Background: Adenosine A2a receptors form a mutually inhibitory heteromeric complex with dopamine D2 receptors such that each receptor exhibits lower sensitivity to its agonist after the opposing receptor agonist is bound. This study analyzed the effects of CGS 21680, an adenosine A2A agonist, on nicotine conditioned place preference (CPP) in adolescence using a rodent model of schizophrenia (SZ). Methods: Rats were treated from postnatal day (P) 1 to P21 with saline or the dopamine D2/D3 agonist quinpirole (NQ treatment) and raised to P41. After an initial preference test, rats were conditioned with saline or nicotine (0.6 mg/kg base) from P43 to P51. CGS 21680 (0.03 or 0.09 mg/kg) was given 15 minutes before nicotine was administered. The post-conditioning test was administered on P52. On P53, the nucleus accumbens (NAcc) was analyzed for brain-derived neurotrophic factor (BDNF) and glial cell-lined neurotrophic factor (GDNF). Results: Results revealed that NQ treatment enhanced nicotine CPP, and both doses of CGS 21680 alleviated this enhancement. Nicotine also resulted in a CPP in controls, which was alleviated by both doses of CGS 21680. BDNF closely followed the behavioral results: CGS 21680 alleviated the enhancement in NAcc BDNF in NQ-treated animals, and eliminated the increase in NAcc BDNF produced by nicotine in controls. NQ-treated animals conditioned to nicotine resulted in an increase of NAcc GDNF, but this was eliminated by CGS 21680. Both BDNF and GDNF correlated with CPP performance. Conclusions: Results revealed that an adenosine A2A agonist decreased the rewarding aspects of nicotine and its accompanying neural plasticity changes in a model of SZ.

No description available.

No description available.

Alterações em estruturas específicas do SNC, em particular, no sistema fronto-límbico, assim como a diminuição das células neuronais e gliais parece estar envolvida com a fisiopatologia do Transtorno do Humor Bipolar (THB). A glia exerce um importante papel no SNC, entre os quais, a produção de neurotrofinas, em especial, o Fator de Crescimento Neurotrófico derivado de Células da Glia (GDNF). Um marcado aumento dos níveis séricos de GDNF em pacientes deprimidos (F= 42.31; p=0.004; one-way ANOVA) e maníacos (F= 42.31; p=0.001; one-way ANOVA) foi demonstrado neste estudo, sugerindo um possível envolvimento desta neurotrofina com o THB. Por outro lado, alterações nos fatores neurotróficos afetam os mecanismos de plasticidade sináptica, podendo contribuir para as deficiências cognitivas apresentadas pelos pacientes. Deficiências cognitivas, em especial, as falhas de memória são descritas, as quais influenciam a funcionalidade destes indivíduos, principalmente a nível ocupacional e social. As altas taxas de disfuncionalidade apresentadas pelos pacientes e a falta de padronização dos instrumentos usados nos estudos para avaliar funcionalidade, nos levaram ao desenvolvimento de uma escala. A Escala Breve de Funcionalidade (FAST) é um instrumento de rápida e fácil aplicação desenvolvida para usar em psiquiatria, em especial, paciente com THB. A FAST avalia objetivamente seis áreas específicas da funcionalidade, tais como autonomia, trabalho, cognição, relacionamentos interpessoais, finanças e lazer. A validação da escala foi realizada através de testes psicométricos, tais como: consistência interna (alfa de Cronbach’s igual a 0.909), validade concorrente comparada com a GAF (r=-0.903; p<0.001), test-retest (0.98; p<0.01), validade em detectar diferenças entre episódios agudos (maníacos: 40.44±9.15 e deprimidos 43.21±13.34) e períodos de remissão (18.55±13.19; F=35.43; p<0.001) e análise fatorial. Os resultados obtidos foram muito positivos, tornando o instrumento válido e prontamente disponível para o uso na prática clínica e investigação. Palavras-chave: transtorno do humor bipolar, GDNF, glia, neurotrofinas, funcionalidade, disfuncionalidade, escalas de funcionalidade. / Alterations in specific structures of CNS, in particular, fronto-lymbic system, and a reduction of neurons and glial cells appear to be involved in the pathophysiology of bipolar disorder. Glial cells have an important role in the CNS, for example, the production of neurotrophins, especially, Glial Cell Line-derived Neurotrophic Factor (GDNF). In this study, we showed a marked increased in the serum levels of GDNF in depressive (F= 42.31; p=0.004; one-way ANOVA) and manic bipolar patients (F= 42.31; p=0.001; one-way ANOVA), which suggested that GDNF could be involved in the physiopathology of bipolar disorder. On the other hand, alterations in the neurotrophic factors hinder synaptic plasticity mechanisms, may result in cognitive impairment in bipolar patients. In particular, memory difficulties have been reported here, and these difficulties influence occupational and social functioning in these subjects. High rates of functional impairment showed by bipolar patients and a lack of standardization of the instruments available to assess functioning in the studies motivated us to development the scale. The Functioning Assessment Short test (FAST) is a rapid instrument and easy to apply developed to use in psychiatry, especially, bipolar patients. It assesses six specific domains of functioning, such as autonomy, occupational functioning, cognitive functioning, financial issues and leisure time. The validation of FAST was performed by psychometric tests such as internal consistency (Cronbach’s alpha: 0.909), concurrent validity compared to the GAF (r=-0.903; p<0.001), validity as a discriminative measure to detect the difference between euthymic (18.55; F=23.59; p<0.001) and acute patients (manic: 38.50; depressive: 42.38; mixed: 43.21), factorial analysis and test-retest reliability (0.953; p<0.01). The FAST scale showed strong psychometric properties and it is now available for use in both clinical practice and investigation settings.

