RESUMEN
The lack of effective drug therapies for motor neuron diseases (MND), and in general for all the neurodegenerative disorders, has increased the interest toward the potential use of stem cells. Among the cell therapy approaches so far tested in MND animal models, systemic injection of human cord blood mononuclear cells (HuCB-MNCs) has proven to reproducibly increase, although modestly, the life span of SOD1G93A mice, a model of familial amyotrophic lateral sclerosis (ALS), even if only few transplanted cells were found in the damaged areas. In attempt to improve the potential efficacy of these cells in the central nervous system, we examined the effect and distribution of Hoechst 33258-labeled HuCB-MNCs after a single bilateral intracerberoventricular injection in two models of motor neuron degeneration, the transgenic SOD1G93A and wobbler mice. HuCB-MNCs significantly ameliorated symptoms progression in both mouse models and prolonged survival in SOD1G93A mice. They were localized in the lateral ventricles, even 4 months after administration. However, HuCB-MNCs were not found in the spinal cord ventral horns. This evidence strengthens the hypothesis that the beneficial role of transplanted cells is not due to cell replacement but is rather associated with the production and release of circulating protective factors that may act both at the central and/or peripheral levels. In particular, we show that HuCB-MNCs release a series of cytokines and chemokines with antiinflammatory properties that could be responsible of the functional improvement of mouse models of motor neuron degenerative disorders.
Asunto(s)
Sangre Fetal/citología , Infusiones Intraventriculares , Enfermedad de la Neurona Motora/patología , Esclerosis Amiotrófica Lateral/patología , Animales , Bisbenzimidazol/farmacología , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Citocinas/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Humanos , Recién Nacido , Ratones , Ratones Transgénicos , Enfermedad de la Neurona Motora/metabolismo , Reacción en Cadena de la Polimerasa/métodos , Médula Espinal/patologíaRESUMEN
The pathogenetic processes underlying the selective motor neuron degeneration in amyotrophic lateral sclerosis (ALS) are complex and still not completely understood even in the cases of inherited disease caused by mutations in the Cu/Zn superoxide dismutase-dependent (SOD1) gene. Recent evidence supports the view that ALS is not a cell-autonomous disease and that glial-neuron cross-talk, throughout cytokines and other toxic factors like the nitric oxide and superoxide, is a crucial determinant for the induction of motor neuron death. This cell-cell interaction may determine the progression of the disease through processes that are likely independent of the initial trigger and that may converge on the activation of intracellular death pathways in the motor neurons. In this review we provide support to the hypothesis that aberrant expression and activity of p38 mitogen protein-activated kinases cascade (p38MAPK) in motor neurons and glial cells may play a role in the development and progression of ALS. Increased activation of p38MAPK may phosphorylate neuron-specific substrates altering their physiological properties and it may turn on responsive genes leading to neurotoxicity.
Asunto(s)
Esclerosis Amiotrófica Lateral/metabolismo , Comunicación Celular/fisiología , Neuronas Motoras/metabolismo , Neuroglía/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Animales , Humanos , Neuronas Motoras/patología , Neuroglía/patología , Receptor Cross-Talk/fisiologíaRESUMEN
The effect of the 5-hydroxytryptamine (5-HT) and noradrenaline (NA) reuptake inhibitor sibutramine was studied in food deprived, neuropeptide Y (NPY)- or muscimol-injected rats. Sibutramine dose-dependently reduced feeding caused by food-deprivation (ED50 = 5.1+/-0.8 mg kg(-1)) or by NPY injection into the paraventricular nucleus of the hypothalamus (ED50 = 6.0+/-0.5 mg kg(-1)). The increase in food intake caused by muscimol injected into the dorsal raphe was not modified by sibutramine (1-10 mg kg(-1)). The hypophagic effect of 5.1 mg kg(-1) sibutramine in food-deprived rats was studied in rats pretreated with different serotonin receptor antagonists. Metergoline (non-selective, 0.3 and 1.0 mg kg(-1)), ritanserin (5-HT2A/2C, 0.5 and 1.0 mg kg(-1)) and GR127935 (5-HT1B/1D), 0.5 and 1.0 mg kg(-1)) did not modify the hypophagic effect of sibutramine, while SB206553 (5-HT2B/2C, 5 and 10 mg kg(-1)) slightly but significantly reduced it (Fint(2.53) = 3.4; P<0.05). The reduction in food intake caused by 6.0 mg kg(-1) sibutramine in NPY-injected rats was not modified by GR127935 (1.0 mg kg(-1)). The results suggest that, with the possible exception of a partial involvement of 5-HT2B/2C receptors in sibutramine's hypophagia in food-deprived rats, 5-HT1 and 5-HT2 receptor subtypes do not play an important role in the hypophagic effect of sibutramine, at least in the first 2 h after injection.
