RESUMO
Current antipsychotic medications used to treat schizophrenia all target the dopamine D2 receptor. Although these drugs have serious side effects and limited efficacy, no novel molecular targets for schizophrenia treatment have been successfully translated into new medications. To identify novel potential treatment targets for schizophrenia, we searched for previously unknown molecular modulators of acoustic prepulse inhibition (PPI), a schizophrenia endophenotype, in the mouse. We examined six inbred mouse strains that have a range of PPI, and used microarrays to determine which mRNA levels correlated with PPI across these mouse strains. We examined several brain regions involved in PPI and schizophrenia: hippocampus, striatum, and brainstem, found a number of transcripts that showed good correlation with PPI level, and confirmed this with real-time quantitative PCR. We then selected one candidate gene for further study, Pdxdc1 (pyridoxal-dependent decarboxylase domain containing 1), because it is a putative enzyme that could metabolize catecholamine neurotransmitters, and thus might be a feasible target for new medications. We determined that Pdxdc1 mRNA and protein are both strongly expressed in the hippocampus and levels of Pdxdc1 are inversely correlated with PPI across the six mouse strains. Using shRNA packaged in a lentiviral vector, we suppressed Pdxdc1 protein levels in the hippocampus and increased PPI by 70%. Our results suggest that Pdxdc1 may regulate PPI and could be a good target for further investigation as a potential treatment for schizophrenia.
Assuntos
Carboxiliases/farmacologia , Inibição Pré-Pulso/genética , Receptores de Dopamina D2/efeitos dos fármacos , Reflexo de Sobressalto/efeitos dos fármacos , Animais , Encéfalo/metabolismo , Carboxiliases/genética , Corpo Estriado/metabolismo , Hipocampo/metabolismo , Masculino , Camundongos , Inibição Pré-Pulso/efeitos dos fármacos , RNA Mensageiro/análise , RNA Mensageiro/genética , RNA Interferente Pequeno/metabolismo , Receptores de Dopamina D2/metabolismo , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismoRESUMO
OBJECTIVE: To investigate the effects of light therapy on serotonin transporter binding (5-HTT BPND ), an index of 5-HTT levels, in the anterior cingulate and prefrontal cortices (ACC and PFC) during winter in seasonal affective disorder (SAD). 5-HTT BPND fluctuates seasonally to a greater extent in SAD relative to health. We hypothesized that in SAD, 5-HTT BPND would be reduced in the ACC and PFC following light therapy. METHODS: Eleven SAD participants underwent [11 C] DASB positron emission tomography (PET) scans to measure 5-HTT BPND before and after 2 weeks of daily morning light therapy. RESULTS: The primary finding was a main effect of treatment on 5-HTT BPND in the ACC and PFC (repeated-measures manova, F(2,9) = 6.82, P = 0.016). This effect was significant in the ACC (F(1,10) = 15.11 and P = 0.003, magnitude of decrease, 11.94%) and PFC (F(1,10) = 8.33, P = 0.016, magnitude of decrease, 9.13%). 5-HTT BPND also decreased in other regions assayed following light therapy (repeated-measures manova, F(4,7) = 8.54, P = 0.028) including the hippocampus, ventral striatum, dorsal putamen, thalamus and midbrain (F(1,10) = 8.02-36.94, P < 0.0001-0.018; magnitude -8.83% to -16.74%). CONCLUSIONS: These results demonstrate that light therapy reaches an important therapeutic target in the treatment of SAD and provide a basis for improvement of this treatment via application of [11 C]DASB PET.
Assuntos
Fototerapia/métodos , Transtorno Afetivo Sazonal/terapia , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Adulto , Feminino , Giro do Cíngulo/metabolismo , Humanos , Masculino , Tomografia por Emissão de Pósitrons/métodos , Córtex Pré-Frontal/metabolismo , Ligação Proteica , Transtorno Afetivo Sazonal/metabolismo , Resultado do TratamentoRESUMO
Chronic ventromedial prefrontal cortex (vmPFC) deep brain stimulation (DBS) improves depressive-like behaviour in rats via serotonergic and neurotrophic-related mechanisms. We hypothesise that, in addition to these substrates, DBS-induced increases in hippocampal neurogenesis may also be involved. Our results show that stress-induced behavioural deficits in the sucrose preference test, forced swim test, novelty-suppressed feeding test (NSFT) and elevated plus maze were countered by chronic vmPFC DBS. In addition, stressed rats receiving stimulation had significant increases in hippocampal neurogenesis, PFC and hippocampal brain-derived neurotrophic factor levels. To block neurogenesis, stressed animals given DBS were injected with temozolomide. Such treatment reversed the anxiolytic-like effect of stimulation in the NSFT without significantly affecting performance in other behavioural tests. Taken together, our findings suggest that neuroplastic changes, including neurogenesis, may be involved in specific anxiolytic effects of DBS without affecting its general antidepressant-like response.