Alterações em estruturas específicas do SNC, em particular, no sistema fronto-límbico, assim como a diminuição das células neuronais e gliais parece estar envolvida com a fisiopatologia do Transtorno do Humor Bipolar (THB). A glia exerce um importante papel no SNC, entre os quais, a produção de neurotrofinas, em especial, o Fator de Crescimento Neurotrófico derivado de Células da Glia (GDNF). Um marcado aumento dos níveis séricos de GDNF em pacientes deprimidos (F= 42.31; p=0.004; one-way ANOVA) e maníacos (F= 42.31; p=0.001; one-way ANOVA) foi demonstrado neste estudo, sugerindo um possível envolvimento desta neurotrofina com o THB. Por outro lado, alterações nos fatores neurotróficos afetam os mecanismos de plasticidade sináptica, podendo contribuir para as deficiências cognitivas apresentadas pelos pacientes. Deficiências cognitivas, em especial, as falhas de memória são descritas, as quais influenciam a funcionalidade destes indivíduos, principalmente a nível ocupacional e social. As altas taxas de disfuncionalidade apresentadas pelos pacientes e a falta de padronização dos instrumentos usados nos estudos para avaliar funcionalidade, nos levaram ao desenvolvimento de uma escala. A Escala Breve de Funcionalidade (FAST) é um instrumento de rápida e fácil aplicação desenvolvida para usar em psiquiatria, em especial, paciente com THB. A FAST avalia objetivamente seis áreas específicas da funcionalidade, tais como autonomia, trabalho, cognição, relacionamentos interpessoais, finanças e lazer. A validação da escala foi realizada através de testes psicométricos, tais como: consistência interna (alfa de Cronbach’s igual a 0.909), validade concorrente comparada com a GAF (r=-0.903; p<0.001), test-retest (0.98; p<0.01), validade em detectar diferenças entre episódios agudos (maníacos: 40.44±9.15 e deprimidos 43.21±13.34) e períodos de remissão (18.55±13.19; F=35.43; p<0.001) e análise fatorial. Os resultados obtidos foram muito positivos, tornando o instrumento válido e prontamente disponível para o uso na prática clínica e investigação. Palavras-chave: transtorno do humor bipolar, GDNF, glia, neurotrofinas, funcionalidade, disfuncionalidade, escalas de funcionalidade. / Alterations in specific structures of CNS, in particular, fronto-lymbic system, and a reduction of neurons and glial cells appear to be involved in the pathophysiology of bipolar disorder. Glial cells have an important role in the CNS, for example, the production of neurotrophins, especially, Glial Cell Line-derived Neurotrophic Factor (GDNF). In this study, we showed a marked increased in the serum levels of GDNF in depressive (F= 42.31; p=0.004; one-way ANOVA) and manic bipolar patients (F= 42.31; p=0.001; one-way ANOVA), which suggested that GDNF could be involved in the physiopathology of bipolar disorder. On the other hand, alterations in the neurotrophic factors hinder synaptic plasticity mechanisms, may result in cognitive impairment in bipolar patients. In particular, memory difficulties have been reported here, and these difficulties influence occupational and social functioning in these subjects. High rates of functional impairment showed by bipolar patients and a lack of standardization of the instruments available to assess functioning in the studies motivated us to development the scale. The Functioning Assessment Short test (FAST) is a rapid instrument and easy to apply developed to use in psychiatry, especially, bipolar patients. It assesses six specific domains of functioning, such as autonomy, occupational functioning, cognitive functioning, financial issues and leisure time. The validation of FAST was performed by psychometric tests such as internal consistency (Cronbach’s alpha: 0.909), concurrent validity compared to the GAF (r=-0.903; p<0.001), validity as a discriminative measure to detect the difference between euthymic (18.55; F=23.59; p<0.001) and acute patients (manic: 38.50; depressive: 42.38; mixed: 43.21), factorial analysis and test-retest reliability (0.953; p<0.01). The FAST scale showed strong psychometric properties and it is now available for use in both clinical practice and investigation settings.

