RESUMEN
BACKGROUND: Smoking relapse is common after successful pharmacologic treatment for smoking cessation. No previous studies have examined long-term drug therapy used expressly for prevention of smoking relapse. OBJECTIVE: To evaluate the efficacy of bupropion to prevent smoking relapse. DESIGN: Randomized, placebo-controlled trial. PARTICIPANTS: 784 healthy community volunteers who were motivated to quit smoking and who smoked at least 15 cigarettes per day. INTERVENTION: The participants received open-label, sustained-release bupropion, 300 mg/d, for 7 weeks. Participants who were abstinent throughout week 7 of open-label treatment were randomly assigned to receive bupropion, 300 mg/d, or placebo for 45 weeks and were subsequently followed for an additional year after the conclusion of the medication phase. Participants were briefly counseled at all follow-up visits. At the end of open-label bupropion treatment, 461 of 784 participants (58.8%) were abstinent from smoking. MEASUREMENT: Self-reported abstinence was confirmed by an expired air carbon monoxide concentration of 10 parts per million or less. RESULTS: The point prevalence of smoking abstinence was significantly higher in the bupropion group than in the placebo group at the end (week 52) of drug therapy (55.1% vs. 42.3%, respectively; P = 0.008) and at week 78 (47.7% vs. 37.7%; P = 0.034) but did not differ at the final (week 104) follow-up visit (41.6% vs. 40.0%). The median time to relapse was significantly greater for bupropion recipients than for placebo recipients (156 days vs. 65 days; P = 0.021). The continuous abstinence rate was higher in the bupropion group than in the placebo group at study week 24 (17 weeks after randomization) (52.3% vs. 42.3%; P = 0.037) but did not differ between groups after week 24. Weight gain was significantly less in the bupropion group than in the placebo group at study weeks 52 (3.8 kg vs. 5.6 kg; P = 0.002) and 104 (4.1 kg vs. 5.4 kg; P = 0.016). CONCLUSIONS: In persons who stopped smoking with 7 weeks of bupropion treatment, sustained-release bupropion for 12 months delayed smoking relapse and resulted in less weight gain.
Asunto(s)
Bupropión/administración & dosificación , Cese del Hábito de Fumar/métodos , Prevención del Hábito de Fumar , Adulto , Bupropión/efectos adversos , Preparaciones de Acción Retardada , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Cooperación del Paciente , Recurrencia , Aumento de PesoRESUMEN
A series of 6-(alkylamino)-9-alkylpurines was synthesized and evaluated for the property of antagonizing the behavioral effects in animals of the dopamine agonist apomorphine. This model for identifying potential antipsychotic agents is based on the hypothesis that agents that antagonize apomorphine-induced aggressive behavior in rats and apomorphine-induced climbing in mice, but that do not block stereotyped behavior, could have an antipsychotic effect in humans without producing extrapyramidal side effects. The antiaggressive-behavior activity of lead compound 1 (6-(dimethylamino)-9-(3-phenylalaninamidobenzyl)-9H-purine) was improved 48-fold with 6-(cyclopropylamino)-9-(cyclopropylmethyl)-2-(trifluoromethyl)-9H- purine (80) (po ED50 of 2 mg/kg), which was obtained through an iterative sequence of structure--activity relationship studies that encompassed evaluation of the effects of structure variations at the purine 9-, 6-, and 2-positions. Potency was enhanced with a 9-cyclopropyl group, the duration of action was improved with the 6-(cyclopropylamino) substituent, potency was further enhanced with an N-formyl prodrug, and an agent with reduced cardiovascular effect emerged with the 2-trifluoromethyl purine 80. This potential antipsychotic agent was not developed further due to undesirable effects on the stomach.
