RESUMEN
Co-administration of desipramine and fluoxetine resulted in a 27% decline in cerebral cortical beta-adrenoceptor density after four days - a time point at which neither agent alone was effective. After 14 days, desipramine- and desipramine + fluoxetine-treated rats showed decreased receptor levels, with a greater decrement seen with the combined treatment. Fluoxetine, alone, had no affect on beta-adrenoceptor density at any time point examined. These effects are attributable to central serotonergic action since they were prevented by prior treatment with p-chlorophenylalanine. Cyproheptadine, a 5-HT2 antagonist, did not block these effects. Independent administration of fluoxetine and desipramine produced approximately 20% decrement in isoproterenol-stimulated cyclic AMP accumulation after four days of treatment. Co-administration of desipramine and fluoxetine resulted in a 35% decrement in cyclic AMP accumulation which was nearly additive with that produced by either drug alone. Consequently, the combination of a norepinephrine and serotonin uptake inhibitor may be an advantageous and rapid treatment for the alleviation of certain forms of depression.
Asunto(s)
Desipramina/farmacología , Fluoxetina/farmacología , Receptores Adrenérgicos beta/efectos de los fármacos , Adenosina Trifosfato/metabolismo , Animales , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , AMP Cíclico/metabolismo , Dihidroalprenolol , Ácido Hidroxiindolacético/metabolismo , Técnicas In Vitro , Masculino , Ratas , Ratas Endogámicas , Serotonina/metabolismoRESUMEN
[3H]Nitrendipine [( 3H]NTD), a specific high-affinity calcium channel antagonist, was used to label dihydropyridine binding sites associated with calcium channels in rat cerebral cortical and cardiac homogenates. A novel lactamimide compound, MDL 12,330A, has been shown previously to have negative inotropic and chronotropic effects in isolated working guinea-pig hearts and these effects are reversed by the administration of calcium. MDL 12,330A is potent in enhancing [3H]NTD binding in membranes prepared from the cerebral cortex and the heart, with EC50 values of 6.1 X 10(-8) and 3.4 X 10(-8) M, respectively, at 37 degrees C. This allosteric effect by MDL 12,330A is similar to that produced by a known calcium channel antagonist, d-cis diltiazem, which has been shown previously to enhance [3H]NTD binding at 37 degrees C. The extent of enhancement by MDL 12,330A depends on incubation temperature (37 degrees C greater than 25 degrees C greater than 0 degrees C). The mechanism of this enhancement by MDL 12,330A is due to a decrease in the dissociation rate constant of the dihydropyridine-calcium channel supramolecular complex. MDL 12,330A is the most potent drug thus far examined which demonstrates the enhancement of [3H]NTD binding.
Asunto(s)
Bloqueadores de los Canales de Calcio/metabolismo , Corteza Cerebral/metabolismo , Iminas/farmacología , Miocardio/metabolismo , Nifedipino/análogos & derivados , Animales , Corteza Cerebral/efectos de los fármacos , Semivida , Corazón/efectos de los fármacos , Técnicas In Vitro , Cinética , Masculino , Nifedipino/metabolismo , Nitrendipino , Ratas , Ratas Endogámicas , Temperatura , TritioAsunto(s)
Antidepresivos/farmacología , Encéfalo/efectos de los fármacos , Receptores Adrenérgicos alfa/efectos de los fármacos , Receptores Adrenérgicos beta/efectos de los fármacos , Receptores Adrenérgicos/efectos de los fármacos , Anfetamina/administración & dosificación , Animales , Antidepresivos/administración & dosificación , Encéfalo/metabolismo , Depresión/tratamiento farmacológico , Sinergismo Farmacológico , Humanos , Masculino , Ratas , Factores de Tiempo , Yohimbina/administración & dosificaciónRESUMEN
Clonidine (0.01 to 0.16 mg/kg) and lofexidine (0.01 to 0.64 mg/kg) produced a dose-dependent inhibition of diarrhea induced by castor oil treatment in the rat. Both drugs were more potent and longer acting than diphenoxylate. Pre- and posttreatment with naloxone (5 mg/kg) failed to prevent or antagonize the antidiarrheal effect of clonidine and lofexidine. These data suggest that clonidine and lofexidine may provide potent antidiarrheal activity of a nonnarcotic nature.
Asunto(s)
Antidiarreicos , Clonidina/análogos & derivados , Clonidina/uso terapéutico , Diarrea/tratamiento farmacológico , Animales , Clonidina/administración & dosificación , Masculino , Narcóticos , RatasRESUMEN
The effects of yohimbine on desipramine-induced adrenoreceptor alterations were examined in murine limbic forebrain areas. Treatment with both drugs in combination resulted in a significant decrease in [3H]dihydroalprenolol binding, which was not manifest after treatment with either drug alone. Moreover, co-administration of yohimbine was found to accelerate the time course and increase the magnitude of desipramine-induced increases in [3H]clonidine binding. The possible physiologic significance of these findings is discussed along with their pharmacologic implications.
Asunto(s)
Desipramina/farmacología , Receptores Adrenérgicos alfa/efectos de los fármacos , Receptores Adrenérgicos beta/efectos de los fármacos , Receptores Adrenérgicos/efectos de los fármacos , Yohimbina/farmacología , Animales , Encéfalo/metabolismo , Clonidina/metabolismo , Dihidroalprenolol/metabolismo , Masculino , Norepinefrina/metabolismo , Ratas , Factores de TiempoAsunto(s)
Anfetamina/farmacología , Encéfalo/efectos de los fármacos , Indoles/farmacología , Iprindol/farmacología , Receptores Adrenérgicos beta/efectos de los fármacos , Receptores Adrenérgicos/efectos de los fármacos , Animales , Masculino , Norepinefrina/metabolismo , Ratas , Receptores Adrenérgicos alfa/efectos de los fármacosRESUMEN
Discontinuation of chronic morphine infusion in rats resulted in the reliable occurrence of withdrawal body shakes. This sign of narcotic withdrawal was dose-dependently reduced by lofexidine (0.04-0.64 mg/kg) and clonidine (0.01-0.16 mg/kg). As with clonidine, the activity of lofexidine was not prevented by naloxone (5 mg/kg). In addition, diarrhea induced by naloxone (5 mg/kg) in morphine dependent rats was also prevented by lofexidine or clonidine pretreatment. These data suggest that lofexidine, like clonidine, may reduce the narcotic withdrawal syndrome in humans.