Asunto(s)
Depresores del Apetito/farmacología , Ciclobutanos/farmacología , Ingestión de Alimentos/efectos de los fármacos , Receptores de Serotonina/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Masculino , Neuropéptido Y/farmacología , Oxadiazoles/farmacología , Piperazinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Serotonina/clasificación , Receptores de Serotonina/fisiologíaRESUMEN
The selective 5-hydroxytryptamine reuptake inhibitor citalopram (10 and 20 mg kg(-1), i.p.) significantly reduced food intake in male rats (CD-COBS) habituated to eat their daily food during a 4-h period. The 5-HT1A receptor antagonist WAY100635 (0.3 mg kg(-1)) administered systemically did not modify feeding but significantly potentiated the reduction in food intake caused by 10 mg kg(-1) i.p. citalopram. The dose of 5 mg kg(-1) i.p. citalopram was not active in animals pretreated with vehicle but significantly reduced feeding in animals pretreated with WAY100635. WAY100635 (0.1 microg 0.5 microl(-1)) injected into the dorsal raphe significantly potentiated the hypophagic effect of 10 mg kg(-1) citalopram. WAY100635 (1.0 microg 0.5 microl(-1)) injected into the median raphe did not modify feeding or the hypophagic effect of 10 mg kg(-1) citalopram. The 5-HT2B/2C receptor antagonist SB206553 (10 mg kg(-1), p.o.) slightly reduced feeding by itself but partially antagonized the effect of WAY100635 administered systemically (0.3 mg kg(-1), s.c.) or into the dorsal raphe (0.1 microg 0.5 microl(-1)) in combination with 10 mg kg(-1) i.p. citalopram. The hypophagic effect of 10 mg kg(-1) i.p. citalopram alone was not significantly modified by SB206553. Brain concentrations of citalopram and its metabolite desmethylcitalopram in rats pretreated with SB206553, WAY100635 and their combination were comparable to those of vehicle-pretreated rats, 90 min after citalopram injection. The hypophagic effect of citalopram was potentiated by blocking 5-HT1A receptors. Only the effect of the WAY100635/citalopram combination seemed to be partially mediated by central 5-HT2C receptors.
Asunto(s)
Citalopram/farmacología , Ingestión de Alimentos/efectos de los fármacos , Receptores de Serotonina/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Antagonistas de la Serotonina/farmacología , Animales , Relación Dosis-Respuesta a Droga , Inyecciones , Masculino , Piperazinas/administración & dosificación , Piperazinas/farmacología , Piridinas/administración & dosificación , Piridinas/farmacología , Núcleos del Rafe/fisiología , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT2C , Receptores de Serotonina 5-HT1 , Antagonistas de la Serotonina/administración & dosificación , Agonistas de Receptores de Serotonina/farmacologíaRESUMEN
The effect of 5-HT1 and 5-HT2 receptor agonists administered into the paraventricular hypothalamus was studied on the hyperphagia caused by neuropeptide Y (NPY) injected into the same area. The 5-HT2A/2C receptor agonist DOI (10-20 nmol/0.5 microliter) significantly reduced NPY overeating while the 5-HT1A/1B receptor agonist RU 24969 (3.5-14 nmol/0.5 microliter) and the 5-HT1B/2C receptor agonist mCPP (5-20 nmol/0.5 microliter) had no such effect. The 5-HT2A receptor antagonist spiperone (5 microgram/0.5 microliter) and the corticotropin releasing factor antagonist alpha-helical-CRF9-41 (0.5-1 micrograms/0.5 microliter) completely antagonized the effect of 10 nmol DOI.