Asunto(s)
Antipsicóticos/síntesis química , Purinas/síntesis química , Agresión/efectos de los fármacos , Alquilación , Animales , Antipsicóticos/farmacología , Apomorfina/farmacología , Carbazoles/síntesis química , Carbazoles/farmacología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Dimetilaminas/síntesis química , Dimetilaminas/farmacología , Vaciamiento Gástrico/efectos de los fármacos , Dosificación Letal Mediana , Ratones , Modelos Químicos , Purinas/farmacología , Ratas , Espectrofotometría Ultravioleta , Relación Estructura-ActividadRESUMEN
We determined the chromosomal localization and partial genomic structure of the coding region of the human PPAR gamma gene (hPPAR gamma), a nuclear receptor important for adipocyte differentiation and function. Sequence analysis and long PCR of human genomic DNA with primers that span putative introns revealed that intron positions and sizes of hPPAR gamma are similar to those previously determined for the mouse PPAR gamma gene[13]. Fluorescent in situ hybridization localized hPPAR gamma to chromosome 3, band 3p25. Radiation hybrid mapping with two independent primer pairs was consistent with hPPAR gamma being within 1.5 Mb of marker D3S1263 on 3p25-p24.2. These sequences of the intron/exon junctions of the 6 coding exons shared by hPPAR gamma 1 and hPPAR gamma 2 will facilitate screening for possible mutations. Furthermore, D3S1263 is a suitable polymorphic marker for linkage analysis to evaluate PPAR gamma's potential contribution to genetic susceptibility to obesity, lipoatrophy, insulin resistance, and diabetes.
Asunto(s)
Mapeo Cromosómico , Cromosomas Humanos Par 3/genética , Receptores Citoplasmáticos y Nucleares/genética , Factores de Transcripción/genética , Tejido Adiposo/metabolismo , Animales , Secuencia de Bases , Bandeo Cromosómico , Clonación Molecular , ADN/genética , Cartilla de ADN/genética , Exones , Ligamiento Genético , Marcadores Genéticos , Humanos , Intrones , Ratones , Sondas de Oligonucleótidos/genética , Reacción en Cadena de la Polimerasa , Polimorfismo GenéticoRESUMEN
11192U90 was submitted to receptor binding and monoamine uptake assays. It bound potently at serotonin 5-HT2, dopaminergic D2, serotonin 5-HT1A, and adrenergic alpha 1 and alpha 2 receptors. It also bound to dopaminergic D1, serotonin 5-HT3, serotonin 5-HT4, and sigma sites, albeit with lower affinity. It was essentially inactive at 22 other sites, including those for cholinergic M1 and M2. It weakly inhibited uptake of 3H-norepinephrine, 3H-serotonin and 3H-dopamine. Acute doses of 1192U90 (5 and 20 mg/kg P.O.) increased whole-brain levels of dopamine metabolites but did not affect levels of norepinephrine, dopamine, and serotonin. Subcutaneous injection of 1192U90 (0.8 mg/kg/day) and clozapine (20 mg/kg/day) for 28 days preferentially decreased the number of spontaneously active dopamine cells in the ventral tegmental area (VTA) but not the substantia nigra (SN) of rats, as measured by population sampling. This outcome is characteristics of atypical antipsychotics like clozapine. Acute injections of 1192U90 reversed the rate-inhibiting effects of microiontophoretically applied dopamine and intravenously injected apomorphine and d-amphetamine on dopamine cell firing. Intravenous injection or iontophoretic application of 1192U90 or the 5-HT1A agonist (+/-)8-OH-DPAT inhibited the firing rates of dorsal raphe nucleus (DRN) neurons in rats, and the effects of both compounds were blocked by iontophoretically applied S(-) propranolol, a 5-HT1A antagonist. The results suggest that 1192U90 is a preferential dopamine D2 antagonist as well as a 5-HT1A agonist that may prove to be an atypical antipsychotic.
