RESUMEN
Chronic Kidney Disease (CKD) is characterized by a progressive and irreversible loss of kidney function which gradually leads to end-stage kidney disease (ESKD). Virtually all the organs are damaged by the toxicity of uremic compounds. The lungs may be affected and the impaired pulmonary function may be the direct result of fluid retention and metabolic, endocrine and cardiovascular alterations, as well as systemic activation of the inflammation. An increased prevalence in sleep disorders (SD) is also reported in patients with CKD, leading to a further negative impact on overall health and quality of life. While these complex relationships are well documented in the adult population, these aspects remain relatively little investigated in children. The aim of this review is to provide a brief overview of the pathophysiology between lung and kidney and to summarize how CKD may affect respiratory function and sleep in children.
Asunto(s)
Fallo Renal Crónico , Insuficiencia Renal Crónica , Trastornos del Sueño-Vigilia , Adulto , Humanos , Niño , Calidad de Vida , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/epidemiología , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/epidemiología , Riñón , Trastornos del Sueño-Vigilia/epidemiología , Trastornos del Sueño-Vigilia/etiologíaRESUMEN
Hypertension is a leading cause of cardiovascular complications in children on dialysis. Volume overload and activation of the renin-angiotensin-aldosterone system play a major role in the pathophysiology of hypertension. The first step in managing blood pressure (BP) is the careful assessment of ambulatory BP monitoring. Volume control is essential and should start with the accurate identification of dry weight, based on a comprehensive assessment, including bioimpedance analysis and intradialytic blood volume monitoring (BVM). Reduction of interdialytic weight gain (IDWG) is critical, as higher IDWG is associated with a worse left ventricular mass index and poorer BP control: it can be obtained by means of salt restriction, reduced fluid intake, and optimized sodium removal in dialysis. Optimization of peritoneal dialysis and intensified hemodialysis or hemodiafiltration have been shown to improve both fluid and sodium management, leading to better BP levels. Studies comparing different antihypertensive agents in children are lacking. The pharmacokinetic properties of each drug should be considered. At present, BP control remains suboptimal in many patients and efforts are needed to improve the long-term outcomes of children on dialysis.
Asunto(s)
Hipertensión/etiología , Hipertensión/terapia , Diálisis Renal/efectos adversos , Antihipertensivos/uso terapéutico , Presión Sanguínea , Niño , Femenino , Humanos , MasculinoRESUMEN
The striatum is viewed as a structure performing fast neurotransmitter-mediated operations through somatotopically organized projections to medium-size spiny neurons. This view is contrasted with another view that depicts the striatum as a site of diffuse modulatory influences mediated by cholinergic interneurons and by dopamine and N-methyl-D-aspartate receptors. These two operational and organizational modes both contribute, through their mutual interaction, to the function of basal ganglia. Detailed knowledge of the neural mechanisms by which such interactions take place and are expressed into behaviour, can provide new insight into the physiopathology and new clues for therapy of disorders of basal ganglia.
Asunto(s)
Acetilcolina/fisiología , Cuerpo Estriado/fisiología , Dopamina/fisiología , N-Metilaspartato/fisiología , Neurotransmisores/fisiología , Animales , Humanos , Receptores Dopaminérgicos/fisiología , Transmisión Sináptica/fisiologíaRESUMEN
In vivo extracellular acetylcholine release from brain hemispheric areas of 2-, 9-, and 18-month-old rats was measured by intracerebral microdialysis coupled with a radioenzymatic assay. Dialysis tubing was inserted transversally through both striata, frontal cortices and dorsal hippocampi 24 hours before the experiments. In the 2-month-old rats, the net average acetylcholine output, corrected for recovery and expressed in fmoles/min/single striatum, cortex and hippocampus, was 902.4 +/- 67, 303.9 +/- 14 and 334 +/- 32, respectively. In 18-month-old rats acetylcholine output was 53, 35 and 37% lower in striatum, cortex and hippocampus, respectively, than in young rats. The release from the striatum in the 9-month-old was intermediate between those of the 2- and 18-month-old rats. The intracerebroventricular injection of hemicholinium-3 caused a marked decrease in acetylcholine release from the striata of 2- and 18-month-old rats. If the decrease with hemicholinium was expressed as percent of the basal release there was no age-related difference between the young and old rats, indicating that the differences observed were due to the lower basal release found in the old rats. The possibility that the deficit in basal acetylcholine release with age may depend on a reduction of acetylcholine synthesis is discussed.