Assuntos
Comportamento Animal/fisiologia , Estimulação Encefálica Profunda , Plasticidade Neuronal/fisiologia , Estresse Psicológico/fisiopatologia , Estresse Psicológico/terapia , Animais , Modelos Animais de Doenças , Masculino , Neurogênese/fisiologia , Ratos , Ratos Endogâmicos F344RESUMO
OBJECTIVE: To investigate the effects of light therapy on serotonin transporter binding (5-HTT BPND ), an index of 5-HTT levels, in the anterior cingulate and prefrontal cortices (ACC and PFC) of healthy individuals during the fall and winter. Twenty-five per cent of healthy individuals experience seasonal mood changes that affect functioning. 5-HTT BPND has been found to be higher across multiple brain regions in the fall and winter relative to spring and summer, and elevated 5-HTT BPND may lead to extracellular serotonin loss and low mood. We hypothesized that, during the fall and winter, light therapy would reduce 5-HTT BPND in the ACC and PFC, which sample brain regions involved in mood regulation. METHOD: In a single-blind, placebo-controlled, counterbalanced, crossover design, [(11) C]DASB positron emission tomography was used measure 5-HTT BPND following light therapy and placebo conditions during fall and winter. RESULTS: In winter, light therapy significantly decreased 5-HTT BPND by 12% in the ACC relative to placebo (F1,9 = 18.04, P = 0.002). In the fall, no significant change in 5-HTT BPND was found in any region across conditions. CONCLUSION: These results identify, for the first time, a central biomarker associated with the intervention of light therapy in humans which may be applied to further develop this treatment for prevention of seasonal depression.
Assuntos
Giro do Cíngulo/metabolismo , Fototerapia/métodos , Tomografia por Emissão de Pósitrons/métodos , Córtex Pré-Frontal/metabolismo , Estações do Ano , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Adulto , Biomarcadores/metabolismo , Estudos Cross-Over , Feminino , Humanos , Masculino , Fototerapia/instrumentação , Ligação Proteica , Método Simples-Cego , Adulto JovemRESUMO
Pramipexole is a clinically important dopamine receptor agonist with reported selectivity for dopamine D3 receptors over other dopaminergic and non-dopaminergic sites. Many of its behavioural effects are therefore attributed to D3 receptor activity. Here we relate pramipexole's ex vivo D2 and D3 receptor binding (measured using [(3)H]-(+)-PHNO binding experiments) to its effects on locomotion and operant responding for primary and conditioned reinforcers. We show that pramipexole has inhibitory behavioural effects on all three behaviours at doses that occupy D3 but not D2 receptor. However, these effects are 1) not inhibited by a D3 selective dose of the antagonist SB-277011-A, and 2) present in D3 receptor knockout mice. These results suggest that a pharmacological mechanism other than D3 receptor activity must be responsible for these behavioural effects. Finally, our receptor binding results also suggest that these behavioural effects are independent of D2 receptor activity. However, firmer conclusions regarding D2 involvement would be aided by further pharmacological or receptor knock-out experiments. The implications of our findings for the understanding of pramipexole's behavioural and clinical effects are discussed.
