RESUMEN
BACKGROUND AIMS: Maternal undernutrition programs metabolic adaptations which are ultimately detrimental to adult. L-tryptophan supplementation was given to manipulate the long-term sequelae of early-life programming by undernutrition and explore whether cultured cells retain circadian clock dysregulation. METHODS: Male rat pups from mothers fed on low protein (8%, LP) or control (18%, CP) diet were given, one hour before light off, an oral bolus of L-tryptophan (125 mg/kg) between Day-12 and Day-21 of age. Body weight, food intake, blood glucose along with the capacity of colonization of primary cells from biopsies were measured during the young (45-55 days) and adult (110-130 days) phases. Circadian clock oscillations were re-induced by a serum shock over 30 hours on near-confluent cell monolayers to follow PERIOD1 and CLOCK proteins by Fluorescent Linked ImmunoSorbent Assay (FLISA) and period1 and bmal1 mRNA by RT-PCR. Cell survival in amino acid-free conditions were used to measure circadian expression of MAP-LC3B, MAP-LC3B-FP and Survivin. RESULTS: Tryptophan supplementation did not alter body weight gain nor feeding pattern. By three-way ANOVA of blood glucose, sampling time was found significant during all phases. A significant interaction between daily bolus (Tryptophan, saline) and diets (LP, CP) were found during young (pâ=â0.0291) and adult (pâ=â0.0285) phases. In adult phase, the capacity of colonization at seeding of primary cells was twice lower for LP rats. By three-way ANOVA of PERIOD1 perinuclear/nuclear immunoreactivity during young phase, we found a significant effect of diets (pâ=â0.049), daily bolus (p<0.0001) and synchronizer hours (pâ=â0.0002). All factors were significantly interacting (pâ=â0.0148). MAP-LC3B, MAP-LC3B-FP and Survivin were altered according to diets in young phase. CONCLUSIONS: Sequelae of early-life undernutrition and the effects of L-tryptophan supplementation can be monitored non-invasively by circadian sampling of blood D-glucose and on the expression of PERIOD1 protein in established primary cell lines.
Asunto(s)
Relojes Circadianos/efectos de los fármacos , Dieta con Restricción de Proteínas , Conducta Alimentaria/efectos de los fármacos , Exposición Materna , Triptófano/farmacología , Envejecimiento/sangre , Envejecimiento/metabolismo , Animales , Animales Recién Nacidos , Autofagia/efectos de los fármacos , Biomarcadores/metabolismo , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Adhesión Celular/efectos de los fármacos , Línea Celular , Ensayo de Unidades Formadoras de Colonias , Metabolismo Energético/efectos de los fármacos , Femenino , Grasa Intraabdominal/anatomía & histología , Grasa Intraabdominal/efectos de los fármacos , Lactancia/efectos de los fármacos , Masculino , Fenotipo , Embarazo , Ratas , Suero/metabolismo , Triptófano Hidroxilasa/metabolismo , Aumento de Peso/efectos de los fármacosRESUMEN
Diverse studies indicate that attention-deficit hyperactivity disorder (ADHD) is associated with alterations in encoding processes, including working or short-term memory. Some ADHD dysfunctional domains are reflected in the spontaneously hypertensive rat (SHR). Because ADHD, drugs and animal models are eliciting a growing interest, hence the aim of this work is to present a brief overview with a focus on the SHR as an animal model for ADHD and memory deficits. Thus, this paper reviews the concept of SHR as a model system for ADHD, comparing SHR, Wistar-Kyoto and Sprague-Dawley rats with a focus on the hypertension level and working, short-term memory and attention in different behavioral tasks, such as open field, five choice serial reaction time, water maze, passive avoidance, and autoshaping. In addition, drug treatments (d-amphetamine and methylphenidate) are evaluated.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/complicaciones , Trastornos del Conocimiento/etiología , Modelos Animales de Enfermedad , Trastornos de la Memoria/etiología , Animales , Humanos , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKYRESUMEN
The serotonin transporter (SERT) has been associated to diverse functions and diseases, though seldom to memory. Therefore, we made an attempt to summarize and discuss the available publications implicating the involvement of the SERT in memory, amnesia and anti-amnesic effects. Evidence indicates that Alzheimer's disease and drugs of abuse like d-methamphetamine (METH) and (+/-)3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") have been associated to decrements in the SERT expression and memory deficits. Several reports have indicated that memory formation and amnesia affected the SERT expression. The SERT expression seems to be a reliable neural marker related to memory mechanisms, its alterations and potential treatment. The pharmacological, neural and molecular mechanisms associated to these changes are of great importance for investigation.