Asunto(s)
Acetilcolina/metabolismo , Envejecimiento/metabolismo , Encéfalo/metabolismo , Animales , Corteza Cerebral/metabolismo , Cuerpo Estriado/metabolismo , Diálisis , Hipocampo/metabolismo , Masculino , Ratas , Ratas Endogámicas , Factores de TiempoRESUMEN
The effect of galanin (GAL) on basal and phorbol-12,13-dibutyrate (PDBu) induced protein phosphorylation in rat ventral hippocampal miniprisms was investigated. GAL (0.5, 1 and 2 microM) inhibited PDBu stimulation in a concentration-dependent manner without altering basal protein phosphorylation. This inhibitory effect was prevented by the GAL antagonist galantide. GAL did not affect either the activity of protein kinase C (PKC) from rat brain or basal phosphorylation in ventral hippocampal hippogenates, suggesting that it did not directly modulate PKC activity. Depolarization of miniprisms from ventral hippocampi by 18 mM K+ prevented the effect of GAL on PDBu-induced phosphorylation. The results indicate that GAL indirectly regulates neuronal protein phosphorylation by a GAL receptor-mediated action.
Asunto(s)
Hipocampo/metabolismo , Neuropéptidos/fisiología , Péptidos/fisiología , Forbol 12,13-Dibutirato/farmacología , Proteínas/metabolismo , Sustancia P/análogos & derivados , Animales , Galanina , Masculino , Fosforilación , RatasRESUMEN
The muscarinic agonist oxotremorine produced a linear dose-dependent increase in membrane fluidity of intact and viable human lymphocytes in vitro. This effect proved to be receptor-mediated because preincubation with 10(-5)M atropine shifted the dose-response curve one order of magnitude rightward. Pirenzepine preincubation did not affect membrane fluidity variation. A cGMP increase was also found after oxotremorine treatment. The results are discussed in terms of possible modulation of guanyl cyclase and adenyl cyclase through membrane fluidity variations.
Asunto(s)
GMP Cíclico/sangre , Linfocitos/metabolismo , Oxotremorina/farmacología , Receptores Muscarínicos/metabolismo , Atropina/farmacología , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Membrana Celular/ultraestructura , Humanos , Cinética , Masculino , Receptores Muscarínicos/efectos de los fármacos , ViscosidadRESUMEN
The synthesis and the biological evaluation of a series of novel pyrroloquinoxaline derivatives are described. In binding studies several compounds proved to be potent and selective 5-HT3 receptor ligands. The most active pyrroloquinoxalines, 11d and 11e, showed a subnanomolar affinity for 5-HT3 receptor and were able to functionally discriminate the central and peripheral 5-HT3 receptor, being agonists and antagonists, respectively. In functional studies ([14C]-guanidinium accumulation test in NG 108-15 cells, in vitro) most of the synthesized compounds showed clear-cut 5-HT3 agonist properties. In in vivo studies on the von Bezold-Jarisch reflex test (a peripheral interaction model) the behavior of the tested compounds ranged from agonist to antagonist, while clear agonist properties were obtained with 12a on cortical acetylcholine release in freely moving rats. Pharmacokinetic studies with 11e and 12c indicate that the compounds easily cross the blood-brain barrier (BBB) after systemic administration with a brain/plasma ratio of 17.5 and 37.5, respectively. Thus compounds 11e and 12c represent the most potent central 5-HT3 agonists identified to date that are able to cross the blood-brain barrier.
Asunto(s)
Quinoxalinas/farmacología , Receptores de Serotonina/efectos de los fármacos , Agonistas de Receptores de Serotonina/farmacología , Animales , Barrera Hematoencefálica , Línea Celular , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Células Híbridas , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Quinoxalinas/química , Quinoxalinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Receptores de Serotonina 5-HT3 , Reflejo/efectos de los fármacos , Agonistas de Receptores de Serotonina/química , Agonistas de Receptores de Serotonina/farmacocinética , Espectrofotometría Infrarroja , Relación Estructura-ActividadRESUMEN
We investigated the role played by the parafascicular thalamostriatal pathway, one of the major excitatory inputs to the striatum, in the D-1 receptor induction of c-fos messenger RNA expression in the rat striatum. The full D-1 receptor agonist, SKF-82958 (0.05, 0.1, 0.5 and 1 mg/kg, s.c., 30 min), dose-dependently induced c-fos messenger RNA in naive rat striatum as determined by northern blot analysis. One day following electrolytic lesion of the parafascicular thalamostriatal nucleus, striatal c-fos signal by itself was not altered but the stimulated expression of c-fos was strongly decreased. Sections of sham-operated and acute-lesioned dorsal striata of vehicle- or SKF-82958-treated rats were processed for in situ hybridization histochemistry at the single-cell level with an RNA probe for c-fos. The basal expression of striatal c-fos was poorly detectable in sham and lesioned groups. Sections of dorsal striata from sham-operated rats treated with SKF-82958 showed two types of labeled neurons for c-fos: the lightly and the very densely labeled neurons which are few in number. Thalamic lesion strongly reduced SKF-82958 stimulated expression of c-fos RNA in both types of labeled cells. The frequency distribution of c-fos labeling per neuron in dorsal striata of lesioned rats treated with SKF-82958 was shifted to the left, and its median was lower than in the sham-operated striata treated with the D-1 receptor agonist. The results provide evidence that the excitatory projections from the parafascicular nucleus of the thalamus, thought to operate primarily through the N-methyl-D-aspartate receptors, exert a facilitatory control over D-1 receptor-induced c-fos gene expression specifically in the dorsal striatum.
