RESUMEN
OBJECTIVE: Prenatal protein malnutrition produces anatomical and functional changes in the developing brain that persist despite immediate postnatal nutritional rehabilitation. Brain networks of prenatally malnourished animals show diminished activation of prefrontal areas and an increased activation of hippocampal regions during an attentional task [1]. While a reduction in cell number has been documented in hippocampal subfield CA1, nothing is known about changes in neuron numbers in the prefrontal or parahippocampal cortices. METHODS: In the present study, we used unbiased stereology to investigate the effect of prenatal protein malnutrition on the neuron numbers in the medial prefrontal cortex and the cortices of the parahippocampal region that comprise the larger functional network. RESULTS: Results show that prenatal protein malnutrition does not cause changes in the neuronal population in the medial prefrontal cortex of adult rats, indicating that the decrease in functional activation during attentional tasks is not due to a reduction in the number of neurons. Results also show that prenatal protein malnutrition is associated with a reduction in neuron numbers in specific parahippocampal subregions: the medial entorhinal cortex and presubiculum. DISCUSSION: The affected regions along with CA1 comprise a tightly interconnected circuit, suggesting that prenatal malnutrition confers a vulnerability to specific hippocampal circuits. These findings are consistent with the idea that prenatal protein malnutrition produces a reorganization of structural and functional networks, which may underlie observed alterations in attentional processes and capabilities.
RESUMEN
There is increasing evidence that the maternal environment exerts enduring influences on the fetal brain. In response to certain environmental stimuli such as reduced protein content, the fetus changes the course of its brain development, which leads to specific and programed changes in brain anatomy and physiology. These alterations produce a brain with a fundamentally altered organization, which then translates to alterations in adult cognitive function. The effects on brain and behavior may be linked, such that a prenatal stimulus relays a signal to alter brain development and encourage the selection and development of brain circuits and behaviors that would be beneficial for the environment in which the animal was anticipated to emerge. At the same time, the signal would deselect behaviors unlikely to be adaptive. We draw on evidence from rodent models to suggest that the brain that develops after a reduction in protein during the prenatal phase is not uniformly dysfunctional, but simply different. This perspective has implications for the role of prenatal factors in the production and expression of behavior, and may account for the elevation of risk factors for neurological and psychiatric illnesses.
Asunto(s)
Desnutrición , Efectos Tardíos de la Exposición Prenatal , Animales , Encéfalo , Femenino , Humanos , EmbarazoRESUMEN
Protein malnutrition during gestation alters brain development and produces specific behavioral and cognitive changes that persist into adulthood and increase the risks of neuropsychiatric disorders. Given evidence for the role of the prefrontal cortex in such diseases, it is significant that studies in humans and animal models have shown that prenatal protein malnutrition specifically affects functions associated with prefrontal cortex. However, the neural basis underlying these changes is unclear. In the current study, prenatally malnourished and control rats performed a sustained attention task with an unpredictable distractor, a task that depends on intact prefrontal cortical function. Radiolabeled 2-deoxyglucose was used to measure neural and brain network activity during the task. Results confirmed that adult prenatally malnourished rats were more distractible than controls and exhibited lower functional activity in prefrontal cortices. Thus, prefrontal activity was a predictor of task performance in controls but not prenatally malnourished animals. Instead, prenatally malnourished animals relied on different brain networks involving limbic structures such as the hippocampus. These results provide evidence that protein reduction during brain development has more wide-reaching effects on brain networks than previously appreciated, resulting in the formation of brain networks that may reflect compensatory responses in prenatally malnourished brains.
Asunto(s)
Atención/fisiología , Encéfalo/crecimiento & desarrollo , Potenciación a Largo Plazo/efectos de los fármacos , Desnutrición/fisiopatología , Animales , Encéfalo/fisiopatología , Trastornos del Conocimiento/fisiopatología , Femenino , Hipocampo/fisiopatología , Potenciación a Largo Plazo/fisiología , Corteza Prefrontal/metabolismo , Embarazo , Ratas Long-EvansRESUMEN
OBJECTIVE: This study assessed the effect of varying prenatal protein levels on the development of homing behavior in rat pups. METHODS: Long-Evans rats were fed one of the four isocaloric diets containing 6% (n = 7 litters), 12% (n = 9), 18% (n = 9), or 25% (n = 10) casein prior to mating and throughout pregnancy. At birth, litters were fostered to well-nourished control mothers fed a 25% casein diet during pregnancy, and an adequate protein diet (25% casein) was provided to weaning. On postnatal days 5, 7, 9, 11, and 13, homing behaviors, including activity levels, rate of successful returns to the nest quadrant and latencies to reach the nest over a 3-minute test period were recorded from two starting positions in the home cage. Adult body and brain weights were obtained at sacrifice (postnatal day 130 or 200). RESULTS: Growth was impaired in pups whose mothers were fed a 6% or, to a lesser extent, a 12% casein diet relative to pups whose mothers were fed the 18 and 25% casein diets. The 6 and 12% prenatal protein levels resulted in lower activity levels, with the greatest reduction on postnatal day 13. However, only the 6% pups had reduced success and higher latencies in reaching the nest quadrant when compared with pups from the three other nutrition groups. Latency in reaching the nest quadrant was significantly and negatively associated with adult brain weight. DISCUSSION: Home orientation is a sensitive measure of developmental deficits associated with variations in prenatal protein levels, including levels of protein deficiency that do not lead to overt growth failure.
