RESUMEN
GABA(B) (gamma-aminobutyric acid type B) receptors are important for keeping neuronal excitability under control. Cloned GABA(B) receptors do not show the expected pharmacological diversity of native receptors and it is unknown whether they contribute to pre- as well as postsynaptic functions. Here, we demonstrate that Balb/c mice lacking the GABA(B(1)) subunit are viable, exhibit spontaneous seizures, hyperalgesia, hyperlocomotor activity, and memory impairment. Upon GABA(B) agonist application, null mutant mice show neither the typical muscle relaxation, hypothermia, or delta EEG waves. These behavioral findings are paralleled by a loss of all biochemical and electrophysiological GABA(B) responses in null mutant mice. This demonstrates that GABA(B(1)) is an essential component of pre- and postsynaptic GABA(B) receptors and casts doubt on the existence of proposed receptor subtypes.
Asunto(s)
Epilepsia/genética , Hiperalgesia/genética , Trastornos de la Memoria/genética , Memoria/fisiología , Neuronas/fisiología , Receptores de GABA-B/fisiología , Animales , Animales Recién Nacidos , Reacción de Prevención/fisiología , Baclofeno/farmacología , Regulación de la Temperatura Corporal , Ritmo Delta/efectos de los fármacos , Epilepsia/fisiopatología , Agonistas del GABA/farmacología , Hipocampo/fisiología , Hipocampo/fisiopatología , Hiperalgesia/fisiopatología , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Trastornos de la Memoria/fisiopatología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Relajación Muscular/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiología , Músculo Esquelético/fisiopatología , Dolor/fisiopatología , Técnicas de Placa-Clamp , Subunidades de Proteína , Receptores de GABA-B/deficiencia , Receptores de GABA-B/genéticaRESUMEN
Coding region and intronic mutations in the tau gene cause frontotemporal dementia and parkinsonism linked to chromosome 17. Some of these mutations lead to an overproduction of tau isoforms with four microtubule-binding repeats. Here we have expressed the longest four-repeat human brain tau isoform in transgenic mice under the control of the murine Thy1 promoter. Transgenic mice aged 3 weeks to 25 months overexpressed human tau protein in nerve cells of brain and spinal cord. Numerous abnormal, tau-immunoreactive nerve cell bodies and dendrites were seen. In addition, large numbers of pathologically enlarged axons containing neurofilament- and tau-immunoreactive spheroids were present, especially in spinal cord. Signs of Wallerian degeneration and neurogenic muscle atrophy were observed. When motor function was tested, transgenic mice showed signs of muscle weakness. Taken together, these findings demonstrate that overexpression of human four-repeat tau leads to a central and peripheral axonopathy that results in nerve cell dysfunction and amyotrophy.
Asunto(s)
Axones/metabolismo , Axones/patología , Debilidad Muscular/patología , Secuencias Repetitivas de Ácidos Nucleicos , Degeneración Walleriana/patología , Proteínas tau/genética , Animales , Axones/ultraestructura , Tronco Encefálico/química , Tronco Encefálico/metabolismo , Tronco Encefálico/patología , Corteza Cerebral/química , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Humanos , Cuerpos de Inclusión/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microscopía Inmunoelectrónica , Debilidad Muscular/genética , Debilidad Muscular/metabolismo , Músculo Esquelético/química , Músculo Esquelético/inervación , Músculo Esquelético/patología , Proteínas de Neurofilamentos/metabolismo , Examen Neurológico , Solubilidad , Médula Espinal/química , Médula Espinal/metabolismo , Médula Espinal/patología , Raíces Nerviosas Espinales/química , Raíces Nerviosas Espinales/metabolismo , Raíces Nerviosas Espinales/patología , Degeneración Walleriana/genética , Degeneración Walleriana/metabolismo , Proteínas tau/análisis , Proteínas tau/metabolismoRESUMEN
SDZ GLC-756, a novel octahydrobenzo[g]quinoline derivative, is equipotent in displacing [3H]SCH23390 from dopamine D1 receptors and [3H]205-501 from dopamine D2 receptor binding sites. It blocks dopamine sensitive adenylate cyclase with the same potency as SCH23390, indicating antagonist properties at dopamine D1 receptors. On the other hand, SDZ GLC 756 inhibits electrically evoked acetylcholine release from rat striatal slices with the same potency as the selective dopamine D2 receptor agonist bromocriptine. This effect is blocked by spiperone suggesting that it is mediated by dopamine D2 receptor activation. The opposing action of SDZ GLC 756 on dopamine D1 and D2 receptors is also evident in vivo. SDZ GLC 756, like SCH23390, blocks apomorphine-induced rearing in mice. On the other hand, it inhibits prolactin secretion and produces circling in unilateral 6-OHDA-lesioned rats, which is compatible with stimulant properties at dopamine D2 receptors. This drug might be a new tool to study linkage between dopamine D1 and D2 receptors.