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Trastornos de la Memoria/metabolismo , Memoria , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Amnesia/tratamiento farmacológico , Amnesia/metabolismo , Animales , Humanos , Memoria/efectos de los fármacos , Proteínas del Tejido Nervioso/agonistas , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/genética , Neuronas/efectos de los fármacos , Serotonina/metabolismo , Serotoninérgicos/farmacología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genéticaRESUMEN
Growing evidence indicates that antagonists of the 5-hydroxytryptamine (serotonin) receptor6 (5-HT6) improve memory and reverse amnesia, although the mechanisms involved are poorly understood. Hence, in this paper an attempt was made to summarize recent findings. Available evidence indicates that diverse 5-HT6 receptor antagonists produce promnesic and/or antiamnesic effects in diverse conditions, including memory formation, age-related cognitive impairments, memory deficits in diseases such as schizophrenia, Parkinson, and Alzheimer's disease (AD). Notably, some 5-HT6 receptor agonists seem to have promnesic and/or antiamnesic effects. At the present, it is unclear why 5-HT6 receptor agonists and antagonists may facilitate memory or may reverse amnesia in some memory tasks. Certainly, 5-HT6 drugs modulate memory, which are accompanied with neural changes. Likewise, memory, aging, and AD modify 5-HT6 receptors and signaling cascades. Further investigation in different memory tasks, times, and amnesia models together with more complex control groups might provide further clues. Notably, human studies suggest a potential utility of 5-HT6 receptor antagonists in mild-to-moderate AD patients. Even individuals with mild cognitive impairment (MCI) offer a great opportunity to test them.
Asunto(s)
Amnesia/tratamiento farmacológico , Química Encefálica/efectos de los fármacos , Memoria/efectos de los fármacos , Receptores de Serotonina/fisiología , Amnesia/inducido químicamente , Amnesia/fisiopatología , Animales , Química Encefálica/fisiología , Modelos Animales de Enfermedad , Humanos , Memoria/fisiologíaRESUMEN
In an attempt to clarify conflicting results about serotonin (5-hydroxytryptamine, 5-HT) 5-HT(1A) and 5-HT(7) receptors in memory formation, their mRNA expression was determined by RT-PCR in key brain areas for explicit and implicit memory. The time-course (0-120 h) of autoshaped responses was progressive and mRNA 5-HT(1A) or 5-HT(7) receptors expression monotonically augmented or declined in prefrontal cortex, hippocampus and raphe nuclei, respectively. At 24-48 h acutely 8-OH-DPAT (0.062 mg/kg) administration enhanced memory and attenuated mRNA 5-HT(1A)<5-HT(7) receptors expression respect to saline group. WAY100635 (0.3 mg/kg) or SB-269970 (10.0 mg/kg) did not affect the former, partially blocked or reversed the latter, respectively. Furthermore, lower WAY100635 (0.001-0.1 mg/kg) or SB-269970 (1.0-5.0 mg/kg) doses plus 8-OHDPAT not affected memory; however both combinations suppressed or up-regulated mRNA expression 5-HT(1A) or 5-HT(7) receptors. In contrast, AS19 (5.0 mg/kg) facilitated memory consolidation, decreased or increased hippocampal 5-HT(7) and 5-HT(1A) receptors expression. Together these data revealed that, when both 5-HT(1A) and 5-HT(7) receptors were stimulated by 8-OHDPAT under memory consolidation, subtle changes emerged, not evident at behavioral level though detectable at genes expression. Notably, high levels of efficient memory were maintained even when serotonergic tone, via either 5-HT(1A) or 5-HT(7) receptor, was down- or up-regulated. Nevertheless, WAY100635 plus SB-269970 impaired memory consolidation and suppressed their expression. Considering that serotonergic changes are prominent in AD patients with an earlier onset of disease the present approach might be useful in the identification of functional changes associated to memory formation, memory deficits and reversing or even preventing these deficits.