Asunto(s)
Dieta con Restricción de Proteínas/efectos adversos , Proteínas en la Dieta/administración & dosificación , Desarrollo Fetal , Trastornos del Crecimiento/etiología , Complicaciones del Embarazo/fisiopatología , Fenómenos Fisiologicos de la Nutrición Prenatal , Deficiencia de Proteína/fisiopatología , Animales , Encéfalo/patología , Caseínas/administración & dosificación , Femenino , Trastornos del Crecimiento/patología , Fenómenos de Retorno al Lugar Habitual , Masculino , Tamaño de los Órganos , Exposición Paterna/efectos adversos , Embarazo , Distribución Aleatoria , Ratas Long-Evans , Organismos Libres de Patógenos Específicos , Aumento de PesoRESUMEN
Prenatal protein malnutrition (PPM) in rats causes enduring changes in brain and behavior including increased cognitive rigidity and decreased inhibitory control. A preliminary gene microarray screen of PPM rat prefrontal cortex (PFC) identified alterations in KCNJ3 (GIRK1/Kir3.1), a gene important for regulating neuronal excitability. Follow-up with polymerase chain reaction and Western blot showed decreased KCNJ3 expression in the PFC, but not hippocampus or brainstem. To verify localization of the effect to the PFC, baseline regional brain activity was assessed with (14)C-2-deoxyglucose. Results showed decreased activation in the PFC but not hippocampus. Together these findings point to the unique vulnerability of the PFC to the nutritional insult during early brain development, with enduring effects in adulthood on KCNJ3 expression and baseline metabolic activity.
Asunto(s)
Desoxiglucosa/metabolismo , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/genética , Desnutrición/genética , Desnutrición/metabolismo , Corteza Prefrontal/metabolismo , Fenómenos Fisiologicos de la Nutrición Prenatal , Animales , Regulación hacia Abajo , Femenino , Expresión Génica , Masculino , Embarazo , Ratas , Ratas Long-EvansRESUMEN
Serotonin 5-hydroxytryptamine type 3 receptors (5HT3R) are Ca2+-permeant, non-selective cation channels that have been localized to presynaptic terminals and demonstrated to modulate neurotransmitter release. In the present study the effect of 5-HT on GABA release in the hippocampus was characterized using both electrophysiological and biochemical techniques. 5-HT elicited a burst-like, 6- to 10-fold increase in the frequency of GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) measured with whole-cell voltage-clamp recordings of CA1 neurons in hippocampal slices. When tetrodotoxin was used to block action potential propagation, the 5-HT-induced burst of IPSCs was still observed. Stimulation of hippocampal synaptosomes with 5-HT resulted in a significant increase in the amount of [3H]GABA released by hyperosmotic saline. In both preparations, the 5-HT effect was shown to be mediated by 5HT3Rs, as it was mimicked by the selective 5HT3R agonist m-chlorophenyl biguanide and blocked by the selective 5HT3R antagonist 3-tropanylindole-3-carboxylate hydrochloride. The 5HT3R-mediated increase in GABA release was blocked by 100 microM cadmium or by omitting Ca2+ in external solutions, indicating the Ca2+-dependence of the effect. The high voltage-activated Ca2+ channel blockers omega-conotoxin GVIA and omega-conotoxin MVIIC and 10 microM cadmium had no significant effect on the 5-HT3R-mediated enhancement of GABA release, indicating that Ca2+ influx through the 5-HT3R facilitates GABA release. Taken together, these data provide direct evidence that Ca2+ entry via presynaptic 5HT3Rs facilitates the release of GABA from hippocampal interneurons.