Alterações em estruturas específicas do SNC, em particular, no sistema fronto-límbico, assim como a diminuição das células neuronais e gliais parece estar envolvida com a fisiopatologia do Transtorno do Humor Bipolar (THB). A glia exerce um importante papel no SNC, entre os quais, a produção de neurotrofinas, em especial, o Fator de Crescimento Neurotrófico derivado de Células da Glia (GDNF). Um marcado aumento dos níveis séricos de GDNF em pacientes deprimidos (F= 42.31; p=0.004; one-way ANOVA) e maníacos (F= 42.31; p=0.001; one-way ANOVA) foi demonstrado neste estudo, sugerindo um possível envolvimento desta neurotrofina com o THB. Por outro lado, alterações nos fatores neurotróficos afetam os mecanismos de plasticidade sináptica, podendo contribuir para as deficiências cognitivas apresentadas pelos pacientes. Deficiências cognitivas, em especial, as falhas de memória são descritas, as quais influenciam a funcionalidade destes indivíduos, principalmente a nível ocupacional e social. As altas taxas de disfuncionalidade apresentadas pelos pacientes e a falta de padronização dos instrumentos usados nos estudos para avaliar funcionalidade, nos levaram ao desenvolvimento de uma escala. A Escala Breve de Funcionalidade (FAST) é um instrumento de rápida e fácil aplicação desenvolvida para usar em psiquiatria, em especial, paciente com THB. A FAST avalia objetivamente seis áreas específicas da funcionalidade, tais como autonomia, trabalho, cognição, relacionamentos interpessoais, finanças e lazer. A validação da escala foi realizada através de testes psicométricos, tais como: consistência interna (alfa de Cronbach’s igual a 0.909), validade concorrente comparada com a GAF (r=-0.903; p<0.001), test-retest (0.98; p<0.01), validade em detectar diferenças entre episódios agudos (maníacos: 40.44±9.15 e deprimidos 43.21±13.34) e períodos de remissão (18.55±13.19; F=35.43; p<0.001) e análise fatorial. Os resultados obtidos foram muito positivos, tornando o instrumento válido e prontamente disponível para o uso na prática clínica e investigação. Palavras-chave: transtorno do humor bipolar, GDNF, glia, neurotrofinas, funcionalidade, disfuncionalidade, escalas de funcionalidade. / Alterations in specific structures of CNS, in particular, fronto-lymbic system, and a reduction of neurons and glial cells appear to be involved in the pathophysiology of bipolar disorder. Glial cells have an important role in the CNS, for example, the production of neurotrophins, especially, Glial Cell Line-derived Neurotrophic Factor (GDNF). In this study, we showed a marked increased in the serum levels of GDNF in depressive (F= 42.31; p=0.004; one-way ANOVA) and manic bipolar patients (F= 42.31; p=0.001; one-way ANOVA), which suggested that GDNF could be involved in the physiopathology of bipolar disorder. On the other hand, alterations in the neurotrophic factors hinder synaptic plasticity mechanisms, may result in cognitive impairment in bipolar patients. In particular, memory difficulties have been reported here, and these difficulties influence occupational and social functioning in these subjects. High rates of functional impairment showed by bipolar patients and a lack of standardization of the instruments available to assess functioning in the studies motivated us to development the scale. The Functioning Assessment Short test (FAST) is a rapid instrument and easy to apply developed to use in psychiatry, especially, bipolar patients. It assesses six specific domains of functioning, such as autonomy, occupational functioning, cognitive functioning, financial issues and leisure time. The validation of FAST was performed by psychometric tests such as internal consistency (Cronbach’s alpha: 0.909), concurrent validity compared to the GAF (r=-0.903; p<0.001), validity as a discriminative measure to detect the difference between euthymic (18.55; F=23.59; p<0.001) and acute patients (manic: 38.50; depressive: 42.38; mixed: 43.21), factorial analysis and test-retest reliability (0.953; p<0.01). The FAST scale showed strong psychometric properties and it is now available for use in both clinical practice and investigation settings.