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Hipocampo/fisiología , Memoria/fisiología , Corteza Prefrontal/fisiología , Núcleos del Rafe/fisiología , Receptor de Serotonina 5-HT1A/metabolismo , Receptores de Serotonina/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralin/administración & dosificación , Animales , Condicionamiento Clásico/efectos de los fármacos , Condicionamiento Clásico/fisiología , Hipocampo/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Fenoles/administración & dosificación , Piperazinas/administración & dosificación , Corteza Prefrontal/efectos de los fármacos , Pirazoles/administración & dosificación , Piridinas/administración & dosificación , ARN Mensajero/metabolismo , Núcleos del Rafe/efectos de los fármacos , Ratas , Ratas Wistar , Agonistas del Receptor de Serotonina 5-HT1 , Antagonistas del Receptor de Serotonina 5-HT1 , Antagonistas de la Serotonina/administración & dosificación , Agonistas de Receptores de Serotonina/administración & dosificación , Sulfonamidas/administración & dosificación , Tetrahidronaftalenos/administración & dosificación , Factores de TiempoRESUMEN
Despite the compelling support for 5-hydroxytryptamine (5-HT) receptors participation in learning and memory in mammal species, the molecular basis had been largely absent from any discussion of its mechanistic underpinnings. Here, we report that reverse transcriptase-polymerase chain reaction (RT-PCR) analysis revealed that there was a higher level of expression of the investigated 5-HT receptor mRNAs in autoshaping-trained relative to untrained groups. Actually, pharmacological naïve untrained and autoshaping-trained rats showed significant differences, the latter groups expressing, in decreasing order, 5-HT1A < 5-HT6 < 5-HT4 < or = 5-HT7 receptors mRNA in prefrontal cortex and hippocampus. In order to determine more precisely mRNA expression and memory consolidation, we combined selective 5-HT7 receptors stimulation or blockade in the same animals, and brain areas individually analyzed. 5-HT7 receptors were strongly expressed in all the three brain areas of vehicle-trained rats relative to untrained group. The potential selective 5-HT7 receptor agonist AS 19 enhanced memory consolidation, attenuated mRNA receptors expression, and the facilitatory memory effect was reversed by SB-269970. Finally, pharmacological stimulation of 5-HT7 receptors reversed scopolamine- or dizocilpine-induced amnesia and receptor down-regulation.
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Condicionamiento Clásico/fisiología , Hipocampo/metabolismo , Corteza Prefrontal/metabolismo , ARN Mensajero/metabolismo , Receptores de Serotonina/metabolismo , Animales , Aprendizaje por Asociación/efectos de los fármacos , Aprendizaje por Asociación/fisiología , Condicionamiento Clásico/efectos de los fármacos , Regulación de la Expresión Génica , Hipocampo/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Memoria/fisiología , Corteza Prefrontal/efectos de los fármacos , Núcleos del Rafe/efectos de los fármacos , Núcleos del Rafe/metabolismo , Ratas , Ratas Wistar , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Serotoninérgicos/farmacologíaRESUMEN
New research in conditioned enhancement of antibody response requires a general paradigm effective with different antigens. In this experiment series we applied a one-trial protocol using keyhole limpet hemocyanin immunization as an unconditioned stimulus. Several different conditions were tested. Two different times between conditioning and test trial, two relevant antigen doses and the use of an antigen booster during test trial were investigated. We did not find a conditioned effect in any of the conditions used. In contrast, we found a reliable albeit modest conditioned effect using hen egg lysozyme as unconditioned stimulus. By comparing these and other findings we conclude that the number of conditioning trials is a possible requirement for a more reliable conditioning of antibody response.