Assuntos
Benzotiazóis/farmacologia , Condicionamento Operante/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Locomoção/efeitos dos fármacos , Receptores de Dopamina D3/deficiência , Reforço Psicológico , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Condicionamento Operante/fisiologia , Relação Dose-Resposta a Droga , Locomoção/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nitrilas/farmacologia , Oxazinas/farmacocinética , Pramipexol , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/genética , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/genética , Tetra-Hidroisoquinolinas/farmacologia , Trítio/farmacocinéticaRESUMO
Neurobiological research supports the characterization of disordered gambling (DG) as a behavioral addiction. Recently, an animal model of gambling behavior was developed (rat gambling task, rGT), expanding the available tools to investigate DG neurobiology. We investigated whether rGT performance and associated risk gene expression in the rat's brain could provide cross-translational understanding of the neuromolecular mechanisms of addiction in DG. We genotyped tagSNPs (single-nucleotide polymorphisms) in 38 addiction-related genes in 400 DG and 345 non-DG subjects. Genes with P<0.1 in the human association analyses were selected to be investigated in the animal arm to determine whether their mRNA expression in rats was associated with the rat's performance on the rGT. In humans, DG was significantly associated with tagSNPs in DRD3 (rs167771) and CAMK2D (rs3815072). Our results suggest that age and gender might moderate the association between CAMK2D and DG. Moderation effects could not be investigated due to sample power. In the animal arm, only the association between rGT performance and Drd3 expression remained significant after Bonferroni correction for 59 brain regions. As male rats were used, gender effects could not be investigated. Our results corroborate previous findings reporting the involvement of DRD3 receptor in addictions. To our knowledge, the use of human genetics, pre-clinical models and gene expression as a cross-translation paradigm has not previously been attempted in the field of addictions. The cross-validation of human findings in animal models is crucial for improving the translation of basic research into clinical treatments, which could accelerate neurobiological and pharmacological investigations in addictions.
Assuntos
Comportamento Aditivo/genética , Jogo de Azar/genética , Adulto , Animais , Comportamento Aditivo/metabolismo , Encéfalo/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Modelos Animais de Doenças , Feminino , Jogo de Azar/metabolismo , Jogos Experimentais , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Receptores de Dopamina D3/genética , Receptores de Dopamina D3/metabolismo , RiscoRESUMO
The GABA(B) receptor (GABA(B)R) agonist baclofen is known to have a beneficial potency in patients who suffer from dystonia, a neurological syndrome characterized by involuntary co-contractions of opposing muscles. The underlying mechanisms of this movement disorder are still unclear. Previous studies in the dt(sz) hamster, an animal model of primary paroxysmal dystonia, revealed alterations of the GABAergic system, including a reduction of striatal GABAergic interneurons and an altered GABA(A) receptor (GABA(A)R) binding in several brain regions. In order to clarify the pathophysiological role of central GABA(B)Rs in the hamster mutant, we performed pharmacological and receptor autoradiographic studies. Systemic administration of the GABA(B)R agonist (R)-baclofen (1.5, 2.5 and 3.5 mg/kg i.p.) produced pronounced antidystonic effects in the dt(sz) hamster. Striatal microinjections of baclofen (0.125, 0.25 and 0.5 microg/0.5 microl) also strongly reduced the severity of dystonia. Single striatal administration of the selective GABA(B)R antagonist CGP 35348 [(3-Aminopropyl)(diethoxymethyl)phosphinic acid, 5 and 10 microg/0.5 microl] did not influence the severity of dystonia, but antagonized the antidystonic effect of baclofen. For receptor autoradiographic studies, [H3]-CGP 54626 ([S-(R*,R*)]-[3-[[1-(3,4-Dichlorophenyl)ethyl]amino]-2-hydroxypropyl](cyclohexylmethyl)phosphinic acid) binding was determined in dt(sz) hamsters in comparison to non-dystonic control hamsters. [H3]-CGP 54626 binding was not altered in motor areas but in some limbic structures of dt(sz) hamsters. In view of the absence of striatal changes in GABA(B) binding, the strong antidystonic effect of baclofen after its striatal microinjection is probably related to a suppression of a pathophysiologically increased synaptic activity.