Indiana University-Purdue University Indianapolis (IUPUI) / The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) are peptides implicated in the inflammatory response. They are released in increased amounts during inflammation and induce thermal hyperalgesia. Whether these molecules directly affect the sensitivity of primary nociceptive sensory neurons is unknown. This information could provide a link between increased inflammation-induced release of GFLs and their ability to promote inflammatory hyperalgesia. These molecules bind to one of four GFRα receptor subtypes, and this GFL-GFRα complex often translocates to the receptor tyrosine kinase, Ret. The focus of this dissertation was to determine whether GFLs modulate the stimulated-release of calcitonin gene-related peptide (CGRP). Isolated sensory neurons and freshly dissociated spinal cord tissue were used to examine the enhancement in stimulated-release of CGRP, a measure of sensitization. Exposure of isolated sensory neurons to GDNF, neurturin, and artemin, enhanced the capsaicin stimulated-release of immunoreactive CGRP (iCGRP). Sensitization by GFLs occurred in freshly dissociated spinal cord tissue. Persephin, another member of the GFL family, did not enhance stimulated-release of iCGRP. These results demonstrate that specific GFLs are mediators of neuronal sensitivity. The intracellular signaling pathways responsible for this sensitization were also evaluated. Inhibition of the mitogen activated protein kinase (MAPK)/extracellular signal-related kinase 1/2 (Erk 1/2) pathway selectively abolished the enhancement of CGRP release by GDNF. NTN-induced sensitization was abolished by inhibition of the phosphatidylinositol-3-kinase (PI-3K) pathway. Reduction in Ret abolished the GDNF-induced sensitization, but did not fully inhibit NTN or ART-induced sensitization. Inhibition of other cell surface receptors (neural cell adhesion molecule (NCAM), and Integrin β-1) had distinct effects on the sensitization capability of each of the GFLs. Ret and NCAM inhibition in combination abolished ART-induced sensitization. It was necessary to inhibit Ret, NCAM, and Integrin β-1 to prevent the NTN-induced sensitization. These data demonstrate that the GFLs use distinct signaling mechanisms to induce the sensitization of nociceptive sensory neurons. The work presented in this thesis provides the first evidence for these novel and distinct Ret-independent pathways for GFL-induced actions and provides insight into the mechanism of sensory neuronal sensitization in general.

<p>Valproic acid (VPA) is clinically utilized as an anti-convulsant and mood stabilizer, though its mechanism of action has not been fully elucidated.<strong> </strong>Evidence suggests an interaction between VPA and the melatonergic system as VPA up-regulated the melatonin MT₁ receptor subtype in rat C6 glioma cells. To determine if the observed effects can translate to an <em>in vivo </em>model, we investigated the effects of chronic VPA administration in a rat model on the expression of MT₁ and MT₂ receptors in the hippocampus. We also investigated the effect of chronic VPA treatment on the expression of the neurotrophic factors BDNF and GDNF in the rat hippocampus and striatum.</p> <p>(1) Animals were separated into two groups with the experimental group receiving VPA (4 mg/mL) for 17 days, and the control receiving vehicle. The hippocampus was dissected and MT₁, MT₂, BDNF and GDNF mRNA were analyzed with RT-PCR. (2) Animals were separated into three groups with the first group receiving VPA (4 mg/mL), the second receiving VPA (3 mg/mL) for 16 days, and the control receiving vehicle. MT₂ mRNA in the hippocampal subregions were analyzed with in situ hybridization.</p> <p>VPA induced the expression of MT₁ and MT₂ mRNA in the hippocampus in the experimental group compared to the control group. VPA also increased MT₂ mRNA expression in the subregions of the hippocampus. Additionally, BDNF and GDNF mRNA expression were increased in the VPA treatment group.</p> <p>These findings raise the interesting question of whether the diverse clinical effects of VPA involve an interaction with the melatonergic system.</p> / Master of Science (MSc)