Asunto(s)
Dopaminérgicos/farmacología , Quinolinas/farmacología , Receptores de Dopamina D1/antagonistas & inhibidores , Receptores de Dopamina D2/agonistas , Acetilcolina/metabolismo , Adenilil Ciclasas/biosíntesis , Animales , Apomorfina/farmacología , Bovinos , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Dopamina/farmacología , Agonistas de Dopamina/farmacología , Técnicas In Vitro , Masculino , Ratones , Músculo Liso Vascular/efectos de los fármacos , Neostriado/efectos de los fármacos , Neostriado/metabolismo , Norepinefrina/metabolismo , Oxidopamina/farmacología , Prolactina/metabolismo , Ensayo de Unión Radioligante , Ratas , Serotonina/metabolismo , Conducta Estereotipada/efectos de los fármacos , Simpaticolíticos/farmacologíaRESUMEN
SDZ PSD 958, a novel benzo[g]quinoxaline derivative exhibits the properties of a potent orally active selective D1 receptor antagonist. It has high affinity for D1-like receptors (D1, D5; pKi = 9.7-9.8) labelled by [3H]SCH23390 and is at least 400 fold less active at D2-like receptors (i.e. D2, D4) labelled by [3H]spiperone. Effects in functional tests are consistent with D1 receptor antagonist properties. SDZ PSD 958 inhibited apomorphine-induced rearing in mice and prevented prolongation of novelty-induced locomotion in rats elicited by the selective D1 receptor agonist CY 208-243. By contrast, SDZ PSD 958 did not induce catalepsy and only weakly inhibited apomorphine-induced stereotyped gnawing in rats. This suggests that SDZ PSD 958 preferentially inhibits responses mediated by dopamine systems innervating the limbic system.
Asunto(s)
Antagonistas de Dopamina/farmacología , Sistema Límbico/efectos de los fármacos , Quinoxalinas/farmacología , Receptores de Dopamina D1/antagonistas & inhibidores , Acetilcolina/metabolismo , Adenilil Ciclasas/metabolismo , Animales , Apomorfina/antagonistas & inhibidores , Enfermedades de los Ganglios Basales/inducido químicamente , Enfermedades de los Ganglios Basales/fisiopatología , Catalepsia/inducido químicamente , Catalepsia/psicología , Bovinos , Antagonistas de Dopamina/metabolismo , Humanos , Técnicas In Vitro , Sistema Límbico/metabolismo , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Prolactina/sangre , Quinoxalinas/farmacocinética , Ensayo de Unión Radioligante , Ratas , Ratas Endogámicas , Ratas Sprague-Dawley , Receptores de Dopamina D1/agonistas , Retina/efectos de los fármacos , Retina/enzimología , Simpatectomía QuímicaRESUMEN
Centrally acting alpha 1-agonists may be of therapeutic value in dementias and other CNS disorders characterized by symptoms of noradrenergic insufficiency. Therefore, on the basis of known peripherally acting alpha 1-agonists two new groups of centrally acting alpha 1-agonists with improved lipophilicity, the hexahydronaphth[2,3-b]-1,4-oxazines type A and the octahydrobenzo[g]quinolines type B were designed. The N-methylated derivatives 14 and 33 demonstrate potent, direct agonistic activity at postjunctional alpha 1-receptors. Ring substituent alterations in compounds of type A and B change the potency of compounds on the rabbit ear artery by over 3 orders of magnitude (pD2 = 5.35-8.40). The efficacy of these compounds varies from 42 to 110%. Those alpha 1-agonists which were selective in the pithed rat increase vigilance in rats. Compound 14 was found to be a centrally acting alpha 1-agonist with good tolerability in different animal species and in healthy volunteers. Furthermore, 14 selectively stimulates the breakdown of phosphatidylinositol in rat cerebral cortex slices. In vivo, the compound reverses behavioral deficits in animals which received noradrenergic lesions following DDC or DPS4 treatment. Oxazine 14 and its close derivatives are by far more lipophilic than commonly known alpha 1-agonists. This is demonstrated in a ClogP-PROBIS plot.