Asunto(s)
Hormona Liberadora de Corticotropina/fisiología , Hiperfagia , Neuropéptido Y/farmacología , Receptores de Serotonina/fisiología , Agonistas de Receptores de Serotonina/farmacología , Anfetaminas/farmacología , Animales , Conducta Alimentaria/efectos de los fármacos , Conducta Alimentaria/fisiología , Indoles/farmacología , Masculino , Núcleo Hipotalámico Paraventricular , Piperazinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT2A , Receptores de Serotonina/efectos de los fármacos , Espiperona/farmacologíaRESUMEN
d-Fenfluramine (0.63 mg/kg i.p.), a serotonin (5-hydroxytryptamine, 5-HT) releaser and re-uptake inhibitor, reduced the eating caused by neuropeptide Y (235 pmol) injected into the paraventricular nucleus of the hypothalamus. The 5-HT1 and 5-HT2 receptor antagonist metergoline (1.0 and 2.0 mg/kg i.p.) and the 5-HT1A and 5-HT1B receptor antagonist (+/-)-cyanopindolol (3.0 and 8.0 mg/kg s.c.) significantly antagonized the effect of d-fenfluramine. The 5-HT2A and 5-HT2C receptor antagonist mesulergine (0.1 and 0.3 mg/kg s.c.) and the 5-HT2A receptor antagonist ketanserin (2.5 and 5.0 mg/kg i.p.) did not significantly modify the effect, nor did the 5-HT1A and 5-HT1B receptor antagonist (-)-propranolol (20-40 nmol), injected bilaterally into the paraventricular nucleus of the hypothalamus. The results suggest that d-fenfluramine reduces neuropeptide Y's hyperphagia by indirectly stimulating 5-HT1B receptors outside the paraventricular nucleus of the hypothalamus.
Asunto(s)
Ingestión de Alimentos/efectos de los fármacos , Fenfluramina/farmacología , Neuropéptido Y/farmacología , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Receptores de Serotonina/efectos de los fármacos , Análisis de Varianza , Animales , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/farmacología , Interacciones Farmacológicas , Ergolinas/administración & dosificación , Ergolinas/farmacología , Fenfluramina/administración & dosificación , Fenfluramina/antagonistas & inhibidores , Hiperfagia/inducido químicamente , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Inyecciones Intraperitoneales , Inyecciones Subcutáneas , Ketanserina/administración & dosificación , Ketanserina/farmacología , Masculino , Metergolina/administración & dosificación , Metergolina/farmacología , Neuropéptido Y/administración & dosificación , Núcleo Hipotalámico Paraventricular/fisiología , Pindolol/administración & dosificación , Pindolol/análogos & derivados , Pindolol/farmacología , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT1B , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/administración & dosificación , Antagonistas de la Serotonina/farmacologíaRESUMEN
1. The effect of the CCKA receptor antagonist, devazepide (100 mg kg-1) on meal parameters during the initial phase of the dark period was studied in free-feeding rats by use of a procedure for continuously monitoring feeding patterns. 2. In a second experiment, the effect of devazepide on the reduction in meal parameters induced by the 5-hydroxytryptamine (5-HT) releaser and uptake inhibitor, (+)-fenfluramine (1.5 mg kg-1) in 4 h food-deprived rats was examined. 3. The hypophagic effect of an intraperitoneal injection of cholecystokinin (CCK-8, 4 micrograms kg-1) was studied in rats treated with the 5-HT receptor antagonist, metergoline (1 and 2 mg kg-1). 4. Devazepide increased the size of the first meal in free-feeding, but not in 4 h food-deprived rats and partially antagonized the effect of (+)-fenfluramine on the size and duration of the first meal. The reduction in eating rate induced by (+)-fenfluramine was not modified by devazepide. No changes in (+)-fenfluramine or (+)-norfenfluramine levels were found in the brain of rats treated with devazepide. 5. The effect of CCK-8 on meal size was completely antagonized by 2 mg kg-1 metergoline. A significant interaction was also found between 2 mg kg-1 metergoline and CCK-8 as regards their effect on the inter-meal interval. 6. The results suggest a reciprocal interaction between 5-HT and CCK-8 in enhancing the satiating effect of food in rats.
