention in aversive inhibitory avoidance test (IA) in rats. The improvement in NOR memory promoted by systemic administration of mangiferin was also observed with intrahippocampal administration. The memory impairment observed systemically in the IA did not occur with the infusion into the hippocampus or amygdala. Ataxic mice also showed improvement in NOR memory after chronic administration of mangiferin, with no effect on IA; a standardized extract of M. indica had not effect on memory in NOR, but facilitated the memory in IA. The results indicate that mangiferin improvement NOR memory involving the hippocampus through a mechanism that may involve increased levels of neurotrophins and cytokines. Valepotriates isolated from V. glechomifolia showed inhibition of the viability of U138-MG tumor cells at doses of 30 and 100μg/μl; 8-BrcAMP, an analogue of cAMP, reversed the inhibition of valepotriates on cell viability, suggesting that valepotriates interact with the cAMP/PKA signaling route in the inhibition of the viability of cancer cells. Systemic administration of valepotriates in mice, 30 minutes before tests, showed the following results: during the open-field, the dose of 10mg/kg caused a reduction in locomotion and exploratory behavior and decreased anxiety in the test of elevated plus maze. There was no difference between treatments in IA or NOR memories, except from the group receiving valepotriates at 3mg/kg, which worsened in the NOR. The results indicated that valepotriates at 10mg/kg caused anxiolytic and sedative activities without inducing memory deficits in IA and NOR. The biological activities in vitro and in vivo found with the studied molecules (notable mangiferin and valepotriates) support further research for potential therapeutic uses in cancer and in memory.

Neste estudo avaliamos atividades biológicas pré-clínicas de moléculas obtidas de Mangifera indica e de Valeriana glechomifolia. Mangiferina, isolada de M. indica, estimulou a proliferação celular e induziu um aumento significativo na secreção do fator de crescimento do nervo e do fator de necrose tumoral em células de glioblastoma humano U138-MG in vitro. Uma injeção sistêmica de mangiferina melhorou a consolidação da memória de longa duração (LTM) de reconhecimento de objetos (RO) e prejudicou a retenção da memória aversiva no teste da esquiva inibitória (EI) em ratos. A melhora da LTM no RO promovida pela administração sistêmica de mangiferina também foi observada com a administração intrahipocampal. Já o prejuízo da memória no teste da EI observado sistemicamente não ocorreu com a infusão no hipocampo ou amígdala. Camundongos atáxicos também apresentaram melhora na memória de RO após administração crônica de mangiferina, sem efeito na EI; um extrato comercializado de M. indica não afetou a memória no RO, mas facilitou a memória na EI. Os resultados indicam que mangiferina melhora a LTM no RO com envolvimento do hipocampo por meio de um mecanismo que pode envolver um aumento dos níveis da neurotrofina NGF e da citocina TNF-α. Valepotriatos, isolados de V. glechomifolia, demonstraram inibição da viabilidade de células tumorais U138-MG nas doses de 30 e 100μg/μl; o 8-Br- AMPc, um análogo do AMPc, atenuou à inibição dos valepotriatos na viabilidade celular, sugerindo que os valepotriatos interagem com a rota de sinalização celular do AMPc/PKA na inibição da viabilidade de células cancerosas. A administração sistêmica de valepotriatos, em camundongos 30 minutos antes dos testes, apresentou os seguintes resultados: durante a exploração no campo aberto, a dose 10mg/kg causou redução na locomoção e no comportamento exploratório e diminuição da ansiedade no teste do labirinto em cruz elevado. Não ocorreu diferença entre os tratamentos na memória de EI e na memória RO, exceto no grupo que recebeu 3mg/kg de valepotriatos que apresentou piora na LTM de RO. Os resultados indicam que os valepotriatos causaram atividades ansiolítica e sedativa sem déficits na memória de EI e RO em camundongos tratados com 10mg/kg. As atividades biológicas in vitro e in vivo encontradas nas moléculas estudadas (especialmente mangiferina e valepotriatos) geram interesse de investigações para utilizações terapêuticas na memória e no câncer. / We evaluated the biological activities of molecules obtained from Mangifera indica and Valeriana glechomifolia. Mangiferin, isolated from M. indica, stimulated cell proliferation and induced a significant increase in levels of nerve growth factor and tumor necrosis factor secreted in human glioblastoma cells U138-MG in vitro. A systemic injection of mangiferin improved long term memory (LTM) consolidation of object recognition (NOR) and impaired memory retention in aversive inhibitory avoidance test (IA) in rats. The improvement in NOR memory promoted by systemic administration of mangiferin was also observed with intrahippocampal administration. The memory impairment observed systemically in the IA did not occur with the infusion into the hippocampus or amygdala. Ataxic mice also showed improvement in NOR memory after chronic administration of mangiferin, with no effect on IA; a standardized extract of M. indica had not effect on memory in NOR, but facilitated the memory in IA. The results indicate that mangiferin improvement NOR memory involving the hippocampus through a mechanism that may involve increased levels of neurotrophins and cytokines. Valepotriates isolated from V. glechomifolia showed inhibition of the viability of U138-MG tumor cells at doses of 30 and 100μg/μl; 8-BrcAMP, an analogue of cAMP, reversed the inhibition of valepotriates on cell viability, suggesting that valepotriates interact with the cAMP/PKA signaling route in the inhibition of the viability of cancer cells. Systemic administration of valepotriates in mice, 30 minutes before tests, showed the following results: during the open-field, the dose of 10mg/kg caused a reduction in locomotion and exploratory behavior and decreased anxiety in the test of elevated plus maze. There was no difference between treatments in IA or NOR memories, except from the group receiving valepotriates at 3mg/kg, which worsened in the NOR. The results indicated that valepotriates at 10mg/kg caused anxiolytic and sedative activities without inducing memory deficits in IA and NOR. The biological activities in vitro and in vivo found with the studied molecules (notable mangiferin and valepotriates) support further research for potential therapeutic uses in cancer and in memory.