Asunto(s)
Agonistas alfa-Adrenérgicos/farmacología , Encéfalo/efectos de los fármacos , Agonistas alfa-Adrenérgicos/síntesis química , Animales , Bencilaminas/farmacología , Masculino , Oxazinas/síntesis química , Oxazinas/farmacología , Quinolinas/síntesis química , Quinolinas/farmacología , Conejos , Ratas , Ratas Endogámicas , Relación Estructura-ActividadRESUMEN
The effects of senescence and of long-term Hydergine treatment on the density and pattern of mossy fibers and on the number of granule cells of the dentate gyrus were studied in the rat hippocampus. Timm's technique for the histochemical demonstration of tissue stores of zinc, associated with quantitative image analysis and microdensitometry, was used for the study of mossy fibers. Consistent with our previous studies, we observed an age-related reduction both in the area occupied by mossy fibers and in the intensity of Timm staining in the mossy fiber area. Moreover, the density of granule cells in the dentate gyrus of hippocampus was reduced with age. Hydergine administration (1 and 3 mg/kg/day, p.o.), started when the rats were 17 months old and continued for 4 months, significantly increased the area occupied by mossy fibers and the intensity of Timm staining in the hippocampus of senescent animals. Moreover, Hydergine treatment was found to counteract the age-dependent decrease in granule cell number in the dentate gyrus of the hippocampus. These findings suggest that treatment with Hydergine is effective in counteracting or in slowing down the morphological disorganization observable in the hippocampal formation with advancing age. Moreover, it is possible that the effects of Hydergine administration in elderly patients might be related to an effect at the level of the hippocampus.
RESUMEN
CQA 206-291, a new D2 dopamine receptor agonist with a biphasic dopaminergic profile, was given to six patients with idiopathic Parkinson's disease after overnight drug withdrawal. With incremental single oral doses of CQA, a dose-related, clinically significant, and prolonged antiparkinsonian effect was observed. Most subjects experienced drowsiness after the drug while a minority of subjects experienced nausea and/or vomiting or postural hypotension. Further study of this drug in humans is indicated.
Asunto(s)
Dopaminérgicos/uso terapéutico , Ergolinas/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Anciano , Dopaminérgicos/farmacología , Relación Dosis-Respuesta a Droga , Evaluación de Medicamentos , Ergolinas/farmacología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Movimiento/efectos de los fármacos , Enfermedad de Parkinson/fisiopatología , Receptores Dopaminérgicos/fisiologíaRESUMEN
The selective dopamine D2-antagonist sulpiride potentiated contralateral circling behaviour induced by the D1-agonist CY 208-243 in rats with unilateral lesions of substantia nigra, but reduced the effects of the selective D2-agonist bromocriptine. Similarly, the D1-antagonist SCH 23390 tended to increase the effects of bromocriptine but markedly inhibited CY 208-243 induced turning. The mixed D1/D2-antagonist fluphenazine was effective in reducing circling behaviour induced by either agonist, whereas pimozide (D1/D2) inhibited only the actions of bromocriptine. These results indicate that the actions of CY 208-243 and bromocriptine are mediated via distinct but interacting receptor subtypes.
Asunto(s)
Benzazepinas/farmacología , Bromocriptina/farmacología , Indoles/farmacología , Actividad Motora/efectos de los fármacos , Fenantridinas/farmacología , Receptores Dopaminérgicos/fisiología , Sulpirida/farmacología , Animales , Hidroxidopaminas/farmacología , Masculino , Oxidopamina , Ratas , Ratas Endogámicas , Receptores Dopaminérgicos/efectos de los fármacos , Receptores de Dopamina D1 , Receptores de Dopamina D2 , Sustancia Negra/fisiologíaRESUMEN
The central dopaminergic effects of an abeorphine derivative 201-678 were compared to those of apomorphine and bromocriptine in different model systems. After oral administration, this compound induced contralateral turning in rats with 6-hydroxydopamine induced nigral lesions and exhibited strong anti-akinetic properties in rats with 6-hydroxydopamine induced hypothalamic lesions. It decreased dopamine metabolism in striatum and cortex, but did not modify noradrenaline and serotonin metabolism in the rat brain. 201-678 counteracted the in vivo increase of tyrosine hydroxylase activity induced by gamma-butyrolactone. In vitro it stimulated DA-sensitive adenylate cyclase and inhibited acetylcholine release from rat striatal slices. This compound had high affinity for 3H-dopamine and 3H-clonidine binding sites. These results indicate that 201-678 is a potent, orally active dopamine agonist with a long duration of action. Furthermore it appears more selective than other dopaminergic drugs.