Assuntos
Baclofeno/farmacologia , Corpo Estriado/metabolismo , Distonia/metabolismo , Receptores de GABA-B/fisiologia , Animais , Animais Geneticamente Modificados , Autorradiografia , Baclofeno/uso terapêutico , Corpo Estriado/fisiopatologia , Cricetinae , Distonia/tratamento farmacológico , Distonia/fisiopatologia , Agonistas dos Receptores de GABA-B , Antagonistas de Receptores de GABA-B , Microinjeções , Compostos Organofosforados/administração & dosagem , Compostos Organofosforados/farmacologiaRESUMO
AIMS: Hyperthermia is a characteristic functional effect of sleep deprivation (SD). We hypothesize here that prostaglandin E2 (PGE2) could be involved in hyperthermia induced by sleep deprivation. MAIN METHODS: To address this issue we examined the effects of a selective cyclo-oxygenase-2 inhibitor (COX-2) agent on hyperthermia induced by SD in rats. We also investigated binding to PGE2 receptors in hypothalamic brain areas of sleep-deprived rats using in vitro autoradiography. Male Wistar rats were deprived of sleep for 96 h using the platform technique. Sleep deprived and control groups received saline or Celecoxib (20, 30 and 40 mg/kg; p.o.) daily during the SD period. Colonic temperature was measured daily. KEY FINDINGS: Results indicated that core temperature of sleep-deprived rats that receiving saline increased from the first to the fourth day of SD compared to baseline and to the respective control group. However, the hyperthermia induced by SD was not blocked by COX-2 inhibitor at any dose. [(3)H]PGE2 binding did not differ significantly among the groups in any of a number of hypothalamic areas examined. SIGNIFICANCE: Although SD rats showed no response to the COX-2 inhibitor and no alterations in [(3)H]PGE2 binding, the possibility remains that other prostaglandin system and/or receptor subtypes may be altered by SD.
Assuntos
Febre , Prostaglandinas/metabolismo , Privação do Sono , Animais , Autorradiografia , Temperatura Corporal/efeitos dos fármacos , Celecoxib , Inibidores de Ciclo-Oxigenase/metabolismo , Dinoprostona/metabolismo , Febre/etiologia , Febre/fisiopatologia , Masculino , Prostaglandinas/farmacologia , Pirazóis/farmacologia , Ratos , Ratos Wistar , Privação do Sono/complicações , Privação do Sono/fisiopatologia , Sulfonamidas/farmacologiaRESUMO
We have recently reported that food spillage increases during sleep deprivation in rats, which may lead to an overestimation of food intake in this condition. The objective of this study was to verify whether sleep deprivation induces an increase in gnawing behavior that could account for increased food spillage and apparent increase in food intake. We introduced wood blocks as objects for gnawing and determined the effects of their availability on food consumption and food spillage during sleep deprivation. Wood block availability reduced the amount of food removed from hoppers and decreased the amount of food spilled. However, weight loss still occurred during the sleep deprivation period, especially in the first 24 h, and it was related to a reduction in food intake. Sleep deprivation causes an increase in stereotyped gnawing behavior which largely accounts for increased food spillage observed during deprivation. Specifically, the observed increase in food removed from feeders seems to be due to an increase in gnawing and not to increased hunger. However, even when appropriately corrected for spillage, food intake decreased in the first 24 h of sleep deprivation, which accounted for most of the body weight loss seen during the 96 h of sleep deprivation.
Assuntos
Ingestão de Alimentos/psicologia , Comportamento Alimentar/psicologia , Hiperfagia/fisiopatologia , Mastigação , Privação do Sono/fisiopatologia , Comportamento Estereotipado/fisiologia , Análise de Variância , Animais , Nível de Alerta/fisiologia , Deslocamento Psicológico , Ingestão de Alimentos/fisiologia , Comportamento Alimentar/fisiologia , Hiperfagia/etiologia , Hiperfagia/psicologia , Masculino , Ratos , Privação do Sono/complicações , Privação do Sono/psicologia , Estatísticas não Paramétricas , Redução de Peso/fisiologiaRESUMO
We have previously described a black-hooded mutant rat (BH.7A/Ztm-ci3/ci3) that displays abnormal lateralized circling behavior, but normal auditory and vestibular functions. Neurochemical determination of dopamine and dopamine metabolite levels in striatum, nucleus accumbens and substantia nigra showed that ci3 rats have a significant asymmetry in striatal dopamine in that dopamine levels were significantly lower in the hemisphere contralateral to the preferred direction of turning. Consistent with this finding, immunohistological examination of dopaminergic neurons in substantia nigra and ventral tegmental area yielded a significant laterality in the medial part of substantia nigra pars compacta with a lower density of tyrosine hydroxylase-positive neurons in the contralateral hemisphere of mutant circling rats, while no laterality was seen in unaffected rats of the background strain. In the present study, quantitative autoradiography was used to examine the binding of [(3)H]SCH 23390, [(3)H]raclopride and [(3)H]7-OH-DPAT (7-hydroxy-N,N-di-n-propyl-2-aminotetralin) to dopamine D1, D2, and D3 receptors, respectively, in various brain regions of ci3 rats and unaffected rats of the background strain (BH.7A(LEW)/Won). No significant differences between circling rats and controls were obtained for D1 and D2 receptor binding in any region, but mutant rats differed from controls in dopamine D3 binding in several regions. A significant decrease in D3 binding was seen in the shell of the nucleus accumbens, the islands of Calleja, and the subependymal zone of ci3 mutant rats. Furthermore, a significant laterality in D3 binding was determined in ci3 rats in that binding was lower in the contralateral hemisphere in the shell of the nucleus accumbens and the islands of Calleja. Our data indicate that alterations of dopamine D3 receptors may be involved in the behavioral phenotype of the ci3 rat, thus substantiating the findings from a recent genetic linkage analysis that indicated the D3 receptor gene as a candidate gene in this rat mutant.