Asunto(s)
Antipsicóticos/metabolismo , Piperazinas/metabolismo , Tiazoles/metabolismo , Anfetamina/farmacología , Animales , Apomorfina/farmacología , Aminas Biogénicas/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Clozapina/metabolismo , Clozapina/farmacología , Masculino , Neuronas/efectos de los fármacos , Neuronas/fisiología , Piperazinas/farmacología , Ensayo de Unión Radioligante , Ratas , Tiazoles/farmacologíaRESUMEN
Binding of 3H-spiperone and 3H-raclopride to membranes of cells stably-transfected with a human dopamine D2 receptor clone was investigated, as was that of 3H-spiperone to those stably-transfected with a human D4 receptor clone. 3H-spiperone and 3H-raclopride labeled the same number of sites in the D2 receptor preparation. The inhibition of binding by clozapine, spiperone, (-) eticlopride, haloperidol and the novel substituted benzamide 1192U90 was also investigated. Clozapine and 1192U90 showed greater inhibition of 3H-raclopride binding than 3H-spiperone binding to the D2 receptor. Comparison with inhibition of 3H-spiperone binding to the D4 receptor revealed that clozapine and 1192U90 displayed apparent selectivity (as assessed by Ki ratios) for the D4 receptor when compared with binding of 3H-spiperone, but not 3H-raclopride, to the D2 receptor.
Asunto(s)
Clozapina/farmacología , Receptores de Dopamina D2/efectos de los fármacos , Sitios de Unión , Membrana Celular/efectos de los fármacos , Antagonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Racloprida , Salicilamidas/farmacología , Espiperona/farmacologíaRESUMEN
1. Administration of the irreversible antagonist, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, (EEDQ, 2 mg kg-1, i.p.) to mice reduced binding of [3H]-RX 821002 (2-methoxy-idazoxan) to alpha 2-adrenoceptors in whole mouse brain by 75% 24 h later. The receptor binding returned over time only being reduced by 25% by 16 days post administration; the time taken for binding to return to 50% of control levels was estimated to be 5.25 days. 2. EEDQ administration also resulted in the loss of the sedative effect of the alpha 2-adrenoceptor agonist, medetomidine, measured by the holeboard test of directed exploration and locomotor activity. Agonist-induced sedation returned to control values by 8 days post EEDQ administration. 3. EEDQ administration also resulted in the loss of the hypothermic response to medetomidine (0.1 mg kg-1, i.p.). Medetomidine-induced hypothermia returned to control values by 12 days post EEDQ administration. 4. Pretreatment with the selective alpha 2-adrenoceptor antagonist, RX 821002 (0.1-3.0 mg kg-1, i.p.) 45 min before EEDQ prevented the loss of alpha 2-adrenoceptors as well as the blockade of medetomide-induced sedation and hypothermia by EEDQ. 5. The results of these experiments indicate that there is significant receptor reserve for alpha 2-adrenoceptor-mediated behavioural and physiological responses.
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 2 , Antagonistas Adrenérgicos alfa/farmacología , Quinolinas/farmacología , Receptores Adrenérgicos alfa 2/metabolismo , Agonistas alfa-Adrenérgicos/farmacología , Animales , Temperatura Corporal/efectos de los fármacos , Dioxanos/farmacocinética , Interacciones Farmacológicas , Conducta Exploratoria/efectos de los fármacos , Hipnóticos y Sedantes/farmacología , Idazoxan/análogos & derivados , Imidazoles/farmacología , Masculino , Medetomidina , Ratones , Actividad Motora/efectos de los fármacos , Ensayo de Unión RadioliganteRESUMEN
The gene for tryptophan 2,3-dioxygenase (TDO) heretofore was believed to be expressed only in liver. The data presented here demonstrate that RNA encoding TDO is present in rodent brain. Oligonucleotide primers based on the rat liver TDO cDNA sequence were synthesized and used to amplify RNA derived from mouse whole brain and liver and rat brain regions by the RNA-PCR. Reaction products were purified and subjected to DNA sequencing. Identical sequences were obtained when mouse whole brain and liver RNAs were amplified, and these sequences were shown to be 96% identical to the published rat liver tryptophan TDO cDNA sequence. In addition, TDO sequences were found in RNA derived from rat brainstem, cerebellum, cortex, hypothalamus, and the remainder of the brain.