Asunto(s)
Colecistoquinina/farmacología , Conducta Alimentaria/efectos de los fármacos , Serotonina/farmacología , Animales , Benzodiazepinonas/farmacología , Encéfalo/metabolismo , Colecistoquinina/antagonistas & inhibidores , Devazepida , Fenfluramina/farmacocinética , Fenfluramina/farmacología , Masculino , Metergolina/farmacología , Ratas , Ratas Sprague-Dawley , Respuesta de Saciedad/efectos de los fármacosRESUMEN
Ritanserin (0.5 and 1 mg/kg) and ketanserin (2.5 mg/kg), two antagonists with high affinity for 5-HT2 receptors, attenuated restraint stress-induced hypophagia in rats. Two injections of the 5-HT2 receptor antagonist cinanserin (30 nmol/0.5 microliter) in the paraventricular nucleus of the hypothalamus completely reversed the effect of stress on food intake. (+/-)Cyanopindolol (3 and 8 mg/kg), an antagonist at 5-HT1A and 5-HT1B receptors, had no effect whereas 8-hydroxy-2-di-n-propylamino)tetralin (30-300 micrograms/kg), an agonist at 5-HT1A receptors, significantly attenuated the hypophagia. The results suggest that restraint stress-induced hypophagia is mediated by 5-HT2 receptors in the paraventricular nucleus of the hypothalamus. The potential utility of this model in anorexia nervosa is discussed.
Asunto(s)
Anorexia/fisiopatología , Conducta Alimentaria/fisiología , Núcleo Hipotalámico Paraventricular/fisiopatología , Receptores de Serotonina/fisiología , Estrés Fisiológico/fisiopatología , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Amidinas/farmacología , Animales , Anorexia/tratamiento farmacológico , Anorexia/etiología , Anorexia Nerviosa/fisiopatología , Modelos Animales de Enfermedad , Conducta Alimentaria/efectos de los fármacos , Ketanserina/farmacología , Ketanserina/uso terapéutico , Masculino , Pindolol/análogos & derivados , Pindolol/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Serotonina/clasificación , Receptores de Serotonina/efectos de los fármacos , Restricción Física , Ritanserina/farmacología , Ritanserina/uso terapéutico , Estrés Fisiológico/complicacionesRESUMEN
The effect of sertraline, a serotonin (5-HT) uptake inhibitor, on 1 h food intake of food-deprived rats was studied in male rats treated intraperitoneally with 1 and 2.5 mg/kg metergoline, a 5-HT1 and 5-HT2 receptor antagonist, 0.5 mg/kg GR 38032F, a 5-HT3 receptor antagonist, or intracerebroventricularly with 6-hydroxy-dopamine to destroy catecholamine-containing neurons. The feeding-suppressant effect of 10 mg/kg sertraline was not significantly modified by any treatment. At 1 and 2.5 mg/kg metergoline did not significantly modify the reduction in total intake and meal size induced by sertraline in slightly-deprived rats whereas at 1 mg/kg the 5-HT receptor antagonist completely blocked the effect of 1.5 mg/kg d-fenfluramine, a 5-HT releaser and uptake inhibitor. In a runway test, metergoline at 1 but not 2.5 mg/kg significantly attenuated the effect of 10 mg/kg sertraline on starting speed in the first and second trial blocks. Both doses tended to attenuate the effect of sertraline on running speed but the interaction was not significant. The reduction in food intake induced by sertraline was antagonized only by 1 mg/kg metergoline in the last trial block. The bulk of these findings argues against an important role of 5-HT receptors in the effect of sertraline on feeding behaviour.
Asunto(s)
1-Naftilamina/análogos & derivados , Conducta Alimentaria/efectos de los fármacos , Receptores de Serotonina/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , 1-Naftilamina/farmacología , Animales , Química Encefálica/efectos de los fármacos , Dopamina/metabolismo , Ingestión de Alimentos/efectos de los fármacos , Privación de Alimentos/fisiología , Masculino , Metergolina/farmacología , Norepinefrina/metabolismo , Ondansetrón/farmacología , Oxidopamina , Ratas , Ratas Sprague-Dawley , Antagonistas de la Serotonina/farmacología , Sertralina , Simpatectomía QuímicaRESUMEN
The hypophagic effect of fluoxetine was studied in rats, injected intracerebroventricularly with 150 micrograms/20 microliters 5,7-dihydroxytryptamine, to destroy serotonin-containing neurones or 250 micrograms/20 microliters 6-hydroxydopamine, to destroy catecholamine-containing neurones. The effect of various serotonin receptor antagonists was assessed as well. Neither neurotoxin significantly modified the effect of 20 mg/kg (i.p.) fluoxetine on food intake. Metergoline (1-5 mg/kg), (-)-propranolol (16 mg/kg) and ICS 205-930 (0.1 and 1 mg/kg) did not modify the hypophagic effect of fluoxetine, while mianserin (1 and 5 mg/kg), ritanserin (0.5 and 1 mg/kg) and xylamidine (3 mg/kg) slightly but significantly reduced it. While the mechanism by which some 5-HT receptor antagonists modify the effect of fluoxetine remains to be elucidated, it seems clear that 5-HT receptors hardly have any significant role in the ability of the drug to suppress food intake.