Assuntos
Química Encefálica/genética , Dopamina/metabolismo , Atividade Motora/genética , Transtornos dos Movimentos/genética , Transtornos dos Movimentos/metabolismo , Receptores de Dopamina D3/genética , Animais , Ligação Competitiva/fisiologia , Agonistas de Dopamina/metabolismo , Antagonistas de Dopamina/metabolismo , Feminino , Lateralidade Funcional/genética , Predisposição Genética para Doença/genética , Ínsulas Olfatórias/metabolismo , Ínsulas Olfatórias/fisiopatologia , Masculino , Transtornos dos Movimentos/fisiopatologia , Mutação/genética , Vias Neurais/metabolismo , Vias Neurais/fisiopatologia , Núcleo Accumbens/metabolismo , Núcleo Accumbens/fisiopatologia , Ensaio Radioligante , Ratos , Ratos Mutantes , Substância Negra/metabolismo , Substância Negra/fisiopatologiaRESUMO
In patients with paroxysmal non-kinesigenic dyskinesias, episodes of dystonia can be provoked by stress and also by methylxanthines (e.g. caffeine), which inhibit adenosine A(1)/A(2A) receptors. In the dt(sz) mutant hamster, a model of this movement disorder, adenosine A(1) receptor antagonists were previously found to worsen dystonia, while adenosine A(1) and A(2A) receptor agonists exerted pronounced beneficial effects. Therefore, in the present study, adenosine receptor A(1) and A(2A) binding was determined by autoradiographic analyses in dt(sz) hamsters under basal conditions, i.e. in the absence of a dystonic attack, and in a group of mutant hamsters which exhibited severe stress-induced dystonic attacks prior to kill. In comparison with non-dystonic control hamsters, [(3)H]DPCPX (8-cyclopentyl-1,3-dipropylxanthine) binding to adenosine A(1) receptors and [(3)H]CGS 21680 (2p-(2carboxyethylphen-ethylamino-5'-N-ethlycarboxamindoadenosine) binding to adenosine A(2A) receptors were significantly lower throughout the brain of dystonic animals. Under normal resting conditions, mutant hamsters showed significant decreases in adenosine A(1) (-12 to-42%) and in A(2A) (-19 to-34%) receptor binding compared with controls. Stressful stimulation increased adenosine A(1) and A(2A) receptor binding in almost all brain regions in both control and dystonic hamsters. The stress-induced increase was more marked in mutant hamsters, leading to a disappearance of differences in most regions compared with stimulated controls, except the striatum. In view of previous findings of striking beneficial effects of adenosine A(1) and A(2A) receptor agonists and of striatal dysfunctions in the dt(sz) mutant, the reduced adenosine receptor binding may be an important factor in the pathogenesis of paroxysmal dystonia.