Asunto(s)
Cuerpo Estriado/metabolismo , Núcleos Talámicos Intralaminares/fisiología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Receptores de Dopamina D1/fisiología , Vías Aferentes/fisiología , Animales , Benzazepinas/farmacología , Cuerpo Estriado/citología , Desnervación , Agonistas de Dopamina/farmacología , Masculino , Neuronas/metabolismo , Proteínas Proto-Oncogénicas c-fos/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-fos/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
We investigated whether the parafascicular thalamostriatal pathway, one of the major excitatory inputs to the striatum, regulates the expression in rat striatum of messenger RNA encoding two isoforms of glutamate decarboxylase (mol. wt 67,000: glutamate decarboxylase 67 and mol. wt 65,000: glutamate decarboxylase 65). Acute (one day) and chronic (14 days) electrolytic lesions of the parafascicular nucleus resulted in 58% and 23% decreases in glutamate decarboxylase 67 messenger RNA expression, respectively, as determined by northern blot analysis. Glutamate decarboxylase 65 messenger RNA was not modified by either lesion. Sections of sham- and acute-lesioned striata were processed for in situ hybridization histochemistry at the single cell level with an RNA probe for glutamate decarboxylase 67. Labelling of glutamate decarboxylase 67 messenger RNA was decreased in both types of cells known to be present in the striatum, i.e. the lightly and the very densely-labelled neurons. The frequency distribution of glutamate decarboxylase 67 labelling per neuron in the lesioned striata, in fact, was shifted to the left and its median was lower than in the sham-lesioned striata. In view of the excitatory nature of the thalamostriatal pathway, we examined the subtype of glutamate receptors modulating the glutamate decarboxylase 67 gene expression. The N-methyl-D-aspartate-type receptor antagonist, dizocilpine, at 0.1-0.5 mg/kg i.p., produced a marked and persistent reduction in striatal glutamate decarboxylase 67 messenger RNA. The non-N-methyl-D-aspartate receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione (12 nmol/side, i.c.v.) had no such effect. The results provide evidence that excitatory thalamostriatal afferents selectively modulate the gene expression of glutamate decarboxylase 67, probably through the N-methyl-D-aspartate subtype of glutamate receptors.
Asunto(s)
Mapeo Encefálico , Cuerpo Estriado/enzimología , Glutamato Descarboxilasa/biosíntesis , Isoenzimas/biosíntesis , Neuronas/enzimología , Núcleos Talámicos/fisiología , Transcripción Genética , Animales , ADN Complementario , Maleato de Dizocilpina/farmacología , Electrólisis , Hibridación in Situ , Masculino , ARN Mensajero/biosíntesis , Ratas , Ratas Sprague-Dawley , Valores de Referencia , Transcripción Genética/efectos de los fármacosRESUMEN
We investigated whether the parafascicular thalamic nucleus and the prefrontal cortex, the two major excitatory inputs to the striatum, modulate the nitric oxide/cyclic GMP pathway in rat striatum. Electrical stimulation (10 pulses of 0.5 ms, 10 V applied at 10 Hz, 140 microA) delivered bilaterally to the parafascicular thalamic nucleus for a total of 4, 10 and 20 min, time-dependently facilitated cyclic GMP output in the dorsal striatum of freely moving rats, assessed by trans-striatal microdialysis. Electrical stimulation to the prefrontal cortex for a total duration of 20 min did not affect striatal cyclic GMP levels. The facilitatory effect observed after electrical stimulation of the parafascicular thalamic nucleus was blocked by co-perfusion with tetrodotoxin, suggesting that the effect is mediated by neuronal process(es). The non-competitive N-methyl-D-aspartate receptor antagonist, dizocilpine maleate (30 microM infused into the dorsal striatum), and the competitive one, 3-[(R)-carboxypiperazin-4-yl]-propyl-phosphonic acid (50 microM infused), but not local perfusion of the alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid antagonist, 6-nitro-7-sulphamoylbenzo(f)quinoxaline-2,3-dione (15 microM perfused locally), abolished the cyclic GMP response in the striatum. The nitric oxide synthase inhibitor, 7-nitroindazole, applied locally (1 mM), blocked the electrically evoked increase in striatal extracellular cyclic GMP. This increase was also prevented by local application (100 and 300 microM) of 1H-(1,2,4)-oxadiazolo-(4,3a)-quinoxalin-1-one, a selective inhibitor of soluble guanylyl cyclase. The results provide direct functional evidence of selective thalamic facilitation of the nitric oxide/cyclic GMP pathway in the dorsal striatum, through activation of N-methyl-D-aspartate receptors.