The vivid memory of an emotional event, as well as memory for incidental details associated with the arousing event, has been referred to collectively as a “flashbulb memory”. An important aspect of flashbulb memory in people is that an emotional event enhances memory of contextual details, such as the weather, or clothes one was wearing at the time of the event. Therefore, an emotional event not only produces a detailed memory of the event, itself, but also enhances memory for contextual details that would otherwise not be remembered. The first goal of this work is to describe the development of my animal model of flashbulb memory, including a discussion of the importance of the timing between an emotional event and incidental, contextual cues. The second goal is to address the time-dependent neuroendocrine processes involved in stress-induced memory enhancement in rats. The involvement of brain structures, namely the hippocampus and amygdala, and hormones, including corticosterone and epinephrine, that interact to produce a composite memory of the contextual cues occurring in close temporal proximity to an emotional event are discussed. The results of Experiment 1 validate the animal model of flashbulb memory whereby an emotional event (predator exposure) produced memory for context cues that, under control conditions, would be forgotten. This memory enhancement only occurred when the emotional event was close in temporal proximity to training in the task. Experiment 2 provided evidence that epinephrine administration close in time to training mimicked the context memory formation induced by brief predator exposure, while propranolol, a β-adrenergic antagonist, as well as CPP, an NMDA receptor antagonist, blocked this effect. The results of Experiment 3 revealed that propranolol, CPP, and dexamethasone also blocked the brief predator stress-induced context memory formation. The results of Experiment 4 revealed that cannulated animals infused with aCSF (control) did not show evidence of predator stress-induced memory, therefore methodological issues within this experiment are addressed. Finally, the results of Experiment 5 revealed that adrenalectomy eliminated the predator stress-induced context memory compared to sham operated animals, suggesting that endogenous stress hormones are required for stress-induced context memory formation. Further, adrenalectomized rats supplemented with epinephrine before training did show evidence of context memory enhancement suggesting that epinephrine eliminated the memory impairment produced by adrenalectomy, and was sufficient to enhance memory in the absence of corticosterone. Overall this approach has provided insight into the time-dependent neuroendocrine processes involved in the formation of flashbulb, and potentially traumatic, memories in people.

The neural pathways underlying the symptoms of Post Traumatic Stress Disorder (PTSD) have not been fully elucidated. Intrusive memories, persistent anxiety and other cognitive deficits have been attributed to maladaptive or otherwise aberrant processing in specific brain regions, including the hippocampus, amygdala and prefrontal cortex. Our laboratory has developed an animal model of PTSD which results in the enhancement of memory for a place associated with exposure to a predator, anxiety-like behavior, increased startle and impaired memory in a non-aversive memory task. To better understand how the interaction of the hippocampus and prefrontal cortex contribute to the different symptoms of the disorder, we investigated the transient inactivation of each structure during an intense stressor. Our results show that long-term contextual fear associations involve activity in both the hippocampus and the prefrontal cortex, but only the prefrontal cortex is involved in cued fear memories as well.