Asunto(s)
ARN/metabolismo , Triptófano Oxigenasa/genética , Animales , Secuencia de Bases , ADN/genética , Ratones , Ratones Endogámicos , Datos de Secuencia Molecular , Sondas de Oligonucleótidos/genética , Reacción en Cadena de la Polimerasa , ARN/genética , Ratas , Ratas Sprague-DawleyRESUMEN
In recent years it has become apparent that the parental origin of genetic material has an impact on gene expression and this effect has become known as genomic imprinting. The evidence for the influence of genomic imprinting on behavior and in the etiology of certain neurobehavioral disorders is discussed. The possibilities for a role for genomic imprinting in the inheritance of behaviors related to alcohol abuse and alcoholism and in the paternal alcohol syndrome are also explored.
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Alcoholismo/genética , Regulación de la Expresión Génica , Fenotipo , Síndrome de Angelman/genética , Análisis Mutacional de ADN , Femenino , Variación Genética , Humanos , Masculino , Síndrome de Prader-Willi/genética , Factores de RiesgoRESUMEN
Caffeine and other methylxanthines induce a dose-dependent reduction in core body temperature in mice. These experiments investigated the effects of neurotransmitter and neuromodulator antagonists on caffeine-induced hypothermia. Pretreatment with the alpha 2-adrenoceptor antagonist, atipamezole; the beta-adrenoceptor antagonist, propranolol; the dopamine antagonist, haloperidol; or the benzodiazepine receptor antagonist, flumazenil had no intrinsic effects on core body temperature nor did they interact significantly with the hypothermic effects of caffeine. The alpha 1-adrenoceptor antagonist, prazosin and the 5-HT receptor antagonist, metergoline significantly enhanced the hypothermic effects of caffeine, probably involving a combined effect with their intrinsic hypothermic actions. Pretreatment with the opiate receptor antagonist, naloxone (3 mg/kg i.p.), had no intrinsic effect on core body temperature but attenuated the hypothermic effect of caffeine reflected in a parallel shift to the right in the caffeine dose-effect curve. The naloxone-induced attenuation of the hypothermic effects of caffeine was also seen to be dose-dependent. The results reveal that opiate receptors (but not adrenoceptors, 5-HT, dopamine or benzodiazepine receptors) may play a role in modulating the hypothermic action of caffeine and possibly other methylxanthines.
Asunto(s)
Temperatura Corporal/efectos de los fármacos , Cafeína/farmacología , Receptores Opioides/fisiología , Animales , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Flumazenil/farmacología , Masculino , Metergolina/farmacología , Ratones , Naloxona/farmacología , Simpaticolíticos/farmacologíaRESUMEN
The effects of two structurally different inhibitors of phenylethanolamine-N-methyltransferase, LY 134046 and CGS 19281A were investigated in a holeboard test of directed exploration and locomotor activity. Both compounds dose-dependently reduced exploratory head-dipping without affecting locomotor activity. The interaction of each drug with ethanol was also studied by testing the ataxia. Administration of these compounds had differential effects in a test of ethanol-induced ataxia. LY 134046 significantly attenuated ethanol-induced ataxia whereas CGS 19281A was without effect or (at 50 mg kg-1) potentiated ethanol's effect. These results suggest that the ethanol attenuating properties of LY 134046 may not solely be due the inhibition of PNMT and that its alpha 2-adrenoceptor blocking properties may be playing a role.