Asunto(s)
Encéfalo/fisiología , Catecolaminas/fisiología , Ingestión de Alimentos/efectos de los fármacos , Fluoxetina/farmacología , Serotonina/fisiología , 5,7-Dihidroxitriptamina/administración & dosificación , Animales , Inyecciones Intraventriculares , Masculino , Oxidopamina/administración & dosificación , Ratas , Ratas EndogámicasRESUMEN
The effect of d-fenfluramine, 1.5 mg/kg i.p., on meal patterns was studied in rats treated i.p. with 1 mg/kg metergoline or 0.5 mg/kg ritanserin or s.c. with 3 mg/kg (+/-)cyanopindolol. d-Fenfluramine significantly reduced eating rate, meal size and total intake in the first 4 h of testing and the effects were antagonized by metergoline. (+/-)Cyanopindolol reduced total intake and the effect of d-fenfluramine on this measure; the effect of d-fenfluramine on meal size (but not on eating rate) was also reduced by (+/-)cyanopindolol. Ritanserin only reduced the rate of eating and the effect of d-fenfluramine on this measure. The results suggest that 5-HT1 receptors, possibly of the 5-HT1B type, are involved in the ability of d-fenfluramine to cause satiety in freely feeding rats.
Asunto(s)
Conducta Alimentaria/efectos de los fármacos , Fenfluramina/farmacología , Receptores de Serotonina/fisiología , Animales , Masculino , Metergolina/farmacología , Pindolol/análogos & derivados , Pindolol/farmacología , Ratas , Ritanserina/farmacología , Antagonistas de la Serotonina , EstereoisomerismoRESUMEN
The effects of d-fenfluramine (1.5 mg/kg) and sertraline (10 mg/kg), administered intraperitoneally once daily for seven days were studied on feeding parameters of rats over various periods. On the first day of treatment both drugs markedly reduced meal size and meal duration during the first hour and, to a lesser extent, the first 4 h. No effects were seen later. The size and duration of eating bouts were also markedly reduced by both drugs in the first hour. There was no significant effect of either drug on meal frequency in any period. Only d-fenfluramine significantly reduced the rate of eating within 4 h from the start of testing. Sertraline, but not d-fenfluramine, markedly increased locomotor activity in the first 4 h after the start of testing. The d-fenfluramine effect on eating rate disappeared by the second day whereas total intake and meal size were still reduced on day five. By days six and seven however the d-fenfluramine-treated rats did not differ from the controls. During the seven-day treatment sertraline always reduced total food eaten and meal size but caused only transient changes of locomotor activity and eating rate. Since the effects of d-fenfluramine and sertraline on meal size and food intake could be separated from the effects on eating rate and arousal, it appears that at appropriate doses these drugs specifically increase the satiating effect of food. Tolerance to this effect appears to develop more rapidly for d-fenfluramine than for sertraline.
Asunto(s)
1-Naftilamina/análogos & derivados , Conducta Alimentaria/efectos de los fármacos , Fenfluramina/farmacología , Respuesta de Saciedad/efectos de los fármacos , 1-Naftilamina/farmacología , Animales , Tolerancia a Medicamentos , Ingestión de Alimentos/efectos de los fármacos , Inyecciones Intraperitoneales , Masculino , Actividad Motora/efectos de los fármacos , Ratas , Ratas Endogámicas , SertralinaRESUMEN
In one experiment, the effect of d-fenfluramine (DF) on gastric emptying was studied in rats treated i.p. with metergoline, a non-selective serotonin (5-HT) receptor antagonist, ritanserin, a selective 5-HT2 and 5-HT1C receptor antagonist, and xylamidine, a 5-HT antagonist which has poor access to the brain. Metergoline (1 mg/kg) but not ritanserin (0.5 mg/kg) or xylamidine (3 mg/kg) blocked the effect of 2.5 mg/kg DF studied 2 and 4 h after injection. In a second experiment, we studied the ability of metergoline to antagonise the effect of DF, administered after a meal, on runway performance, food intake and gastric emptying assessed 4 h later. Metergoline at a dose of 1 mg/kg did not antagonise the effect of DF (2.5 mg/kg) on runway performance but completely blocked the effect on gastric emptying. The data clearly show that DF delays gastric emptying by indirectly activating 5-HT1 receptors; this effect is not important for the ability of DF to reduce runway performance and food intake when the drug is injected after a pre-feeding period. While there is evidence that DF hastens the termination of the meal by a 5-HT mechanism, the data suggest that DF may prolong the satiating effect of food during the post-absorptive phase by mechanisms other than 5-HT.