Asunto(s)
Bicuculina/análogos & derivados , Calcio/metabolismo , Hipocampo/metabolismo , Receptores Presinapticos/metabolismo , Receptores de Serotonina 5-HT3/metabolismo , Sinaptosomas/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Animales , Animales Recién Nacidos , Bicuculina/farmacología , Biguanidas/farmacología , Cadmio/farmacología , Calcio/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Estimulación Eléctrica/métodos , Antagonistas del GABA/farmacología , Hipocampo/citología , Hipocampo/efectos de los fármacos , Técnicas In Vitro , Indoles/farmacología , Potenciales de la Membrana , Inhibición Neural/efectos de los fármacos , Inhibición Neural/efectos de la radiación , Neuronas/efectos de los fármacos , Neuronas/fisiología , Técnicas de Placa-Clamp/métodos , Ratas , Ratas Sprague-Dawley , Receptores Presinapticos/efectos de los fármacos , Serotonina/farmacología , Antagonistas del Receptor de Serotonina 5-HT3 , Agonistas de Receptores de Serotonina/farmacología , Sacarosa/farmacología , Sinaptosomas/efectos de los fármacos , Sinaptosomas/efectos de la radiación , Tritio/metabolismo , TropisetrónRESUMEN
Prenatal protein malnutrition has been demonstrated to result in alterations in the serotonergic and GABAergic neurotransmitter systems in the rat hippocampus. In the present study, whole-cell patch clamp recordings of CA1 pyramidal cells were employed in an effort to gain insight into the specific cellular locus and functional consequences of the previously reported changes. Hippocampal slices were prepared from Sprague-Dawley rats whose dams were fed either a normal (25% casein) or low (6% casein) protein diet during pregnancy. The development of GABA(A) receptor-mediated miniature inhibitory postsynaptic currents (mIPSCs) and their modulation by the benzodiazipine agonist zolpidem were compared in cells from the two nutritional groups at postnatal days 7, 14, 21 and >90. The modulation of mIPSCs by serotonin was also examined in cells from 21 day old rats. No significant differences were observed in the characteristics of mIPSCs in cells from control vs. prenatally protein malnourished rats at any of the ages studied, although there was a trend for a higher frequency of mIPSCs in adult (>p90) prenatally protein malnourished rats. At all ages, zolpidem produced a significant increase in the mean decay time of mIPSCs that was not significantly different in cells from the two nutritional groups. Serotonin application resulted in a significant increase in the frequency of mIPSCs in CA1 pyramidal cells but there was no significant difference between cells from the two nutritional groups in the characteristics of this effect. These data demonstrate that the previously observed alterations in the serotonergic and GABAergic systems that result from prenatal protein malnutrition do not have significant functional consequences at a single cell level in the CA1 region of the rat hippocampus as measured in vitro.
Asunto(s)
Hipocampo/fisiología , Efectos Tardíos de la Exposición Prenatal , Desnutrición Proteico-Calórica/fisiopatología , Células Piramidales/fisiología , Receptores de GABA-A/fisiología , Transmisión Sináptica/fisiología , Envejecimiento/fisiología , Animales , Potenciales Postsinápticos Excitadores/fisiología , Femenino , Técnicas In Vitro , Embarazo , Ratas , Ratas Sprague-Dawley , Programas InformáticosRESUMEN
The effects of the competitive NMDA receptor antagonist CPP on the initiation of behavioral sensitization to acute cocaine and basal and acute cocaine-induced dopamine (DA) release in the nucleus accumbens (NAC) were assessed in female Sprague-Dawley rats. Cocaine pretreated rats (30 mg/kg IP, once daily for 7 days) challenged with cocaine (10 mg/kg) on day 8 displayed increased motor activity relative to controls challenged with cocaine on day 8. This effect was blocked in rats receiving CPP (2 mg/kg) 15 min prior to all cocaine pretreatments. Basal DA levels in the NAC of both cocaine-pretreated and CPP plus cocaine-pretreated rats were higher on day 8 compared to controls. Acute cocaine challenge on day 8 resulted in increased extracellular DA concentrations in the NAC in control rats, no increase in rats pretreated with CPP plus cocaine, and a decrease in rats pretreated with cocaine only. These data demonstrate that development of behavioral sensitization to cocaine in female Sprague-Dawley rats can be completely blocked by a peripherally administered competitive NMDA receptor antagonist and that an increase in DA release in the NAC after a cocaine challenge is not an absolute requirement for expression of motor sensitization to cocaine in female rats.