Asunto(s)
Indoles/farmacología , Receptores Dopaminérgicos/efectos de los fármacos , Acetilcolina/metabolismo , Adenilil Ciclasas/análisis , Animales , Química Encefálica/efectos de los fármacos , Clonidina/metabolismo , AMP Cíclico/biosíntesis , Dopamina/análisis , Hipotálamo/fisiología , Técnicas In Vitro , Levodopa/metabolismo , Masculino , Actividad Motora/efectos de los fármacos , Norepinefrina/análisis , Ratas , Ratas Endogámicas , Receptores Dopaminérgicos/metabolismo , Serotonina/análisis , Conducta Estereotipada/efectos de los fármacos , Sustancia Negra/fisiologíaRESUMEN
Rats were trained in 4 consecutive trials to obtain a liquid reward in a labyrinth system. Drugs were given s.c. 2-4 hours before each trial, and starting time (ST), running time (RT) and number of errors (NE) were recorded on the fourth trial. Hydergine reduced NE independently of its effect on ST and RT. Dihydroergocristine and dihydroergocornine prolonged ST, dihydro-alpha-ergokryptine reduced NE whilst dihydro-beta-ergokryptine did not induce any significant effect on the three parameters. These results demonstrated that none of the Hydergine components exerts a similar effect to that of Hydergine in this model. It is also known that Hydergine influences neurotransmitters like serotonin, dopamine, noradrenaline and acetylcholine in vivo and in vitro. Therefore, the effects of Hydergine on cognitive functions in rats appear to be the consequence of its different actions on the cerebral transmission.
Asunto(s)
Cognición/efectos de los fármacos , Dihidroergotoxina/farmacología , Animales , Aprendizaje/efectos de los fármacos , Masculino , Ratas , Factores de TiempoRESUMEN
Animals with 6-hydroxydopamine-induced partial unilateral lesions of the substantia nigra exhibit spontaneous recovery from motor asymmetry, a transitory increase in dopamine turnover and an increase in tyrosine hydroxylase activity in the denervated striatum. The recovery of function in these animals seems to be due to the compensatory increase in dopamine metabolism as well as due to the time-dependent increase in tyrosine hydroxylase resulting from either enzyme activation or following reinnervation of the denervated striatum by nigral efferents spared by the partial lesions.
Asunto(s)
Hidroxidopaminas/farmacología , Actividad Motora/efectos de los fármacos , Sustancia Negra/fisiología , Ácido 3,4-Dihidroxifenilacético/metabolismo , Anfetamina/farmacología , Animales , Apomorfina/farmacología , Dopamina/metabolismo , Femenino , Lateralidad Funcional , Ácido Homovanílico/metabolismo , Oxidopamina , Ratas , Ratas Endogámicas , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismo , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Investigation of the influence of lithium upon the down-regulation of serotonin2 receptors in rat frontal cortex induced by long-term treatment with dibenzepin, an antidepressant without appreciable affinity to serotonin2 receptors. Groups of rats were treated orally for four weeks with either dibenzepin, lithiumcarbonate, or dibenzepine + lithium carbonate. Serotonin2 receptors were labelled with the new selective ligand [3H]mesulergine. Chronic treatment with dibenzepin caused down-regulation of serotonin2 receptors in the frontal cortex. Chronic treatment with lithiumcarbonate alone did not change the specific [3H]mesulergine binding. Given simultaneously with dibenzepin lithium did not prevent the down-regulation of serotonin2 receptors seen after dibenzepin alone.
Asunto(s)
Dibenzazepinas/farmacología , Lóbulo Frontal/metabolismo , Litio/farmacología , Receptores de Serotonina/efectos de los fármacos , Animales , Ergolinas , Masculino , Ensayo de Unión Radioligante , Ratas , Factores de TiempoRESUMEN
Studies with selective lesions of cerebral structures have revealed the involvement of serotonin in sleep and wakefulness. However, the mechanisms underlying the role of serotonin remain obscure. An appreciation of the interrelationships between serotonin and other transmitter systems might lead to a better understanding of the functions subserved by serotonin. A serotoninergic projection from the median raphé nucleus to dopamine neurons in the substantia nigra has been reported. We have therefore investigated the possible influence of the raphé system on the nigro striatal dopamine pathway in the rat using the "turning" model described by UNGERSTEDT (1971). An unilateral lesion in the median raphé nucleus induces contralateral turning similar to that observed following apomorphine administration to rats with a unilaterally degenerated nigro striatal pathway. Similarly, unilateral application of 2.5 micrograms of LSD 25 to the median raphé nucleus of normal rats also provokes contralateral turning. On the other hand, unilateral injection of LSD 25 into the zona compacta of the substantia nigra induces turning ipsilateral to the site of injection. The above results, and also those from several experiments in which apomorphine or LSD 25 was applied systematically, suggest that serotonin neurons in the median raphé nucleus exert an inhibitory influence on the dopaminergic nigro striatal system. These studies demonstrate that the serotoninergic median raphé system, in addition to its involvement in sleep and wakefulness, also exerts an important influence on motor functions.