Asunto(s)
Conducta Alimentaria/efectos de los fármacos , Fenfluramina/farmacología , Vaciamiento Gástrico/efectos de los fármacos , Receptores de Serotonina/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Masculino , Metergolina/farmacología , Piperidinas/farmacología , Proglumida/farmacología , Ratas , Ritanserina , Antagonistas de la Serotonina/farmacologíaRESUMEN
Sertraline, administered i.p. in single doses or as three injections in 24 h, significantly reduced the immobility of rats in the forced swimming test at 64 and 100 mumol/kg. The effect of three doses of 64 mumol/kg in 24 h was not modified in animals treated i.p. with metergoline (5 mg/kg) 3 h before testing. I.c.v. administration of 150 micrograms 5,7-dihydroxytryptamine, which depleted brain serotonin, or infusion of 6 micrograms 6-hydroxydopamine in the locus coeruleus, which markedly depleted noradrenaline in terminal regions, was also ineffective. The effect of 64 mumol/kg sertraline, once daily for 7 days, was not modified by i.c.v. 5,7-dihydroxytryptamine. The effect of three doses of 64 mumol/kg sertraline in 24 h was instead completely antagonized by 100 mg/kg sulpiride given 90 min before testing. The exact mechanism of this effect and its relevance for the favourable effects of sertraline in human depression remain to be clarified.
Asunto(s)
1-Naftilamina/análogos & derivados , Neuronas/fisiología , Antagonistas de la Serotonina/farmacología , Serotonina/fisiología , 1-Naftilamina/farmacología , 5,7-Dihidroxitriptamina/farmacología , Animales , Conducta Animal/efectos de los fármacos , Hidroxidopaminas/farmacología , Inyecciones Intraventriculares , Locus Coeruleus/citología , Locus Coeruleus/efectos de los fármacos , Locus Coeruleus/fisiología , Masculino , Actividad Motora/efectos de los fármacos , Oxidopamina , Esfuerzo Físico/fisiología , Ratas , Ratas Endogámicas , Sertralina , NataciónRESUMEN
The effects of sulpiride isomers injected into the nucleus accumbens on the anti-immobility activity of desipramine in rats were studied to clarify the role of dopamine receptors. (-)-Sulpiride 100 ng/0.5 microliters injected bilaterally into the nucleus accumbens 5 min before testing reduced the effect of a 7-day treatment with 10 mg/kg per day desipramine in the swimming test but 5 micrograms/0.5 microliter (+)-sulpiride injected in the same area had no effect. Fluphenazine, 5 micrograms/0.5 microliter, or 6-hydroxydopamine-induced depletion of dopamine in the nucleus accumbens also reduced the anti-immobility effect of desipramine. The data further support the hypothesis that dopamine transmission in the nucleus accumbens has a permissive role in the effect of desipramine in the forced swimming test.