Asunto(s)
Conducta Animal/efectos de los fármacos , Cocaína/farmacología , Inhibidores de Captación de Dopamina/farmacología , Dopamina/metabolismo , Núcleo Accumbens/metabolismo , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Femenino , Microdiálisis , Actividad Motora/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Piperazinas/metabolismo , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
Since our major hypothesis is that prenatal protein malnutrition significantly affects hippocampal neuroplasticity, this study examined the effects of prenatal protein malnutrition on the modulation of dentate granule cell excitability in freely moving rats at 15, 30 and 90 days of age across the vigilance states of quiet waking (QW), slow-wave sleep (SWS) and rapid eye movement (REM) sleep. Using paired-pulse stimulation, the paired-pulse index (PPI), a measure of the type and degree of modulation of dentate granule cell excitability elicited by stimulation of the medial perforant path, was obtained for each vigilance state at each stage of development. Four specific measures of granule cell excitability were computed, namely, PPI using both population spike amplitude (PSA) and EPSP slope measures, absolute values of PSA(1) and EPSP(1) slope. PPI values obtained at 15, 30 and 90 days of age, however, were altered during normal ontogenetic development, but not by vigilance state. At 15 days of age, the malnourished group exhibits greater early inhibition of the PPI using the PSA measure at IPIs between 20 and 30 ms regardless of vigilance state, while at 30 days of age, the malnourished group exhibits greater facilitation at IPIs between 50 and 70 ms during QW and SWS, but not during REM sleep. In the control adult (PND90) and juvenile (PND30) animal, PSA(1) values are significantly higher during SWS than in QW or REM sleep. However, for the younger malnourished animals (PND15 and PND30), PSA(1) values were found to be significantly greater during REM sleep rather than SWS. Therefore, as the animal matures, there appears to be a shift in vigilance state dependent synaptic transmission through the hippocampal trisynaptic circuit from REM sleep to SWS in both control and malnourished animals, with the change occurring later in malnourished animals when compared to control ones. Furthermore, our findings suggests that prenatal protein malnutrition significantly alters modulation of dentate granule cell excitability (i.e., PPI values using the PSA measure) during the earlier stages of development but not in adulthood.
Asunto(s)
Envejecimiento/fisiología , Giro Dentado/fisiología , Neuronas/fisiología , Complicaciones del Embarazo , Efectos Tardíos de la Exposición Prenatal , Desnutrición Proteico-Calórica , Fases del Sueño/fisiología , Animales , Giro Dentado/crecimiento & desarrollo , Potenciales Postsinápticos Excitadores , Femenino , Embarazo , Ratas , Ratas Sprague-Dawley , Sueño REM/fisiología , Vigilia/fisiologíaRESUMEN
Our previous work had shown an enhanced inhibition in the hippocampal formation of prenatally protein malnourished rats. We have also found a diminishment in 5-hydroxytryptamine (5-HT) fibers in the hippocampal formation of malnourished rats as well as increased levels of 5-HT in the brain. The purpose of the present study was to determine 5-HT release in the dorsal hippocampal formation following electrical stimulation of the median raphé nucleus (MRN) in unanesthetized prenatally malnourished rats. Stimulation of this nucleus at 20 Hz in malnourished rats resulted in a significantly diminished release of 5-HT compared to well-nourished rats. The latter group showed a lesser, though still significant, decrease in 5-HT release following raphé stimulation. Basal release of 5-HT prior to stimulation was significantly higher in malnourished rats as compared to well-nourished controls. This may be the result of a decreased density of 5-HT neurons leading to a diminished control of release. Stimulation of the MRN in behaving malnourished animals may markedly affect the recurrent negative feedback collaterals onto somatodendritic 5-HT(1A) and 5-HT(1D) autoreceptors thus enhancing the inhibitory effects of stimulation of the median raphé on 5-HT release. Studies are underway to examine the sensitivity of both the somatodendritic and terminal 5-HT autoreceptors in malnourished animals, in order to understand possible mechanisms for our findings.