Assuntos
Distúrbios Distônicos/metabolismo , Receptores Purinérgicos P1/metabolismo , Animais , Animais Geneticamente Modificados , Autorradiografia/métodos , Cricetinae , Modelos Animais de Doenças , Distúrbios Distônicos/genética , Ligação Proteica/efeitos dos fármacos , Antagonistas de Receptores Purinérgicos P1 , Trítio/farmacocinética , Xantinas/farmacocinéticaRESUMO
The dtsz mutant hamster represents a model of primary paroxysmal dystonia, in which dystonic episodes occur in response to stress. Previous examinations demonstrated striatal dysfunctions in dtsz hamsters. In the present study, in situ hybridization was used to examine preproenkephalin and prodynorphin expression as potential indices of imbalances between the striatopallidal and striatonigral pathways. Brain analyses were performed in dtsz hamsters under basal conditions, i.e., in the absence of dystonia, as well as mutant hamsters that exhibited severe stress-induced dystonic attacks immediately prior to sacrifice. In the striatum the basal expression of prodynorphin tended to be higher, while that of preproenkephalin tended to be lower in mutant hamsters in comparison to non-dystonic control hamsters. Significant basal changes were restricted to higher levels of prodynorphin in the ventrolateral striatum and lower prodynorphin and preproenkephalin mRNA expression in the hippocampus and/or in subregions of the hypothalamus. After stressful stimulation, the neuropeptides increased in several regions in both animals groups. In comparison to stimulated control hamsters, a significantly lower prodynorphin expression was found in several limbic areas of stimulated mutant hamsters during the manifestation of dystonia, while preproenkephalin mRNA was significantly lower in the anterior and dorsal striatal subregions and in nucleus accumbens. Since changes in the expression of these opioid peptides have been suggested to be related to abnormal dopaminergic activity, the present findings may reflect disturbances in striatal dopaminergic systems, and also in limbic structures in the dtsz mutant, particularly during the expression of dystonia.
Assuntos
Gânglios da Base/metabolismo , Distonia/genética , Encefalinas/genética , Precursores de Proteínas/genética , RNA Mensageiro/metabolismo , Análise de Variância , Animais , Gânglios da Base/fisiopatologia , Encéfalo/metabolismo , Coreia/genética , Coreia/fisiopatologia , Cricetinae , Modelos Animais de Doenças , Distonia/fisiopatologia , Encefalinas/metabolismo , Regulação da Expressão Gênica , Hibridização In Situ , Mutação , Precursores de Proteínas/metabolismo , Valores de Referência , Distribuição TecidualRESUMO
Behavioral sensitization to drugs of abuse seems to involve learning processes. In mice, ethanol-induced locomotor sensitization is potentiated by repeated pairing of ethanol (EtOH) injections and the testing chamber. The present study aimed to test: (1). the association between the performance in a contextual conditioning task and the development of behavioral sensitization to EtOH in mice; (2). whether EtOH sensitization would be expressed in a different testing environment. Male albino Swiss mice (n=72) were initially submitted to a contextual fear conditioning task. After 2 weeks without manipulation, the animals received daily i.p. injections of 2.2 g/kg EtOH (n=52) or saline (n=20), for 21 days. They were tested weekly for locomotor activity in activity cages. After 1 week of withdrawal, all mice received 2.2 g/kg EtOH and had their locomotor activity recorded in an open-field. According to the locomotor behavior displayed along the 21-day treatment, EtOH-treated mice were classified as sensitized (n=15) or non-sensitized (n=15). When these subgroups and saline-treated mice were compared for the freezing response in the conditioning test, sensitized mice displayed a greater freezing time than non-sensitized mice. When challenged with EtOH in the open-field, none of the EtOH-treated subgroups expressed behavioral sensitization. These results suggest that the development of EtOH sensitization seems to be positively associated with contextual learning, and further confirms that the expression of sensitization is highly dependent on contextual cues.