Asunto(s)
GMP Cíclico/fisiología , Neostriado/fisiología , Óxido Nítrico/fisiología , Corteza Prefrontal/fisiología , Núcleos Talámicos/fisiología , Animales , GMP Cíclico/metabolismo , Estimulación Eléctrica , Electrodos Implantados , Inhibidores Enzimáticos/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Guanilato Ciclasa/antagonistas & inhibidores , Indazoles/farmacología , Masculino , Microdiálisis , Neostriado/efectos de los fármacos , Neostriado/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo I , Ratas , Ratas Endogámicas , Receptores AMPA/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Tetrodotoxina/farmacologíaRESUMEN
Two major systems of cholinergic projection neurons are found within the centrum of the mammalian brain: the basal nuclear complex, projecting predominantly to the cerebral cortex, amygdala, and hippocampus, and the pontomesencephalotegmental network, innervating primarily the thalamus. Neurons comprising the latter network also project to the basal forebrain, but the functional properties of that fiber connection, if any, are unknown. In an attempt to address this issue, the extracellular concentration of acetylcholine was measured in the basal nuclear complex of freely moving rats, both singularly and in combination with lesions and pharmacologic manipulations. Acetylcholine release monitored in the presence of physostigmine sulfate in the basal forebrain was (a) calcium-dependent, (b) increased by systemic scopolamine injection, the rise persisting in the presence of quisqualate lesions of the basal nuclear complex, (c) blocked by tetrodotoxin, and (d) abolished by ablation of cell bodies in the pontomesencephalic tegmentum, which also produced a decrease of choline acetyltransferase activity in the nucleus basalis/substantia innominata region, but not by quisqualate lesions of the basal forebrain. It is concluded from these data that the calcium-dependent release of acetylcholine in the basal nuclear complex (a) is largely axonal in nature, (b) derives substantially from axons of the cholinergic pontomesencephalic tegmentum, and (c) appears to be controlled by presynaptic muscarinic receptors on axon terminals of the latter system. The pontomesencephalotegmental cholinergic complex might thus influence cortical acetylcholine release, in part at least, by means of serial-order cholinergic-cholinergic interactions in the basal nuclear complex.