Asunto(s)
Hipocampo/metabolismo , Efectos Tardíos de la Exposición Prenatal , Desnutrición Proteico-Calórica , Núcleos del Rafe/fisiología , Serotonina/metabolismo , Análisis de Varianza , Animales , Estimulación Eléctrica , Femenino , Masculino , Embarazo , Ratas , Ratas Sprague-DawleyRESUMEN
Dentate granule cell population responses to paired-pulse stimulation applied to the perforant pathway across a range of interpulse intervals (IPIs) were examined during different vigilance states-quiet waking (QW), slow-wave sleep (SWS), and rapid-eye movement (REM) sleep-in freely moving rats at 15, 30 and 90 days of age. Using these evoked field potentials, the paired-pulse index (PPI), a measure of the type and degree of modulation of dentate granule cell excitability, was computed and shown to be altered as a function of age. Animals, 15 days old, showed significantly lower levels of early inhibition (20-40 ms IPIs), i.e., greater PPI values, during all three vigilance states when compared to both the 30- and 90-day old animals. Adult, i.e, 90-day old animals, on the other hand, showed significantly greater levels of late inhibition (300-1000 ms IPIs), i.e., lower PPI values, than the younger animals (15- and 30-day old) during QW and SWS. These results indicate that as the dentate field of the hippocampal formation matures there are significant alterations in the modulation of dentate granule cell activity.
Asunto(s)
Nivel de Alerta/fisiología , Atención/fisiología , Giro Dentado/citología , Locomoción/fisiología , Animales , Giro Dentado/crecimiento & desarrollo , Giro Dentado/fisiología , Masculino , Ratas , Ratas Sprague-Dawley , Sueño/fisiología , Sueño REM/fisiologíaRESUMEN
Effects of D(-)2-amino-7-phosphonohepatanoic acid (AP-7), an N-methyl-D-aspartic acid (NMDA) receptor antagonist, administered into rostral ventrolateral medulla (RVLM) on changes in mean arterial pressure (MAP), heart rate (HR), extracellular levels of serotonin (5-HT), dopamine (DA), and norepinephrine (NE) during static muscle contraction were investigated in anesthetized rats. Tibial nerve stimulation-evoked muscle contraction increased MAP and HR by 25+/-3 mmHg and 29+/-4 bpm, respectively. Microdialysis of AP-7 (1 microM) into the RVLM for 30 min attenuated the contraction-evoked cardiovascular responses with similar developed muscle tensions, without baseline HR or blood pressure changes. Administration of AP-7 into the caudal ventrolateral medulla had no effect on MAP or HR responses during contraction. Muscle contraction increased extracellular 5-HT in the RVLM by 144+/-35%, DA by 104+/-15% and NE by 62+/-12%. Perfusion of AP-7 for 30 min into the RVLM attenuated contraction-evoked increases in monoamines, concomitant to attenuating cardiovascular responses. Results demonstrate that NMDA-receptor blockade within the RVLM, but not the CVLM, inhibits cardiovascular responses during muscle contraction. Furthermore, NMDA receptor antagonism within the RVLM results in a decrease of biogenic amine release during muscle contraction, suggesting that extracellular biogenic amine concentrations are modulated by NMDA receptors.
Asunto(s)
Aminas Biogénicas/metabolismo , Bulbo Raquídeo/química , Bulbo Raquídeo/metabolismo , Contracción Muscular/fisiología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacología , Animales , Química Encefálica/efectos de los fármacos , Química Encefálica/fisiología , Dopamina/metabolismo , Antagonistas de Aminoácidos Excitadores/farmacología , Masculino , Bulbo Raquídeo/efectos de los fármacos , Microdiálisis , Músculo Esquelético/inervación , Músculo Esquelético/fisiología , Neostriado/química , Neostriado/metabolismo , Norepinefrina/metabolismo , Ratas , Ratas Sprague-Dawley , Serotonina/metabolismoRESUMEN
We have studied 5-hydroxytryptamine (5-HT) release in the hippocampal formation following electrical stimulation of the dorsal and median raphé nuclei in the behaving rat. The primary finding in this study is a decrease in neuronal release of serotonin in the dorsal hippocampal formation following electrical stimulation of either the dorsal or median raphé nucleus in conscious rats. At no time did electrical stimulation of either raphé nucleus result in behavioral, including vigilance state, changes. The amount of 5-HT released was found to be frequency dependent with higher frequencies (20 Hz) producing larger decreases in release of 5-HT. However, the pattern of release differs between the two raphé nuclei. Extracellular levels of 5-HT decrease during stimulation of the dorsal raphé, whereas levels decrease only following cessation of stimulation of the median raphé nucleus. This may relate to the patterns of innervation of the dorsal hippocampal formation by these two midbrain raphé nuclei and also may reflect an inhibition of median raphé cell firing during stimulation of the dorsal raphé. Electrical stimulation of the dorsal raphé in anesthetized animals resulted in an enhanced release of 5-HT. The suppression of 5-HT release in the dorsal hippocampal formation in behaving animals was long-lasting (over 2 h), suggesting that the control mechanisms that regulate 5-HT release operate over a long time-course. This difference in release between non-anesthetized and anesthetized animals may relate to anesthesia blocking long- and/or short-loop serotonin recurrent axonal collaterals negatively feeding back onto 5-HT1A and 5-HT1D somatodendritic autoreceptors on raphé neurons. Further, the anesthetized animal has diminished monoaminergic "gating" influences on the hippocampal formation, whereas the behaving animal is more complex with behavioral (vigilance) states associated with different patterns of gating of information flow through the hippocampal formation.