Asunto(s)
Depresión/fisiopatología , Desipramina/farmacología , Dopamina/fisiología , Sistema Límbico/fisiología , Animales , Flufenazina/farmacología , Hidroxidopaminas/farmacología , Inyecciones , Masculino , Actividad Motora/efectos de los fármacos , Núcleo Accumbens , Oxidopamina , Ratas , Ratas Endogámicas , Receptores Dopaminérgicos/efectos de los fármacos , Sulpirida/administración & dosificación , Sulpirida/farmacología , Natación , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Transmisión Sináptica/efectos de los fármacosRESUMEN
The influence of alpha 2-adrenoceptor blockade on the activity of desipramine in an experimental model of depression was studied by using idazoxan and 1-(pyrimidinyl)piperazine (1-PP). The two drugs antagonists at these receptors, were studied for their ability to modify the effect of repeated treatment with the antidepressant, desipramine in the forced swimming test. Idazoxan (0.03, 0.3 and 3 mg/kg s.c.) and 1-PP (0.3 and 3 mg/kg p.o.) given with the last dose of a 7-day schedule of 10 mg/kg i.p. desipramine significantly reduced the effect of the latter on immobility. On its own neither drug modified the immobility time of rats at any dose. Infusion of various concentrations of idazoxan (1.6, 8 and 40 ng/microliters) in the rat locus coeruleus (LC), dose dependently antagonized the effect of desipramine without causing any appreciable change in motor behavior or immobility. The effect of idazoxan (8 ng/microliters) infusion in the LC was completely prevented by administering 6 micrograms 6-hydroxydopamine in the same region 12 days earlier. It thus appears that alpha 2-adrenoceptor blockade prevents the effect of desipramine in the forced swimming test, presumably by an effect on noradrenaline-containing cells in the LC. The question of how blockade or activation of alpha 2-adrenoceptors, both in the LC and in other sites, could influence antidepressant activity is discussed.
Asunto(s)
Antagonistas Adrenérgicos alfa/farmacología , Depresión/psicología , Desipramina/antagonistas & inhibidores , Actividad Motora/efectos de los fármacos , Animales , Buspirona/análogos & derivados , Buspirona/farmacología , Depresión/fisiopatología , Dioxanos/farmacología , Hidroxidopaminas/farmacología , Idazoxan , Locus Coeruleus/fisiología , Masculino , Oxidopamina , Ratas , NataciónRESUMEN
1-(3-Trifluoromethylphenyl)piperazine (TFMPP), a serotonin1 (5-HT1) receptor agonist, injected i.p. in doses of 0.1 and 0.6 mg/kg, did not modify the immobility time of rats in the forced swimming test but significantly antagonized the effect of a 7 days treatment with 10 mg/kg per day desipramine (DMI). A similar effect was found on infusing 1 and 5 micrograms/microliters TFMPP bilaterally into the ventral tegmental area (VTA). Infusion of 5 micrograms/microliters TFMPP into the nucleus accumbens or into the globus pallidus did not modify the effect of DMI. The effect of 5 micrograms TFMPP infused into the VTA was prevented by the i.p. administration of 5 mg/kg metergoline, a non-selective serotonin receptor antagonist. Infusion of 5 micrograms/microliters 8-hydroxy-2-(di-n-propylamino)tetralin, a specific 5-HT1A receptor agonist, into the VTA did not modify the effect of DMI. Besides acting as a 5-HT1B receptor agonist, TFMPP may also act on other 5-HT receptor types, but available evidence suggests that its former action is more important. It thus appears that 5-HT1 receptors in the VTA, presumably of the 5-HT1B type, act by preventing the anti-immobility effect of DMI. The role of VTA dopamine and non-dopamine cells in the effect of TFMPP is discussed.
Asunto(s)
Depresión/metabolismo , Desipramina/antagonistas & inhibidores , Piperazinas/farmacología , Receptores de Serotonina/efectos de los fármacos , 8-Hidroxi-2-(di-n-propilamino)tetralin , Animales , Inyecciones , Masculino , Metergolina/farmacología , Piperazinas/administración & dosificación , Ratas , Natación , Tegmento Mesencefálico , Tetrahidronaftalenos/farmacologíaRESUMEN
The role of mu opioid receptors in the nucleus raphe dorsalis (DR) in the control of apomorphine-induced aggression was studied in rats. Administration in the DR of a selective mu opioid receptor agonist, (D-Ala2,N-Me-Phe4,Gly5-ol)-enkephalin (DAGO), in doses ranging from 0.01 to 1 microgram/0.5 microliter, dose-dependently reduced aggression caused by apomorphine 20 mg/kg intraperitoneally. 0.01 microgram DAGO significantly reduced the time spent by the animals in aggressive posture and 0.1 and 1 microgram markedly reduced both aggressive postures and attacks. 5 micrograms (in 0.5 microliter) naloxone in the DR completely antagonized the anti-aggressive effect of DAGO (0.1 microgram/0.5 microliter) injected in the same area. 0.1 and 1 microgram but not 0.01 microgram DAGO significantly increased serotonin (5-HT) metabolism in the striatum, a terminal area almost exclusively innervated by DR, indicating that the activity of 5-HT cells in the DR was modified by DAGO. In animals given 6 micrograms/3 microliters 5,7-dihydroxytryptamine in the DR 11 days before, in which striatal 5-HT levels were markedly depleted, no significant changes were found in the time spent by the apomorphine-treated animals in aggressive postures, numbers of attacks or anti-aggressive effect of 0.1 and 1 microgram DAGO administered in the DR. The study shows for the first time that activation of mu opioid receptors in the DR has a powerful anti-aggressive effect in one model of experimental aggression by a mechanism apparently not involving changes in the activity of 5-HT cells in this area.