Asunto(s)
Acetilcolina/metabolismo , Ganglios Basales/metabolismo , Neuronas/metabolismo , Sistema Nervioso Parasimpático/metabolismo , Puente/metabolismo , Tegmento Mesencefálico/metabolismo , Animales , Ganglios Basales/efectos de los fármacos , Calcio/fisiología , Colina O-Acetiltransferasa/metabolismo , Femenino , Inmunohistoquímica , Neuronas/efectos de los fármacos , Sistema Nervioso Parasimpático/citología , Sistema Nervioso Parasimpático/efectos de los fármacos , Fisostigmina/farmacología , Puente/citología , Puente/efectos de los fármacos , Ácido Quiscuálico/farmacología , Ratas , Ratas Endogámicas , Escopolamina/farmacología , Tegmento Mesencefálico/citología , Tegmento Mesencefálico/efectos de los fármacos , Tetrodotoxina/farmacologíaRESUMEN
We investigated the involvement of glutamatergic neurotransmission in the modulation of D1 receptor-mediated stimulation of acetylcholine outflow in dorsal striatum in freely moving rats, and the relative roles of the thalamostriatal and corticostriatal pathways in this regulation using in vivo microdialysis. The selective N-methyl-D-aspartate non-competitive antagonist dizocilpine maleate (0.1 mg/kg i.p.), but not the kainate/quisqualate receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione (3 micrograms per side i.c.v.), completely prevented the rise in striatal extracellular acetylcholine elicited by maximal effective doses of the full D1 agonist SKF 82958 (3 mg/kg s.c.) and of the dopamine releaser d-amphetamine (2 mg/kg s.c.). Acute bilateral electrolytic lesions of the parafascicular nucleus of the thalamus prevented the stimulation of striatal acetylcholine output by SKF 82958 and d-amphetamine but only slightly reduced basal acetylcholine release. In contrast acute interruption of the corticostriatal pathway did not alter the effect of the two dopaminergic drugs although it markedly reduced basal striatal acetylcholine release. Lesions of the parafascicular thalamic nucleus, or a low dose of dizocilpine maleate (0.1 mg/kg i.p.), also prevented the acetylcholine-increasing effect of the neuroleptic remoxipride (10 mg/kg s.c.), an effect known to be D1 receptor dependent. The results suggest that striatal projections arising from the parafascicular thalamic nucleus and utilizing N-methyl-D-aspartate receptors play a critical role in the D1-mediated stimulation of acetylcholine release in dorsal striata.
Asunto(s)
Acetilcolina/metabolismo , N-Metilaspartato/fisiología , Neostriado/metabolismo , Receptores de Dopamina D1/fisiología , Transmisión Sináptica/fisiología , Núcleos Talámicos/fisiología , Animales , Benzazepinas/farmacología , Dextroanfetamina/farmacología , Maleato de Dizocilpina/farmacología , Agonistas de Dopamina/farmacología , Antagonistas de Dopamina/farmacología , Inhibidores de Captación de Dopamina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Masculino , Microdiálisis , Neostriado/efectos de los fármacos , Neostriado/fisiología , Degeneración Nerviosa/efectos de los fármacos , Degeneración Nerviosa/fisiología , Neuronas Aferentes/efectos de los fármacos , Neuronas Aferentes/fisiología , Corteza Prefrontal/citología , Corteza Prefrontal/fisiología , Ratas , Ratas Endogámicas , Receptores de Dopamina D1/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Remoxiprida/antagonistas & inhibidores , Remoxiprida/farmacología , Transmisión Sináptica/efectos de los fármacos , Núcleos Talámicos/efectos de los fármacosRESUMEN
The role of vesicular and newly synthesized dopamine in the action of amphetamine was investigated by studying the effect of reserpine and alpha-methyl-p-tyrosine pretreatment on amphetamine-induced changes in extracellular dopamine and acetylcholine, estimated by brain microdialysis, and on c-fos expression, estimated by quantitative immunohistochemistry of the Fos antigene, in the dorsal caudate-putamen of rats. Blockade of dopamine synthesis by alpha-methyl-p-tyrosine pretreatment (1 or 2 h) only partially prevented the increase in extracellular dopamine concentrations elicited by 0.5 and 2 mg/kg s.c. of amphetamine. Inactivation of vesicular amine uptake by reserpine pretreatment (3 h) reduced the increase in extracellular dopamine by 2 mg/kg but not by 0.5 mg/kg of amphetamine. Combined pretreatment with reserpine (3 h) and alpha-methyl-p-tyrosine (1 h) drastically reduced the increase in extracellular dopamine by both doses of amphetamine (0.5 and 2 mg/kg s.c.). alpha-Methyl-p-tyrosine pretreatment reduced c-fos expression stimulated by amphetamine (2 mg/kg) in the dorsomedial and dorsolateral caudate-putamen while reserpine pretreatment reduced it only in the dorsolateral caudate-putamen. Amphetamine (2 mg/kg s.c.) stimulated acetylcholine release but this effect was not modified by reserpine or alpha-methyl-p-tyrosine pretreatment. The results indicate that blockade of dopamine synthesis, by itself, is insufficient to prevent the stimulation of dopamine transmission by amphetamine and, conversely, that inactivation of vesicular dopamine significantly reduces amphetamine effects at pre- and postsynaptic levels. Therefore, vesicular dopamine appears to contribute to the stimulation of dopamine transmission elicited by amphetamine in the dorsal caudate-putamen.