Asunto(s)
Hipocampo/metabolismo , Neuronas/metabolismo , Núcleos del Rafe/fisiología , Serotonina/metabolismo , Animales , Estimulación Eléctrica , Hipocampo/efectos de los fármacos , Masculino , Neuronas/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Tetrodotoxina/farmacología , Factores de TiempoRESUMEN
The effects of an opioid agonist, [D-Ala2]methionine enkephalinamide (DAME), administered into the rostral ventrolateral medulla (rVLM) or caudal ventrolateral medulla (cVLM) on cardiovascular responses to isometric muscle contraction were determined in anesthetized rats. A 30-s contraction evoked by tibial nerve stimulation increased mean arterial pressure (MAP) and heart rate (HR) by 34 +/- 6 mmHg and 40 +/- 7 beats/min, respectively, with a developed tension of 322 +/- 30 g, after bilateral insertion of microdialysis probes into the rVLM. Thirty-minute dialysis of DAME (10 and 100 microM) attenuated the contraction-evoked cardiovascular changes dose dependently (10 microM: MAP = 25 +/- 4 mmHg, HR = 27 +/- 3 beats/min, tension = 333 +/- 25 g; 100 microM: MAP = 14 +/- 4 mmHg, HR = 16 +/- 5 beats/min, tension = 330 +/- 34 g). Preadministration of an opioid antagonist, naloxone (100 microM), augmented contraction-evoked MAP and HR responses and blocked effects of 100 microM DAME. Microdialysis of DAME into the cVLM produced no changes in the pressor response to contraction. At end of each experiment, tibial nerve stimulation after neuromuscular blockade evoked no MAP or HR change. Results demonstrate that opioid receptor activation within the rVLM modulates cardiovascular responses to isometric muscle contraction.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Mapeo Encefálico , Encefalina Metionina/análogos & derivados , Frecuencia Cardíaca/efectos de los fármacos , Contracción Isométrica/efectos de los fármacos , Bulbo Raquídeo/fisiología , Músculo Esquelético/fisiología , Presorreceptores/fisiología , Receptores Opioides/fisiología , Nervio Tibial/fisiología , Animales , Presión Sanguínea/fisiología , Estimulación Eléctrica , Encefalina Metionina/administración & dosificación , Encefalina Metionina/farmacología , Frecuencia Cardíaca/fisiología , Contracción Isométrica/fisiología , Masculino , Bulbo Raquídeo/efectos de los fármacos , Microdiálisis , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/inervación , Presorreceptores/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
Effects of administering 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) at a concentration that preferentially blocks alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors into rostral ventrolateral medulla (rVLM) or caudal ventrolateral medulla (cVLM) on cardiovascular responses elicited during static muscle contraction were investigated using anesthetized rats. Two microdialysis probes were inserted bilaterally into either the rVLM or the cVLM using stereotaxic guides. A tibial nerve stimulation-evoked static muscle contraction for 30 s increased mean arterial pressure (MAP) and heart rate (HR) by 27 +/- 3 mmHg and 28 +/- 4 beats/min, respectively. Microdialysis of CNQX into the rVLM for 30 min attenuated the contraction-evoked increases in MAP and HR (10 +/- 2 mmHg and 12 +/- 2 beats/min). Developed tensions were similar during the contractions before and after microdialyzing CNQX. In contrast, administration of CNQX into the cVLM potentiated the muscle contraction-evoked cardiovascular responses (MAP, 25 +/- 4 vs. 39 +/- 6 mmHg; HR, 27 +/- 3 vs. 42 +/- 3 beats/min), with no change in developed tensions. Results demonstrate that AMPA receptors within the rVLM and the cVLM appear to play opposite modulatory roles in the central integration of cardiovascular responses elicited during static muscle contraction.