Asunto(s)
Benzazepinas/farmacología , Carbolinas/farmacología , Etanol/farmacología , Conducta Exploratoria/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Feniletanolamina N-Metiltransferasa/antagonistas & inhibidores , Análisis de Varianza , Animales , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Masculino , Ratones , Ratones Endogámicos , Valores de ReferenciaRESUMEN
Caffeine induces a dose-dependent decrease in core body temperature in mice and the hypothermia induced by a 100 mg/kg dose of caffeine was seen to persist for greater than 160 min. Other alkylxanthines including theophylline, enprophylline, isbutylmethylxanthine and 1,3-dipropyl-7-methylxanthine also showed dose-dependent reductions in body temperature. The dose of these drugs required to reduce body temperature by 2 degrees C was calculated and correlated with the affinities for the compounds at adenosine A1 and A2 receptors and their activities in inhibiting calcium dependent and independent phosphodiesterases. Significant relationships were found between the 2 degrees C hypothermic dose (HD2) and soluble and membrane calcium-independent phosphodiesterase inhibiting activity (r2s = 0.950 and 0.940, respectively). No significant relationship was seen between HD2 and soluble calcium-dependent phosphodiesterase inhibiting activity or with A2 adenosine receptor affinity. The relationship between HD2 and A1 adenosine receptor affinity (r2 = 0.739) did however almost reach statistical significance. These results would suggest that phosphodiesterase inhibition, instead of or in addition to adenosine receptor blockade, may play an important role in the effects of alkylxanthines on body temperature.
Asunto(s)
Temperatura Corporal/efectos de los fármacos , Inhibidores de Fosfodiesterasa/farmacología , Xantinas/farmacología , Animales , Cafeína/farmacología , Calcio/fisiología , Relación Dosis-Respuesta a Droga , Hipotermia/inducido químicamente , Masculino , Ratones , Antagonistas Purinérgicos , Factores de TiempoRESUMEN
The role of central adrenoceptors in the ethanol-attenuating effects of alpha-2 adrenoceptor blockers was investigated in mice; the centrally active antagonist atipamezole was compared with L 659,066, which penetrates the brain poorly. L 659,066 (1-10 mg/kg) had no effect on the hypothermia induced by ethanol (2 g/kg) or ethanol ataxia (2.4 g/kg), whereas atipamezole (1 mg/kg) significantly attenuated both ethanol-induced hypothermia and ataxia. Atipamezole (1-3 mg/kg) significantly attenuated the ethanol-induced reduction in exploratory head-dipping in a holeboard test whereas L 659,066 was only effective at a dose of 1 mg/kg, higher doses (3 and 10 mg/kg) and a lower dose (0.3 mg/kg) were ineffective. Atipamezole was without effect on ethanol's locomotor stimulant effect in the holeboard but L 659,066 attenuated this effect at doses less than 3 mg/kg Many alpha-2 adrenoceptor ligands also have affinity for nonadrenergic imidazoline-binding sites. The role these sites may play in attenuating ethanol's effects was investigated by comparing RX 821002 (methoxy idazoxan), which has little or no affinity for imidazoline-binding sites with atipamezole. Both atipamezo 1 e (1 mg/kg) and RX 821002 (0.06-0.2 mg/kg) significantly attenuated ethanol-induced hypothermia, ataxia and reduction in head-dipping, but were without effect on ethanol-induced locomotor stimulation. These results suggest that nonadrenergic imidazoline-binding sites are not implicated in the ethanol-attenuating properties of alpha-2 adrenoceptor antagonists.