Asunto(s)
Dextroanfetamina/farmacología , Dopamina/fisiología , Neostriado/fisiología , Proteínas Proto-Oncogénicas c-fos/biosíntesis , Transmisión Sináptica/fisiología , Vesículas Sinápticas/metabolismo , Acetilcolina/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Inmunohistoquímica , Masculino , Metiltirosinas/farmacología , Microdiálisis , Neostriado/efectos de los fármacos , Neostriado/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Presinapticos/efectos de los fármacos , Receptores Presinapticos/metabolismo , Reserpina/farmacología , Estimulación Química , Transmisión Sináptica/efectos de los fármacos , Vesículas Sinápticas/efectos de los fármacos , Tirosina 3-Monooxigenasa/antagonistas & inhibidores , alfa-MetiltirosinaRESUMEN
We investigated whether the neuropeptide galanin affects the nitric oxide synthase/cyclic GMP pathway in rat hippocampus by measuring in vivo the extracellular cyclic GMP levels during microdialysis. Galanin (2.5 and 3.5 nmol; i.c.v.) dose-dependently raised the extracellular levels of cyclic GMP in the ventral but not the dorsal hippocampus. The effect of 3.5 nmol galanin was blocked by local application of tetrodotoxin and inhibited by the high-affinity galanin antagonist M40 (galanin-[1-12]-Pro3-[Ala-Leu]2-Ala amide). The non-competitive N-methyl-D-aspartate receptor antagonist dizocilpine maleate (30 microM infused into the ventral hippocampus or 0.2 mg/kg, i.p.) and the competitive one, 3-([R]-carboxypiperazin-4-yl)-propyl-phosphonic acid (50 microM infused), but not local perfusion of the AMPA antagonist 6-nitro-7-sulphamoylbenzo(f)quinoxaline-2,3-dione (15 microM) abolished the galanin-evoked cyclic GMP response in the hippocampus. Inhibitors of nitric oxide synthase, L-Arg(NO2)-OMe.HCl and 7-nitroindazole monosodium salt, applied locally, blocked the galanin-induced increase in hippocampal extracellular cyclic GMP. This increase was also prevented by local application of 1H-(1,2,4)oxadiazolo(4,3a) quinoxalin-1-one, a selective inhibitor of soluble guanylyl cyclase. The galanin receptors mediating the rise in cyclic GMP reside outside the hippocampus, as galanin (0.35-3 nmol) locally applied had no effect. The results provide in vivo evidence that galanin stimulates the N-methyl-D-aspartate receptor/nitric oxide synthase/cyclic GMP pathway in the ventral hippocampus, which may be of importance in memory processes.
Asunto(s)
GMP Cíclico/metabolismo , Galanina/farmacología , Hipocampo/metabolismo , Óxido Nítrico/metabolismo , Fragmentos de Péptidos/farmacología , Receptores de N-Metil-D-Aspartato/fisiología , Animales , Maleato de Dizocilpina/farmacología , Inhibidores Enzimáticos/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Hipocampo/química , Hipocampo/efectos de los fármacos , Locomoción , Masculino , Microdiálisis , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Oxadiazoles/farmacología , Piperazinas/farmacología , Quinoxalinas/farmacología , Ratas , Ratas Endogámicas , Receptores AMPA/agonistas , Receptores AMPA/fisiología , Receptores de N-Metil-D-Aspartato/agonistas , Tetrodotoxina/farmacologíaRESUMEN
Previous single exposure (priming) to a dopamine receptor agonist greatly enhances the contralateral turning behaviour elicited by dopamine D1 receptor agonists in unilaterally 6-hydroxydopamine lesioned rats. In the present study we have investigated the levels of glutamate decarboxylase 67 and glutamate decarboxylase 65 messenger RNA in the striatum of 6-hydroxydopamine-lesioned rats primed with L-3,4-dihydroxyphenylalanine (L-DOPA) and challenged with the D1 receptor agonist SKF 38393, three days thereafter. As previously reported, levels of glutamate decarboxylase 67 messenger RNA increased in the striatum denervated by the 6-hydroxydopamine lesion as compared with the intact one. Striatal glutamate decarboxylase 67 messenger RNA levels, measured three days after priming with L-DOPA (50 mg/kg), further increased in the lesioned striatum while were not modified in the intact one. Administration of SKF 38393 (3 mg/kg) elicited a more intense contralateral turning behaviour in primed than in drug-naive 6-hydroxydopamine-lesioned rats but did not induce any change in striatal glutamate decarboxylase 67 messenger RNA. In contrast, striatal levels of glutamate decarboxylase 65 messenger RNA were not modified by either 6-hydroxydopamine lesions or priming with L-DOPA. The results show that priming with L-DOPA induces long-lasting changes in GABAergic neurons of the 6-hydroxydopamine-lesioned striatum. These changes might play a role in the increased behavioural response of striatal D1 receptors induced by priming.