Asunto(s)
Presión Sanguínea/fisiología , Bulbo Raquídeo/metabolismo , Contracción Muscular , Receptores AMPA/antagonistas & inhibidores , 6-Ciano 7-nitroquinoxalina 2,3-diona/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Antagonistas de Aminoácidos Excitadores/farmacología , Femenino , Frecuencia Cardíaca/fisiología , Masculino , Microdiálisis , Ratas , Ratas Sprague-DawleyRESUMEN
The effects of administering 8-hydroxy-2-(di-n-propylamine) tetralin [8-OH-DPAT, a serotonin 1A (5-HT1A) receptor agonist] into the rostral ventrolateral medulla (RVLM) on cardiovascular responses during tibial nerve stimulation-evoked muscle contraction were investigated using anesthetized rats. Stimulation of the tibial nerve (3 times motor threshold, 0.1 ms, 40 Hz) for 30 s increased mean arterial pressure (MAP), heart rate (HR), and muscle tension by 25 +/- 3 mmHg, 24 +/- 4 beats/min, and 299 +/- 35 g, respectively. Bilateral microdialysis of 8-OH-DPAT (10 mM) for 30 min attenuated the stimulation-evoked increases in MAP (8 +/- 2 mmHg) and HR (11 +/- 5 beats/min), without a change in muscle tension (292 +/- 30 g). However, administration of 1 mM 8-OH-DPAT had no effect on the cardiovascular responses. Thirty minutes of microdialysis of 8-OH-DPAT (10 mM) into the caudal ventrolateral medulla produced no effect on cardiovascular responses during muscle contraction. Prior administration of 10 mM 1-[2-methoxyphenyl]-4-[4-(2-phthalimido)-butyl]piperazine (NAN-190), a 5-HT1A receptor antagonist, for 30 min into the RVLM blocked the attenuating effects of subsequent microdialysis of 8-OH-DPAT (10 mM). Results suggest that activation of 5-HT1A receptors within the RVLM inhibit cardiovascular responses elicited during static muscle contraction.
Asunto(s)
8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Presión Sanguínea/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Bulbo Raquídeo/fisiología , Contracción Muscular/fisiología , Músculo Esquelético/inervación , Receptores de Serotonina/fisiología , Nervio Tibial/fisiología , 8-Hidroxi-2-(di-n-propilamino)tetralin/administración & dosificación , Animales , Ácido Glutámico/administración & dosificación , Ácido Glutámico/farmacología , Masculino , Bulbo Raquídeo/efectos de los fármacos , Microdiálisis , Contracción Muscular/efectos de los fármacos , Fármacos Neuromusculares Despolarizantes/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina 5-HT1 , Agonistas de Receptores de Serotonina/administración & dosificación , Agonistas de Receptores de Serotonina/farmacología , Tubocurarina/farmacologíaRESUMEN
The electrical stimulation of the dorsal raphé nucleus was used as a training cue in a discrimination paradigm. Sprague-Dawley rats were trained to discriminate between electrical stimulation (ES; 200 microA) of the dorsal raphé nucleus (DRN) and non-stimulation. This was accomplished by associating ES with intraperitoneal (i.p.) injection of lithium chloride (LiCl), following the session with electrical stimulation. This made the drinking of saccharin during ES aversive by conditioned taste aversion. Following training, rats decreased saccharin consumption in ES sessions. This discrimination was learned within three pairings of the ES with LiCl. Lowering the ES current to 50-100 microA resulted in levels of saccharin consumption similar to non-stimulation levels, whereas 150 microA showed a response intermediate between the stimulation response at 200 microA and non-stimulation. The discrimination of ES of the DRN (200 microA) was not affected by prior administration of the 5-HT2 antagonist ketanserin (1 or 2 mg/kg, i.p.), suggesting that activation of 5-HT2 receptors is not the primary discriminative cue generated by ES. However, the 5-HT2A/2C agonist DOI (0.25-0.5 mg/kg, i.p.), substituted for ES of the DRN, i.e. animals reduced saccharin consumption following DOI administration. This substitution of DOI for ES was antagonized by the administration of ketanserin (1 mg/kg, i.p.). These results suggest that ES of the DRN has properties that are similar to the activation of 5-HT2A/2C receptors by DOI. However, other stimuli such as activation of other 5-HT receptors are also involved, given that the discriminative cues of ES are not blocked by the 5-HT2A/2C antagonist ketanserin.