Asunto(s)
Antagonistas Adrenérgicos alfa/farmacología , Encéfalo/efectos de los fármacos , Etanol/antagonistas & inhibidores , Imidazoles/farmacología , Quinolizinas/farmacología , Receptores Adrenérgicos alfa/efectos de los fármacos , Receptores de Droga/efectos de los fármacos , Animales , Ataxia/inducido químicamente , Temperatura Corporal/efectos de los fármacos , Encéfalo/fisiología , Dioxanos/farmacología , Etanol/farmacología , Idazoxan/análogos & derivados , Receptores de Imidazolina , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Receptores Adrenérgicos alfa/fisiología , Receptores de Droga/fisiologíaRESUMEN
Pretreatment with pertussis toxin (0.5 and 1.0 microgram/animal, i.c.v., seven days prior to testing) reversed the reduction in locomotor activity in the holeboard test caused by administration of the alpha 2-adrenoceptor agonist, medetomidine (0.1 mg/kg, i.p.). Intrinsic behavioral effects of pertussis toxin treatment were also observed, these included a reduction in exploratory head-dipping and an increase in locomotor activity. These doses of pertussis toxin also reduced the ataxia induced by a 2.4 g/kg dose of ethanol. Pertussis toxin treated animals also exhibited a diminished hypothermic response to ethanol (2 g/kg), although the pertussis toxin treated animals had lower body temperatures prior to ethanol administration compared to sham treated animals. Neither the behavioral effect of pertussis holotoxin in the holeboard nor its effects on reversing medetomidine hypolocomotion or ethanol-induced ataxia were seen following administration of the binding oligomer of pertussis toxin which binds to the cell membrane but does not possess the enzymatically active subunit. These findings implicate mechanisms involving pertussis toxin sensitive G-proteins in modulating some behavioral and physiological effects of ethanol.
Asunto(s)
Ataxia/inducido químicamente , Temperatura Corporal/efectos de los fármacos , Etanol/farmacología , Toxina del Pertussis , Factores de Virulencia de Bordetella/farmacología , Animales , Etanol/sangre , Proteínas de Unión al GTP/fisiología , Imidazoles/farmacología , Inyecciones Intraventriculares , Masculino , Medetomidina , Ratones , Actividad Motora/efectos de los fármacosRESUMEN
The effect of pretreatment with pertussis toxin on N-methyl-D-aspartate (NMDA)-induced seizures was investigated in mice. In animals treated with pertussis toxin (0.5 micrograms/animal i.c.v) five days prior to testing the convulsant ED50 of NMDA was calculated to be 18 mg/kg whereas it was calculated to be 107 mg/kg in sham-treated animals. These results suggest the pertussis toxin enhances sensitivity to NMDA, possibly via its actions on inhibitory G-proteins.
Asunto(s)
N-Metilaspartato/farmacología , Toxina del Pertussis , Convulsiones/inducido químicamente , Factores de Virulencia de Bordetella/toxicidad , Animales , Sinergismo Farmacológico , Proteínas de Unión al GTP/antagonistas & inhibidores , Inyecciones Intraventriculares , Masculino , Ratones , N-Metilaspartato/administración & dosificación , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Transmisión Sináptica/efectos de los fármacos , Factores de Virulencia de Bordetella/administración & dosificaciónRESUMEN
The putative 5-HT1A receptor antagonist properties of 1-(2-methoxyphenyl)-4-[4-(2-phtalimmido)butyl] piperazine (NAN-190) were studied in mice. The responses studied were hypothermia- and hyperglycemia-induced by the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). NAN-190 (0.3-3 mg/kg) did not antagonize either response, but rather appeared to be additive with the effect produced by 8-OH-DPAT (0.25 mg/kg) alone, at least with respect to temperature. NAN-190, given alone in similar doses, caused hypothermia and hyperglycemia. These results suggest that NAN-190 has similar properties to 8-OH-DPAT with regard to temperature and glucose effects. Therefore, it does not appear to be a effective antagonist for all 5-HT1A-mediated responses.