Asunto(s)
Cuerpo Estriado/fisiología , Regulación Enzimológica de la Expresión Génica , Glutamato Descarboxilasa/genética , Levodopa/farmacología , Neuronas/fisiología , Receptores de Dopamina D1/fisiología , Transcripción Genética , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/enzimología , Lateralidad Funcional , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Isoenzimas/genética , Masculino , Actividad Motora/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/enzimología , Oxidopamina/toxicidad , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D1/agonistas , Factores de Tiempo , Transcripción Genética/efectos de los fármacos , Ácido gamma-Aminobutírico/metabolismoRESUMEN
We investigated whether D1 dopaminergic receptors modulate in vivo acetylcholine output in the shell and core areas of rat nucleus accumbens using the microdialysis technique. Subcutaneous injection (1, 2 and 3 mg/kg) of the D1 agonist SKF 82958 enhanced acetylcholine output in both areas of the nucleus accumbens while the selective D1 antagonist SCH 39166 (0.15 and 0.30 mg/kg, s.c.) lowered it. Both SKF 82958 and SCH 39166 were more effective in the shell than in the core region. The increase in acetylcholine release induced by SKF 82958 in the shell was tetrodotoxin-sensitive. The dopamine release inducer d-amphetamine (1 and 2mg/kg, s.c.) and the dopamine uptake inhibitor cocaine (10 and 20 mg/kg, i.p.) dose-dependently raised acetylcholine release in the shell and core areas. The dopaminergic stimulants, like the direct-acting D1 compounds, were more effective in the shell than in the core compartment of the nucleus accumbens. The acetylcholine increases in the shell induced by d-amphetamine (2 mg/kg), cocaine (20 mg/kg) and SKF 82958 (3 mg/kg) were antagonized by the D1 antagonists SCH 39166 (5 microM) and SCH 23390 (10 microM), applied locally by reverse dialysis. The results suggest that dopamine acting at the D1 receptors exerts a tonic stimulatory control over the cholinergic function of the shell and core compartments of the nucleus accumbens with the shell being more strongly influenced.
Asunto(s)
Acetilcolina/fisiología , Benzazepinas/farmacología , Agonistas de Dopamina/farmacología , Antagonistas de Dopamina/farmacología , Núcleo Accumbens/fisiología , Receptores de Dopamina D1/fisiología , Transmisión Sináptica/fisiología , Animales , Cocaína/farmacología , Dextroanfetamina/farmacología , Femenino , Microdiálisis , Núcleo Accumbens/efectos de los fármacos , Ratas , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/antagonistas & inhibidores , Transmisión Sináptica/efectos de los fármacos , Tetrodotoxina/farmacologíaRESUMEN
The effect of pargyline on dopamine neurotransmission was investigated by trans-striatal microdialysis combined with Fos immunohistochemistry. Pargyline, 75 mg/kg i.p., increased dopamine and acetylcholine output while drastically decreased dopamine deaminated metabolites. Administration of pargyline resulted in the appearance of Fos-positive nuclei distributed along a gradient around the dialysis probe. Pretreatment with the D1 antagonist SCH 23390 potentiated the effect of pargyline on dopamine output while preventing that on acetylcholine output and on Fos formation. Similarly, lack of calcium in the perfusion medium abolished the effect of pargyline on dopamine and acetylcholine output and on Fos formation. In rats not implanted with dialysis probes pargyline administration resulted in only rare Fos-positive nuclei in the dorsal caudate. The present study indicates that pargyline stimulates dopamine transmission in the dorsal caudate in the area around the dialysis probe but not distant from the fibre or in unimplanted rats. This effect appears to reflect an interaction between the drug-induced changes and those locally elicited by the probe.