Assuntos
Depressores do Sistema Nervoso Central/farmacologia , Condicionamento Psicológico/efeitos dos fármacos , Etanol/farmacologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal , Tolerância a Medicamentos , Estimulação Elétrica , Medo/efeitos dos fármacos , Medo/psicologia , Masculino , Camundongos , Atividade Motora/efeitos dos fármacosRESUMO
Previous pharmacological studies suggested that glutamatergic overactivity contributes to manifestation of dystonic attacks in mutant hamsters (dt(sz)), a model of idiopathic paroxysmal dystonia in which episodes of dystonia occur in response to stress. In the present study, [(3)H]AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate) receptor binding was determined by autoradiographic analyses in 41 brain (sub)regions of dt(sz) hamsters under basal conditions, i.e., in the absence of dystonia, and in a group of mutant hamsters that exhibited severe stress-induced dystonic attacks immediately prior to sacrifice. In comparison to nondystonic control hamsters the basal [(3)H]AMPA binding was significantly higher in the ventromedial and ventrolateral caudate putamen, the anterior cingulate cortex, the hippocampus, and the lateral septum of dystonic brains. During dystonic attacks the [(3)H]AMPA binding was significantly lower in the dorsomedial, dorsolateral, and posterior caudate putamen; the ventromedial thalamus; and the frontal cortex of mutant hamsters compared with control animals that were exposed to the same external stimulation. The basal increase in AMPA receptor density within limbic structures may contribute to the susceptibility of stress-inducible dystonic episodes in mutant hamsters. Since AMPA receptor activation is known to cause a fast reduction of the affinity and an internalization of postsynaptic AMPA receptors, the latter finding could reflect a glutamatergic overactivity within the striato-thalamo-cortical circuit during the expression of dystonia, which is in line with previous neurochemical and pharmacological data in dt(sz) hamsters.
Assuntos
Ligação Competitiva , Distonia/fisiopatologia , Receptores de AMPA/metabolismo , Animais , Autorradiografia , Ligação Competitiva/genética , Encéfalo/metabolismo , Encéfalo/patologia , Cricetinae , Modelos Animais de Doenças , Distonia/genética , Distonia/patologia , Mutação , Valores de Referência , Estresse Fisiológico/fisiopatologia , Distribuição Tecidual , Trítio , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/farmacocinéticaRESUMO
Although the pathophysiology of primary dystonias is currently unknown, it is thought to involve changes in the basal ganglia-thalamus-cortex circuit, particularly activity imbalances between direct and indirect striatal pathways. Substance P, a member of the tachykinin family of neuropeptides, is a major component in the direct pathway from striatum to basal ganglia output nuclei. In the present study quantitative autoradiography was used to examine changes in neurokinin-1 (NK-1) and neurokinin-3 (NK-3) receptors in mutant dystonic hamsters (dt(sz)), a well characterized model of paroxysmal dystonia. NK-1 receptors were labeled in 10 dystonic brains and 10 age-matched controls with 3 nM [(3)H]-[Sar(9), Met(O(2))(11)]-SP. NK-3 binding sites were labeled in adjacent sections with 2.5 nM [(3)H]senktide. NK-1 binding was found to be unaltered in 27 brain areas examined. In contrast, NK-3 binding was significantly reduced in layers 4 and 5 of the prefrontal (-46%), anterior cingulate (-42%) and parietal (-45%) cortices, ventromedial thalamus (-42%) and substantia nigra pars compacta (-36%) in dystonic brains compared to controls. The latter effects may be particularly relevant in view of evidence that activation of NK-3 receptors on dopaminergic neurons in the substantia nigra pars compacta can increase nigrostriatal dopaminergic activity. Since previous studies indicated that a reduced basal ganglia output in mutant hamsters is based on an overactivity of the direct pathway which also innervates substantia nigra pars compacta neurons, the decreased NK-3 binding could be related to a receptor down-regulation. The present finding of decreased NK-3 receptor density in the substantia nigra pars compacta, thalamic and cortical areas substantiates the hypothesis that disturbances of the basal ganglia-thalamus-cortex circuit play a critical role in the pathogenesis of paroxysmal dystonia.
Assuntos
Encéfalo/metabolismo , Distonia/metabolismo , Receptores da Neurocinina-1/metabolismo , Receptores da Neurocinina-3/metabolismo , Animais , Gânglios da Base/metabolismo , Córtex Cerebral/metabolismo , Cricetinae , Distonia/genética , Feminino , Masculino , Valores de Referência , Tálamo/metabolismoRESUMO
Hyperhomocysteinemia has been associated with pathological and stressful conditions and is a risk factor for cardiovascular disease. Since sleep deprivation is a stressful condition that is associated with disruption of various physiological processes, we investigated whether it would also be associated with increases in plasma homocysteine levels. Further, since hyperhomocysteinemia may promote oxidative stress, and we had previously found evidence of oxidative stress in brain following sleep deprivation, we also searched for evidence of systemic oxidative stress by measuring glutathione and thiobarbituric acid reactive substance levels. Rats were sleep deprived for 96 h using the platform technique. A group was killed after sleep deprivation and another two groups were allowed to undergo sleep recovery for 24 or 48 h. Contrary to expectation, plasma homocysteine was reduced in sleep-deprived rats as compared with the control group and did not revert to normal levels after 24 or 48 h of sleep recovery. A trend was observed towards decreased glutathione and increased thiobarbituric acid reactive substance levels in sleep-deprived rats. It is possible that the observed decreases in homocysteine levels may represent a self-correcting response to depleted glutathione in sleep-deprived animals, which would contribute to the attenuation of the deleterious effects of sleep deprivation.