Asunto(s)
Agresión/efectos de los fármacos , Apomorfina/farmacología , Encefalinas/farmacología , Núcleos del Rafe/fisiología , Receptores Opioides/fisiología , Serotonina/fisiología , Animales , Relación Dosis-Respuesta a Droga , Endorfinas/farmacología , Endorfinas/fisiología , Encefalina Ala(2)-MeFe(4)-Gli(5) , Masculino , Núcleos del Rafe/efectos de los fármacos , Ratas , Ratas Endogámicas , Receptores Opioides/efectos de los fármacos , Receptores Opioides muRESUMEN
8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a selective serotonin1A (5-HT1A) receptor agonist, was studied for its anti-immobility activity in the forced swimming test when administered into the raphe nuclei medianus and dorsalis of rats. At concentrations ranging from 0.5 to 5 micrograms, 8-OH-DPAT significantly reduced the immobility of rats when administered into the nucleus raphe dorsalis, but only 5 micrograms was effective when administered into the nucleus medianus. The activity of rats in an open-field under conditions identical to those used in the forced swimming test was not significantly changed by various concentrations of 8-OH-DPAT administered into the nucleus raphe dorsalis, but was significantly increased by an infusion of 5 micrograms 8-OH-DPAT into the nucleus raphe medianus. The effect of an infusion of 1 micrograms 8-OH-DPAT into the nucleus dorsalis was prevented by infusing 2.5 micrograms (-)-propranolol or 2.5 micrograms (-)-pindolol into the same area 5 min before 8-OH-DPAT or by treating the animals with sulpiride systemically (100 mg/kg i.p.) or centrally (in the nucleus accumbens; 1 microgram/0.5 microliter). The results suggest that 8-OH-DPAT reduces the immobility of rats by activating dopamine transmission, probably in the nucleus accumbens, as a consequence of its ability to reduce the activity of 5-HT neurons that originate in the nucleus raphe dorsalis. In view of the similarities between the effects of well-established antidepressants and 8-OH-DPAT in the forced swimming test, it is suggested that 5-HT1A receptor agonists may constitute a novel class of antidepressant agents.
Asunto(s)
Antidepresivos , Naftalenos/farmacología , Núcleos del Rafe/efectos de los fármacos , Receptores de Serotonina/efectos de los fármacos , Tetrahidronaftalenos/farmacología , 8-Hidroxi-2-(di-n-propilamino)tetralin , Animales , Inmovilización , Masculino , Núcleos del Rafe/fisiología , Ratas , NataciónRESUMEN
Buspirone, a drug with high affinity for serotonin1A receptors, was studied for its ability to reduce rats' immobility in the forced swimming test when injected systemically or into the nucleus raphe dorsalis (DR). Between 0.1 and 10 mg/kg buspirone had no effect on rats' immobility when injected systemically as a single dose or as a 3-injection course during 24 hours. Direct injection of 1 and 5 mu/0.5 microliter buspirone in the DR significantly reduced the duration of immobility without changing rats' activity in an open field. The anti-immobility effect of 1 microgram/0.5 microliter buspirone in the DR was completely prevented by injecting 2.5 micrograms (-)-propranolol in the same area. Oral administration of 0.3-1.0 mg/kg 1-(2-pyrimidinyl)piperazine (1-PP), one of the main metabolites of buspirone, and 0.3-3.0 mg/kg s.c. idazoxan, two substances with alpha 2 adrenergic blocking properties, completely antagonized the effect of 0.25 mg/kg s.c. 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), an agent with selective affinity for serotonin1A receptors. The anti-immobility effect of an infusion of 1 microgram/0.5 microliter buspirone or 8-OH-DPAT in the DR was also antagonized by 1 mg/kg p.o. 1-PP. The results suggest that buspirone possesses potential antidepressant properties but its effects may be masked in certain tests by its metabolite, 1PP, through its alpha 2 adrenergic blocking activity.