Indiana University-Purdue University Indianapolis (IUPUI) / Early life trauma is a risk factor for a number of neuropsychiatric disorders, including schizophrenia (SZ) and depression. Animal models have played a critical role in understanding how early-life trauma may evoke changes in behavior and biomarkers of altered brain function that resemble these neuropsychiatric disorders. However, since SZ is a complex condition with multifactorial etiology, it is difficult to model the breadth of this condition in a single animal model. Considering this, it is necessary to develop rodent models with clearly defined subsets of pathologies observed in the human condition and their developmental trajectory. Episodic memory is among the cognitive deficits observed in SZ. Theta (6-10 Hz), low gamma (30-50 Hz), and high gamma (50-100 Hz) frequencies in the hippocampus (HC) are critical for encoding and retrieval of memory. Also, theta-gamma comodulation, defined as correlated fluctuations in power between these frequencies, may provide a mechanism for coding episodic sequences by coordinating neuronal activity at timescales required for memory encoding and retrieval. Given that patients with SZ have impaired recognition memory, the overall objectives of these experiments were to assess local field potential (LFP) recordings in the theta and gamma range from the dorsal HC during a recognition memory task in an animal model that exhibits a subclass of symptoms that resemble SZ. In Aim 1, LFPs were recorded from the HC to assess theta and gamma power to determine whether rats that were maternally deprived (MD) for 24-hrs on postnatal day (PND 9), had altered theta and high/low gamma power compared to sham rats during novel object recognition (NOR). Brain activity was recorded while animals underwent NOR on PND 70, 74, and 78. In Aim 2, the effects of theta-low gamma comodulation and theta-high gamma comodulation in the HC were assessed during NOR between sham and MD animals. Furthermore, measures of maternal care were taken to assess if high or low licking/grooming behaviors influenced recognition memory. It was hypothesized that MD animals would have impaired recognition memory and lower theta and low/high gamma power during interaction with both objects compared to sham animals. Furthermore, it was hypothesized that sham animals would have higher theta-gamma comodulation during novel object exploration compared to the familiar object, which would be higher than the MD group. Measures of weight, locomotor activity, and thigmotaxis were also assessed. MD animals were impaired on the NOR task and had no change in theta or low/high gamma power or theta-gamma comodulation when interacting with the novel or familiar object during trials where they performed unsuccessfully or successfully. However, higher theta and gamma power and theta-gamma comodulation was observed in sham animals depending on the object they were exploring or whether it was a successful or unsuccessful trial. These data indicate altered functioning of the HC following MD and a dissociation between brain activity and behavior in this group, providing support that early life trauma can induce cognitive and physiological impairments that are long-lasting. In conclusion, these data identify a model of early life stress with a translational potential, given that there are points of contact between human studies and the MD model. Furthermore, these data provide a set of tools that could be used to further explore how these altered neural mechanisms may influence cognition and behavior.

Yes / Rationale: Nicotinic α7 acetylcholine receptors (nAChRs) have been highlighted as a target for cognitive enhancement in schizophrenia. Aim: To investigate whether the deficits induced by sub-chronic phencyclidine (PCP) in reversal learning and novel object recognition could be attenuated by the selective α7 nAChR full agonist, PNU-282987. Methods: Adult female hooded-Lister rats received sub-chronic PCP (2 mg/kg) or vehicle i.p. twice daily for seven days, followed by 7-days washout. In cohort 1, PCP-treated rats then received PNU-282987 (5, 10, 20 mg/kg; s.c.) or vehicle and were tested in the reversal learning task. In cohort 2, PCP-treated rats received PNU-282987 (10 mg/kg; s.c.) or saline for 15 days and were tested in the novel object recognition test on day 1 and on day 15, to test for tolerance. Results: Sub-chronic PCP produced significant deficits in both cognitive tasks (P<0.01-0.001). PNU-282987 attenuated the PCP-induced deficits in reversal learning at 10 mg/kg (P<0.01) and 20 mg/kg (P<0.001), and in novel object recognition at 10 mg/kg on day 1 (P<0.01) and on day 15 (P<0.001). Conclusions: These data show that PNU-282987 has efficacy to reverse PCP-induced deficits in two paradigms of relevance to schizophrenia. Results further suggest that 15 day daily dosing of PNU-282987 (10 mg/kg s.c.) does not cause tolerance in rat. This study suggests that activation of α7 nAChRs, may represent a suitable strategy for improving cognitive deficits of relevance to schizophrenia. / SL McLean was supported by a joint University of Bradford–GSK postgraduate studentship.