Assuntos
Homocisteína/sangue , Privação do Sono , Animais , Cromatografia Líquida de Alta Pressão , Glutationa/sangue , Masculino , Estresse Oxidativo , Ratos , Ratos Wistar , Substâncias Reativas com Ácido Tiobarbitúrico/análiseRESUMO
RATIONALE: The number of receptors occupied by a given drug is a central construct in understanding drug action in the brain. Two techniques have been commonly used to measure drug receptor occupancy. In one method, the drug and the radioligand used to measure occupancy compete in vivo while in the other method, the drug is injected into the living animal, the animal killed and the radioligand competes for available receptors ex vivo. While these methods are often used interchangeably, there has been no systematic comparison of their sensitivities and consistency. OBJECTIVES: In this study, we performed a systematic within-animal comparison of drug-induced receptor occupancy as measured by the in vivo vs the ex vivo methods. METHODS: We examined the occupancy of dopamine Do receptors by different doses of the drug raclopride using the in vivo and ex vivo autoradiographic methods in the same rat with 11C-raclopride and 3H-raclopride as radioligands, respectively. RESULTS: The in vivo method showed a significantly greater sensitivity and internal consistency while the ex vivo method was less sensitive, and increasingly so as a function of longer incubation times. The lack of sensitivity was accounted for by the unidirectional dissociation of the drug from the receptors in the incubation medium. CONCLUSIONS: Our data suggest that these two methods are not interchangeable; the ex vivo method is much less sensitive, lacks internal consistency and hence is best avoided.
Assuntos
Ensaio Radioligante/métodos , Animais , Ligação Competitiva/efeitos dos fármacos , Ligação Competitiva/fisiologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Antagonistas de Dopamina/administração & dosagem , Antagonistas de Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Injeções Subcutâneas , Masculino , Racloprida/administração & dosagem , Racloprida/metabolismo , Racloprida/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
Tissue engineering can lead to novel controlled release devices and controlled release strategies (e.g., of growth factors) can enhance the performance of tissue engineered constructs. There are however a number of technical challenges that must be overcome before these goals can be realized. The apparently 'simple' challenge of implanting the device (e.g., capsules) in the optimal site must be met. In addition, adequate nutrient supply to the capsules is required to maintain cell viability. To illustrate this problem we describe a guide and delivery cannula technique to provide reliable and reproducible delivery of up to 120 PC12 cell containing capsules into the caudate putamen (CPu). Microencapsulation of mammalian cells is potentially a powerful means of delivering therapeutically important molecules such as insulin. It can also have numerous applications as a platform for gene therapy. However, realizing this potential has been more difficult than first anticipated.
Assuntos
Encéfalo/fisiologia , Transplante de Células/métodos , Preparações de Ação Retardada/química , Dopamina/biossíntese , Animais , Composição de Medicamentos , Imuno-Histoquímica , Masculino , Células PC12 , Ratos , Ratos Sprague-Dawley , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Recent findings from this laboratory revealed that sleep deprivation reduces total glutathione (GSH) levels in hypothalamus, suggesting an increased vulnerability to oxidative damage. Since melatonin has been shown to prevent oxidative damage in other experimental situations, the present study tested the effects of exogenous melatonin on sleep deprivation-induced GSH decreases. Rats were deprived of sleep for 96 h on small platforms, and melatonin (10 mg/kg body weight; i.p.) or vehicle was given twice a day. Hypothalamic GSH levels were significantly reduced in sleep-deprived groups, irrespective of melatonin treatment. Indeed, unexpectedly, melatonin treatment resulted in lower hypothalamic GSH levels in all groups, including cage controls. These results confirm that sleep deprivation reduces hypothalamic GSH and further indicate that melatonin treatment not only is ineffective in reversing this effect but may actually potentiate it.