Asunto(s)
Acetilcolina/metabolismo , Núcleo Caudado/metabolismo , Dopamina/metabolismo , Pargilina/farmacología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Putamen/metabolismo , Acetilcolina/análisis , Animales , Benzazepinas/farmacología , Calcio/farmacología , Núcleo Caudado/efectos de los fármacos , Diálisis/métodos , Dopamina/análisis , Inmunohistoquímica/métodos , Cinética , Masculino , Inhibidores de la Captación de Neurotransmisores/farmacología , Piperazinas/farmacología , Proteínas Proto-Oncogénicas c-fos/análisis , Putamen/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
CM 54903, a new psychotropic drug with a particular pharmacological profile, produced a widespread but short-lasting decrease in acetylcholine content in rat brain hemispheric regions but not in the midbrain-hindbrain or cerebellum at the dose of 40 mg/kg, i.p. The decrease was most conspicuous in the striatum. Brian regional choline contents were unaltered as were the acetylcholine turnover rates in the striatum and hippocampus. Neither choline acetyltransferase nor acetylcholinesterase activities were altered after the in vitro incubation or the in vivo administration of high amounts of the drug. CM 54903 was found to be a competitive, reversible inhibitor of the sodium-dependent high affinity uptake of choline by crude hippocampal and striatal synaptosomal preparations showing an IC50 of 10 microM in vitro. Despite the fact that the drug readily crosses the blood-brain barrier and achieves brain concentrations several-fold greater than its in vitro IC50, CM 54903 did not inhibit choline uptake in vivo although it was capable of preventing the pentylenetetrazol-stimulated choline uptake by hippocampal synaptosomes. The changes in striatal acetylcholine content induced by the blockade or the stimulation of muscarinic cholinergic receptors or dopaminergic receptors did not interfere with the effect of CM 54903 on striatal acetylcholine content while pentylenetetrazol completely prevented the decrease. The results taken together indicate that the major effect of CM 54903 on the cholinergic neurons is at the presynaptic level to compete with choline at its uptake sites.
Asunto(s)
Adamantano/análogos & derivados , Química Encefálica/efectos de los fármacos , Sistema Nervioso Parasimpático/efectos de los fármacos , Psicotrópicos/farmacología , Acetilcolina/análisis , Adamantano/metabolismo , Adamantano/farmacología , Animales , Colina/metabolismo , Femenino , Psicotrópicos/metabolismo , Ratas , Ratas Endogámicas , Sodio/farmacologíaRESUMEN
The expression of galanin (GAL) mRNA was determined by in situ hybridization after frontal deafferentation and colchicine treatment in the rat hypothalamus. Frontal deafferentation significantly increased the signal in the paraventricular nucleus (PVN), the supraoptic nucleus (SON), and dorsomedial nucleus (DMN). Colchicine treatment induced a diffuse enhancement of GAL mRNA in hypothalamic nuclei. When the two treatments were combined there was an additivity of GAL mRNA expression in the previous hypothalamic nuclei and also in the arcuate nucleus (AN), where the single treatments did not modify the signal. These results suggest the regulation of GAL mRNA expression mediated by a multineuronal pathway, separate from the colchicine-induced GAL mRNA increase.
Asunto(s)
Vías Aferentes/fisiología , Corteza Cerebral/fisiología , Colchicina/farmacología , Hipotálamo/fisiología , Neuropéptidos/biosíntesis , Biosíntesis de Péptidos , ARN Mensajero/metabolismo , Animales , Autorradiografía , Galanina , Glutamatos/metabolismo , Ácido Glutámico , Hipotálamo/efectos de los fármacos , Masculino , Hibridación de Ácido Nucleico , Sondas de Oligonucleótidos , Especificidad de Órganos , Péptidos/genética , ARN Mensajero/análisis , ARN Mensajero/genética , Ratas , Radioisótopos de AzufreRESUMEN
Previously, only in vitro studies have shown that chronic administration of morphine provokes long-lasting enhanced activity of accumbal cholinergic neurons, which may contribute to the behavioural sensitization, positive reinforcement and aversive effects associated with enhanced drug-seeking. The present study was aimed at clarifying whether these adaptive changes would also be supported by in vivo microdialysis measurements in freely moving rats, distinguishing between the accumbal substructures shell and core, and observing behavioural changes simultaneously. Acute administration of morphine dose-dependently decreased acetylcholine (ACh) release in the nucleus accumbens (NAc), with 10 mg/kg s.c. being most effective, 5 mg/kg ineffective. On day 5 of spontaneous abstinence from chronic morphine treatment (10-40 mg/kg morphine dose once daily for 5 days), when withdrawal symptoms were still present, even a lower morphine dose (5 mg/kg) was effective in decreasing ACh release in the NAc. During the later phase of abstinence, when no withdrawal symptoms were detectable, the opposite effect, i.e. an increase of ACh release was found. This later effect may represent a long-lasting neuroadaptive effect of morphine. These adaptive effects seemed to be more prominent in the NAc shell. Concurrent with these changes in ACh release, morphine challenges produced marked behavioural stereotypes, possibly indicating behavioural sensitization.