Due to the blood-brain barrier, delivery of many drugs to the brain has required intracranial surgery which is prone to complication. Here we show that Dopamine Neuron Stimulating Peptide 11 (DNSP-11), following non-invasive intranasal administration, protects dopaminergic neurons from a lesion model of Parkinson’s disease in the rat. A significant and dose-dependent increase in an index of dopamine turnover (the ratio of DOPAC to dopamine) was observed in the striatum of normal young adult Fischer 344 rats by whole-tissue neurochemistry compared to vehicle administered controls. Among animals challenged with a moderate, unilateral 6-hydroxy-dopamine (6-OHDA) lesion of the substantia nigra, those treated repeatedly with intranasally administered DNSP-11 exhibited greater numbers of tyrosine hydroxylase (TH) positive dopaminergic neuronal cell bodies in the substantia nigra and greater TH+ fiber density in the striatum when compared to animals treated intranasally with vehicle only or a scrambled version of the DNSP-11 sequence. Lesioned animals that received intranasal DNSP-11 treatment did not exhibit abnormal, apomorphine-induced rotation behavior, contrasted with animals that received only vehicle or scrambled peptide that did exhibit significantly greater rotation behavior. In addition, the endogenous expression of DNSP-11 from the pro-region of GDNF was investigated by immunohistochemistry with a custom, polyclonal antibody. Signal from the DNSP-11 antibody was found to be differentially localized from the mature GDNF protein both spatially and temporally. While DNSP-11-like immunoreactivity extensively colocalizes with GDNF immunoreactivity at post-natal day 10, the day of maximal GDNF expression, DNSP-11-like signal was found to be present in the 3 month old rat brain with signal in the substantia nigra, ventral thalamic nucleus, dentate gyrus of the hippocampus, with the strongest signal observed in the locus ceruleus where GDNF is not expressed. Results from immunoprecipitation of brain homogenate were not consistent with the synthetic, amidated 11 amino-acid rat DNSP-11 sequence. However, binding patterns in the literature of NPY, the only homologous sequence present in the CNS, do not recapitulate the immunoreactive patterns observed for the DNSP-11 signal. This study provides evidence for a potential easy-to-administer intranasal therapeutic using the DNSP-11 peptide for protection from a 6-OHDA lesion rat model of Parkinson’s disease.

In this study, the origin and development of the intrinsic innervation in the foetal mouse lung is described and experimental evidence is provided to support the involvement of glial cell line-derived neurotrophic factor (GDNF) in the guidance of nerves and neuronal precursors in the developing lung. Antibodies were used to stain for neuronal precursors, neurones, nerve fibres, primordial epithelium and smooth muscle. These structures were revealed in whole mounts of foetal mouse lungs by immunofluorescence and confocal microscopy, and their spatial and temporal distribution was mapped from the onset of lung development and through the pseudoglandular period. The results showed that neuronal precursors, positive for neural crest cell markers, were present in the vagal tract of the foregut at embryonic day 10 (E10), the time of the evagination of the lung buds. These neural crest-derived cells (NCC) migrated into the lung at E11, along nerve processes directed from the vagus to the smooth musclecovered trachea and emerging lobar bronchi. During E11-E14, a network of nerves and ganglia became established along the dorsal trachea, and large ganglia formed a plexus at the ventral hilum. Nerve trunks issued from these ganglia, travelled along the smooth muscle-covered bronchi, providing a pathway for migrating NCC. To investigate the role of GDNF in the innervation of the lung, an in vitro model of left lung lobes was established. Lung growth and tubule branching was comparable to that in vivo, and neural tissue and smooth muscle continued to grow and thrive. A significant increase in nerve growth occurred when explants were cultured with GDNF compared to controls. Nerves extended, and NCC migrated towards GDNF-impregnated beads suggesting that GDNF may be the molecule guiding nerve fibres and NCC in the lung. The migrating NCC were negative for GDNF-family receptor α1 (GFRα1) during their migration into the lung while the nerves were positive. Since GDNF needs to be associated with its binding receptor, GFRα1, for cellular signalling, GDNF may induce the migration of the NCC if they migrate along the GFRα1-positive nerve fibres. It is concluded that neural tissue and smooth muscle become integral components of the lung shortly after the onset of lung development. The results show that the migration of neural crest-derived cells into the lung and the establishment of the innervation requires coordinated cross-talk between NCC, nerves and smooth muscle throughout development.