Asunto(s)
Discriminación en Psicología/efectos de los fármacos , Ketanserina/farmacología , Núcleos del Rafe/fisiología , Antagonistas de la Serotonina/farmacología , Anfetaminas/farmacología , Animales , Señales (Psicología) , Estimulación Eléctrica , Generalización del Estimulo/efectos de los fármacos , Masculino , Núcleos del Rafe/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Sacarina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Edulcorantes/farmacología , Gusto/efectos de los fármacosRESUMEN
This study determined whether muscle contraction causes an increase in extracellular levels of serotonin (5-HT) in the rostral (rVLM) or caudal ventrolateral medulla (cVLM) in anesthetized rats. Muscle contraction, evoked by tibial nerve stimulation, increased mean arterial blood pressure (MAP) by 27 +/- 4 mmHg (n = 8). In addition, 5-HT levels in the rVLM were elevated by 65 +/- 9% during the contraction (n = 8). Results were similar over two repeated contractions. In contrast, muscle contraction increased MAP, but not 5-HT, levels in the cVLM (n = 6). Tibial nerve stimulation after muscle paralysis had no effect on either MAP or 5-HT levels in both rVLM and cVLM. Microdialysis of a 5-HT1A agonist, 8-OH-DPAT (10 mM), into the rVLM for 30 min (n = 6) blunted the MAP change and reduced 5-HT release during contraction. Administration of NAN-190, a 5-HT1A antagonist, into the rVLM had no effect on 5-HT release and cardiovascular responses during muscle contraction and blocked the changes in 5-HT, MAP, and heart rate to static contraction after subsequent microdialysis of 8-OH-DPAT. Results demonstrate that 5-HT levels in the rVLM increase during muscle contraction and that 5-HT1A-receptor activation in the rVLM blunts MAP response to muscle contraction via a decrease in the extracellular concentration of 5-HT.
Asunto(s)
8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Presión Sanguínea/fisiología , Bulbo Raquídeo/fisiología , Contracción Muscular/fisiología , Unión Neuromuscular/fisiología , Receptores de Serotonina/fisiología , Agonistas de Receptores de Serotonina/farmacología , Serotonina/metabolismo , Nervio Tibial/fisiología , Animales , Presión Sanguínea/efectos de los fármacos , Estimulación Eléctrica , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Cinética , Masculino , Bulbo Raquídeo/efectos de los fármacos , Microdiálisis , Contracción Muscular/efectos de los fármacos , Unión Neuromuscular/efectos de los fármacos , Parálisis , Piperazinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina 5-HT1 , Antagonistas de la Serotonina/farmacologíaRESUMEN
Electrical stimulation of the dorsal raphe nucleus of Sprague-Dawley rats was used as the cue for discrimination using a taste aversion paradigm. Rats were trained to associate saccharin drinking during electrical stimulation of the dorsal raphe nucleus with LiCl injection after the session as the aversive unconditioned stimulus. In sessions without stimulation, rats were allowed to consume saccharin and received a saline injection after the session. Suppression of saccharin consumption during electrical stimulation was learned within 12 trials. Rats trained in the reverse discrimination, i.e., sessions with no electrical stimulation paired with LiCl injection, showed a similar learning curve. Animals injected prior to the session with the hallucinogenic 5-HT2 agonist (+/-)-DOI associated DOI with electrical stimulation of the dorsal raphe nucleus. Thus, animals may be trained to discriminate electrical stimulation of the dorsal raphe nucleus. Furthermore, animals generalize from activation of 5-HT2 receptors to electrical stimulation of the dorsal raphe nucleus.
Asunto(s)
Anfetaminas/farmacología , Aprendizaje Discriminativo/efectos de los fármacos , Generalización del Estimulo/efectos de los fármacos , Núcleos del Rafe/fisiología , Agonistas de Receptores de Serotonina/farmacología , Animales , Señales (Psicología) , Estimulación Eléctrica , Cloruro de Litio/farmacología , Masculino , Ratas , Ratas Sprague-Dawley , Gusto/efectos de los fármacosRESUMEN
Persistent hindlimb flexion was induced in pentobarbital anesthetized rats using a prolonged, electrical stimulus. Intrathecal (i.t.) N-methyl-D-aspartate NMDA) (1 mM, 5 microliters) applied prior to stimulation increased flexion relative to stimulated controls subsequent to stimulation (156%); 3 days later (109%) and after spinalization at 3 days (91%). Pretreatment with MK-801 (3 mg/kg, i.p.) prevented the enhancement of flexion. Withdrawal latencies to a thermal stimulus also were measured. I.t. NMDA plus stimulation reduced mean latency relative to controls only subsequent to stimulation. Latencies were increased by MK-801 post-injection, post-stimulation and at 3 days. The results suggest that the induction of persistent hindlimb flexion depends upon spinal NMDA receptors.