Asunto(s)
Apomorfina/farmacología , Dietilamida del Ácido Lisérgico/farmacología , Actividad Motora/efectos de los fármacos , Serotonina/fisiología , Animales , Lateralidad Funcional , Haloperidol/farmacología , Hidroxidopaminas/farmacología , Cinética , Masculino , Núcleos del Rafe/efectos de los fármacos , Núcleos del Rafe/fisiología , Ratas , Sustancia Negra/efectos de los fármacos , Sustancia Negra/fisiologíaRESUMEN
Neurochemical and neuropharmacological investigations with four ergot derivatives reveal differential pharmacodynamic effects of these compounds. Bromocriptine and CM 29-712 showed actions typical of postsynaptic dopamine receptor stimulants, in particular in the extrapyramidal system. CM 29-712 proved to be more potent than bromocriptine, with an early onset of action. CF 25-397 and dihydroergotoxine, while not showing all actions typical of central dopamine agonists, appeared to exert some of their effects by means of a stimulation of central serotoninergic sites. In the rat sleep-wakefulness cycles and in reserpine-induced ponto-geniculooccipital waves in the cat, they mimicked the effects of 5-hydroxytryptophan. In the latter test, CF 25-397 proved to be particularly potent. In addition, bromocriptine, dihydroergotoxine and CM 29-712 showed neurochemical effects consistent with central alpha-adrenergic blockade or an enhanced impulse flow in central noradrenergic neurons.
Asunto(s)
Dihidroergotoxina/farmacología , Ergolinas/farmacología , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/metabolismo , Bromocriptina/farmacología , Catecolaminas/metabolismo , Fenómenos Químicos , Química , Electroencefalografía , Humanos , Locomoción/efectos de los fármacos , Masculino , Ratones , Morfina/antagonistas & inhibidores , Trastornos del Movimiento/inducido químicamente , Conejos , Ratas , Receptores Dopaminérgicos/efectos de los fármacos , Reserpina , Sueño/efectos de los fármacos , Conducta Estereotipada/efectos de los fármacosRESUMEN
The effects of drugs which interfere with alpha-adrenergic and dopaminergic mechanisms, involved in GH and PRL secretion, have been analyzed in urethane anesthetized rats. Clonidine induced a dose-dependent release of GH (0.0032--0.1 mg/kg i.v.) as well as of PRL (0.032--1.0 mg/kg i.v.). The lowest dose of clonidine, when given into the third ventricle, provoked a very pronounced release of GH. Phentolamine, given intravenously, inhibited the clonidine-induced GH release in a dose-dependnet manner. L-Dopa administered intravenously and apomorphine administered intravenously or intraventricularly did not affect basal secretion of GH bu- produced a dose-dependnet inhibition of clonidine-induced GH release. Pimozide did not change basal GH secretion. Furthermore pimozide did not attenuate the inhibition of clonidine-induced GH secretion seen after apomorphine administration, however, it completely reversed apomorphine-induced PRL inhibition. These findings demonstrate that an alpha-adrenoceptor-mediated stimulatory mechanism is involved in GH and PRL secretion. An inhibitory dopaminergic mechanism is confirmed for PRL secretion and suggested for GH secretion.
Asunto(s)
Hormona del Crecimiento/sangre , Simpaticolíticos/farmacología , Simpatomiméticos/farmacología , Animales , Apomorfina/farmacología , Clonidina/farmacología , Relación Dosis-Respuesta a Droga , Inyecciones Intraventriculares , Levodopa/farmacología , Masculino , Norepinefrina/farmacología , Fentolamina/farmacología , Pimozida/farmacología , Prolactina/sangre , Ratas , UretanoRESUMEN
Intravenous injection of 0.1 mg/kg clonidine into rats under urethane anaesthesia induced a prompt and long-lasting release of growth hormone, estimated by radioimmunoassay (IRGH), which could be abolished by 0.2 mg/kg phentolamine given into the 3rd ventricle. Injection of 3 mug/kg clonidine into the 3rd ventricle stimulated also the release of IRGH significantly. Intravenous administration of 0.32 mg/kg phenylephrine caused a small and transient release of IRGH only. These results provide evidence that central alpha-adrenergic stimulation resulting in an increased GH secretion is one important mechanism in the regulation of this hormone in the rat.