Phencyclidine (PCP) is a non-competitive NMDA receptor antagonist that has been shown to induce schizophrenia-like psychotic symptoms that are clinically indistinguishable from schizophrenia in patients. When administered to rodents, PCP produces an array of behaviours that are characteristic of schizophrenia. Schizophrenia is associated with continual and treatment resistant cognitive deficits which are now recognised as a core feature of the disease. The aim of the studies reported in chapter 3 were to establish a set of objects with equal preference in the NOR (novel object recognition) test. Furthermore, the inter-trial-interval (ITI) of the NOR test was investigated in an attempt to elucidate the effects of time and location of the rats during the ITI on the cognitive impairments following sub-chronic PCP treatment. The experiments in chapter 4 were designed to compare the performance of male and female rats in the NOR test following treatment with acute d-amphetamine (d-amph), PCP and sub-chronic PCP treatment. In chapter 5, validation of the cognitive deficits induced by sub-chronic PCP treatment was assessed using carefully selected pharmacological agents. The aim of the studies in chapter 6 was to determine the effects of isolation rearing on cognitive performance in the NOR test following increasing ITIs. Additionally, the sensitivity of isolation reared rats compared to social controls following acute administration of PCP and d-amph was assessed using the NOR test. Studies in chapter 8 utilised the 16-holeboard maze to determine the effects of acute treatment with d-amphetamine, PCP and scopolamine on working memory in the rat. NOR is a visual learning and memory test that measures recognition memory which is impaired in patients with schizophrenia. Studies presented in this thesis demonstrate the importance of careful pilot studies when selecting objects for use in the NOR test. Initial studies in sub-chronic PCP (2 mg/kg for 7 days followed by 7 days drug free) treated female hooded-Lister rats revealed a preference of the rats for the wooden cone object; subsequently this object was eliminated from further NOR experiments. Sub-chronic PCP treated rats were found to be highly susceptible to the disruptive influence of distraction during the short 1 min inter-trial-interval (ITI) in the NOR test. These results are consistent with clinical findings of the effects of distraction on cognition in schizophrenia patients. Following the initial validation experiments, a 1 min ITI in the home cage was selected for all subsequent NOR studies. Further experiments provided evidence to confirm that information presented in the acquisition trial is encoded but not retained in the retention trial of the NOR test by IV PCP-treated rats. Male rats were less sensitive to the recognition memory deficits induced by acute treatment with PCP and d-amphetamine compared with females. Following sub-chronic PCP treatment, both males and females showed object recognition deficits, however, the impairments were more robust in female rats. Female rats were therefore selected for all subsequent experiments. Pharmacological validation was carried out using carefully selected agents which were assessed for their ability to restore the sub-chronic PCP induced cognitive deficit in the object recognition test. It was found that the classical antipsychotic agents haloperidol and fluphenazine, the benzodiazepine anxiolytic chlordiazepoxide and the SSRI antidepressant fluoxetine were ineffective. Further studies showed that the atypical antipsychotic agents, clozapine and risperidone, the analeptic agent modafinil, the nAChR full agonist nicotine, and full agonist and positive allosteric modulator of the ¿7 nAChR (PNU-282987 and PNU120596 respectively) reversed the recognition memory deficit induced by sub-chronic PCP treatment in the NOR test. Isolation rearing of rats at weaning is an environmental stressor that has relevance for modelling the symptomatology and pathology of schizophrenia. Isolates had a significantly increased locomotor activity (LMA) response to a novel environment and enhanced sensitivity to time delay-induced recognition memory deficits, compared with their socially reared counterparts. Isolates were less sensitive to an acute PCP-induced recognition memory deficit but more sensitive to an acute d-amphetamine induced recognition memory deficit in the NOR test compared to social controls. Preliminary results from the 16-holeboard maze experiments reveal that acute administration of the mAChR antagonist scopolamine, d-amphetamine, PCP and sub-chronic PCP treatment reduced working memory scores compared to vehicle treated controls. Taken together, these findings suggest that sub-chronic treatment with PCP induces cognitive deficits in behavioural tests of relevance to cognition associated with schizophrenia. This may allow the detection of novel pharmacotherapies to alleviate these cognitive deficits and exploration of the nature of cognitive disturbances in these patients.

yes / In many species, seasonal changes in day length (photoperiod) have profound effects on physiology and behavior. In humans, these include cognitive function and mood. Here we investigated the effect of photoperiod and high fat diets on cognitive deficits, as measured by novel object recognition, in the photoperiod-sensitive F344 rat, which exhibits marked natural changes in growth, body weight and food intake in response to photoperiod. 32 male juvenile F344 rats were housed in either long or short photoperiod and fed either a high fat or nutrient-matched chow diet. Rats were tested in the novel object recognition test before photoperiod and diet intervention and re-tested 28 days after intervention. In both tests during the acquisition trials there was no significant difference in exploration levels of the left and right objects in the groups. Before intervention, all groups showed a significant increase in exploration of the novel object compared to the familiar object. However, following the photoperiod and diet interventions the retention trial revealed that only rats in the long photoperiod-chow group explored the novel object significantly more than the familiar object, whereas all other groups showed no significant preference. These results suggest that changing rats to short photoperiod impairs their memory regardless of diet. The cognitive performance of rats on long photoperiod-chow remained intact, whereas the high fat diet in the long photoperiod group induced a memory impairment. These findings suggest that rats exposed to long photoperiod have different cognitive responses to rats exposed to short photoperiod and high fat diet.