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Hiperglucemia/prevención & control , Hipotermia Inducida , Piperazinas/farmacología , Antagonistas de la Serotonina/farmacología , Tetrahidronaftalenos/farmacología , 8-Hidroxi-2-(di-n-propilamino)tetralin , Animales , Hiperglucemia/inducido químicamente , Masculino , Ratones , Piperazinas/administración & dosificación , Premedicación , Tetrahidronaftalenos/administración & dosificaciónRESUMEN
1. The effects of pretreatment with two novel and relatively specific alpha 2-adrenoceptor antagonists on the hypothermic and hyperglycaemic responses induced by the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) were investigated in mice. The alpha 2-adrenoceptor antagonists used were, atipamezole, which occupies both central and peripheral receptors, and L 659,066, which poorly penetrates the blood brain barrier. 2. Atipamezole (1 and 3 mg kg-1) alone had no effect on body temperature but significantly attenuated the 8-OH-DPAT-induced hypothermic response. The hyperglycaemic effect of 8-OH-DPAT was also attenuated by pretreatment with atipamezole; however, 3 mg kg-1 atipamezole did cause some hypoglycaemia when administered alone. 3. Pretreatment with L 659,066 (3-30 mg kg-1) failed to alter the hypothermic effects of 8-OH-DPAT. All doses of L 659,066 tested attenuated 8-OH-DPAT-induced hyperglycaemia, but the highest dose (30 mg kg-1) produced hypoglycaemia when administered alone. 4. The results suggest that the attenuation of 8-OH-DPAT-induced hypothermia by alpha 2-adrenoceptor antagonist may be centrally mediated whereas the blockade of 8-OH-DPAT-induced hyperglycaemia may involve peripheral mechanisms.
Asunto(s)
Antagonistas Adrenérgicos alfa/farmacología , Glucemia/metabolismo , Temperatura Corporal/efectos de los fármacos , Antagonistas de la Serotonina/farmacología , Tetrahidronaftalenos/farmacología , 8-Hidroxi-2-(di-n-propilamino)tetralin , Animales , Barrera Hematoencefálica/efectos de los fármacos , Imidazoles/farmacología , Masculino , Ratones , Quinolizinas/farmacologíaRESUMEN
The effect of tryptophan on immobility in Porsolt's swim test was studied in male NIH Swiss mice. Preexposure to a swim or fight-stressor was included in the design. Doses of tryptophan (0, 12.5, 50, 75, 100, 125 and 200 mg/kg) were administered intraperitoneally 60 min prior to the swim test. In the nonstressed mice tryptophan had an U-shaped dose-response relationship: immobility in the water was dose-dependently shortened after doses from 0 to 100 mg/kg, whereas after 125 and 200 mg/kg tryptophan the immobility times did not differ from the values obtained after a saline injection. Preexposure to a swim- or fight-stressor did not make mice more sensitive to the effects of tryptophan. Tryptophan (0-300 mg/kg) had no effect on exploratory behavior or locomotor activity in the holeboard, suggesting that sedation was not a factor in the swim test results. The findings suggest that tryptophan has antidepressant -like properties in Porsolt's swim test.
Asunto(s)
Antidepresivos , Actividad Motora/efectos de los fármacos , Estrés Psicológico/tratamiento farmacológico , Triptófano/farmacología , Animales , Modelos Animales de Enfermedad , Masculino , Ratones , Pruebas Psicológicas/métodos , NataciónRESUMEN
The present study examined behavior of streptozotocin-diabetic mice in Porsolt's swim test, a putative animal model of depression, in the holeboard test of exploration and locomotor activity, in the plus maze test of anxiety, and in the resident-intruder paradigm of aggression. Two weeks after an IP injection of 200 mg/kg streptozotocin, which caused a 20% weight loss and increased fluid consumption and urination, male NIH Swiss mice were found to show lengthened duration of immobility in the swim test. One week of insulin treatment (0.1 IU/g/day) partially antagonized this change. The locomotor activity scores in the streptozotocin-treated mice were lower in the holeboard but higher in the plus maze than in the controls; therefore, the lengthened immobility was not likely to be due to a general motor impairment. No significant changes in the time spent in social interaction or aggressive behavior were found in the streptozotocin-treated mice. The results indicate that streptozotocin-treated mice show lengthened immobility in the swim test.