RESUMEN
After acute administration of low doses, alprazolam displays unusual behavioral and neurochemical characteristics. To determine whether chronic low-dose alprazolam has unique effects, we treated mice for 1-14 days with alprazolam 0.2 mg/kg per day and evaluated open-field activity, benzodiazepine receptor binding, t-butylbicyclophosphorothionate binding, and muscimol-stimulated chloride uptake. Open-field activity in treated mice was similar to that of control mice at each timepoint during alprazolam administration. Similarly, benzodiazepine receptor binding in vivo was unchanged in five brain regions. Benzodiazepine receptor binding in vivo was unchanged in five brain regions. Benzodiazepine binding in vitro in the cortex was unaffected by alprazolam treatment, as was t-butylbicyclophosphorothionate binding in the cortex. However, muscimol-stimulated chloride uptake was increased after 2 and 4 days of alprazolam compared with results after 1, 7, and 14 days. These results are consistent with prior reports of unusual effects of low-dose alprazolam and extend these findings to chronic administration.
Asunto(s)
Alprazolam/farmacología , Nivel de Alerta/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Receptores de GABA-A/efectos de los fármacos , Alprazolam/farmacocinética , Animales , Corteza Cerebral/metabolismo , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Bombas de Infusión Implantables , Masculino , Tasa de Depuración Metabólica/fisiología , Ratones , Actividad Motora/fisiología , Receptores de GABA-A/fisiologíaRESUMEN
Prenatal exposure to benzodiazepines may lead to developmental abnormalities in humans and animals. To assess the behavioral and neurochemical effects of such exposure, pregnant mice were treated with lorazepam, 2 mg/kg/day, from days 13-20 of gestation, and open-field activity was assessed in offspring at 3 and 6 weeks of age and the function of GABAA receptors at 6 weeks of age. Activity was increased in mice exposed to lorazepam, compared to untreated or vehicle-treated controls at 3 weeks, but was unchanged at 6 weeks. Muscimol-stimulated uptake of chloride was decreased in lorazepam-treated mice, compared to controls, with a decrease in maximum uptake but no change in the EC50 for muscimol. Concentrations of lorazepam in maternal plasma and brain showed a similar brain:plasma ratio as previously reported and concentrations in fetal brain were about 50% of maternal levels. Lorazepam persisted for 48 hours after birth in dams but not in the offspring. These results indicate persistent behavioral and neurochemical alterations after prenatal exposure to lorazepam. This model may be useful in assessing other effects of prenatal exposure to benzodiazepine.
Asunto(s)
Encéfalo/metabolismo , Corteza Cerebral/fisiología , Lorazepam/farmacología , Actividad Motora/efectos de los fármacos , Receptores de GABA-A/fisiología , Animales , Encéfalo/embriología , Corteza Cerebral/efectos de los fármacos , Cloruros/metabolismo , Femenino , Edad Gestacional , Lorazepam/farmacocinética , Intercambio Materno-Fetal , Ratones , Muscimol/farmacología , Embarazo , Receptores de GABA-A/efectos de los fármacos , Valores de ReferenciaRESUMEN
Acute cocaine administration has been reported to alter central benzodiazepine binding in animals. The authors examined the effects of chronic cocaine use on binding at the peripheral benzodiazepine site on platelets in cocaine users (N = 8), heavy ethanol users (N = 4), and controls (N = 7). The groups were matched for age and sex. None of the subjects reported recent benzodiazepine use, but neither serum nor urine testing was performed. Apparent affinity at the peripheral benzodiazepine site was similar in the three groups. However, the number of binding sites was significantly greater in cocaine users. These results indicate that cocaine use affects peripheral benzodiazepine binding in humans and might also alter central benzodiazepine effects.
Asunto(s)
Plaquetas/metabolismo , Cocaína/farmacología , Receptores de GABA-A/efectos de los fármacos , Adulto , Alcoholismo/sangre , Alcoholismo/metabolismo , Benzodiazepinonas/metabolismo , Plaquetas/efectos de los fármacos , Convulsivantes/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Receptores de GABA-A/metabolismo , Trastornos Relacionados con Sustancias/sangre , Trastornos Relacionados con Sustancias/metabolismoRESUMEN
Several lines of evidence indicate a possible interaction between the major inhibitory and excitatory cortical neurotransmitters, GABA and glutamate. To assess the neurochemical basis for such an interaction, we examined the effects of glutamate and several analogs on GABA-dependent chloride uptake in a mouse cortical synaptoneurosome preparation. L-Glutamate and the specific receptor subtype ligands kainate and quisqualate led to a small but significant enhancement in chloride uptake in the presence, but not the absence, of the GABA analog muscimol (5 microM). Enhancement was seen at excitatory amino acid (EAA) concentrations of 2-10 microM, but not at higher concentrations. D-Glutamate, NMDA, the NMDA-related antagonists APV and MK801, and the kainate/quisqualate antagonist CNQX, had no effect on chloride uptake. However, CNQX (50 microM) but not APV (50 microM) blocked the increase in chloride uptake due to kainate or quisqualate (10 microM). In addition, depolarization of synaptoneurosomes using high potassium (40 mM KC1) or ouabain pretreatment (5 microM) blocked the effects of kainate and quisqualate. Glutamate, kainate, and quisqualate had no effect on binding at the benzodiazepine, TBPS, or GABA sites on the GABAA receptor complex.
Asunto(s)
Corteza Cerebral/metabolismo , Cloruros/metabolismo , Glutamatos/farmacología , Ácido Kaínico/farmacología , Ácido Quiscuálico/farmacología , Ácido gamma-Aminobutírico/fisiología , 2-Amino-5-fosfonovalerato/farmacología , 6-Ciano 7-nitroquinoxalina 2,3-diona , Animales , Transporte Biológico/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Canales de Cloruro , Maleato de Dizocilpina/farmacología , Ácido Glutámico , Canales Iónicos/efectos de los fármacos , Canales Iónicos/fisiología , Masculino , Proteínas de la Membrana/fisiología , Ratones , Ratones Endogámicos , N-Metilaspartato/farmacología , Quinoxalinas/farmacología , Receptores de GABA-A/efectos de los fármacos , Receptores de GABA-A/metabolismoRESUMEN
Discontinuation of chronic treatment with alprazolam may cause a characteristic clinical syndrome. To assess the basis of this syndrome, mice were treated with alprazolam, 2 mg/kg, for 7 days, a regimen associated with the development of tolerance and downregulation of receptors. Effects on motor activity and the binding and function of GABA receptors were evaluated 1, 2, 4 and 7 days after discontinuation. Motor activity was similar to controls 1 day after cessation of alprazolam, increased from days 2 to 4 after-alprazolam, and returned to control values by 7 days. The binding of benzodiazepines in vivo and in vitro was increased in the cortex 2 and 4 days after alprazolam and in the hypothalamus at 4 days after alprazolam. Binding returned to control values in all areas by 7 days. Binding at the chloride channel, using [35S]t-butylbicyclophosphorothionate, was not significantly altered after discontinuation. Muscimol-stimulated uptake of [36Cl-] in cortical synaptoneurosomes was increased at 4 days after alprazolam, compared to days 1, 2 and 7. Thus, behavioral and neurochemical alterations was associated with the discontinuation of alprazolam. These alterations were qualitatively similar to those observed following discontinuation of lorazepam but occurred more rapidly and with differing regional specificity.
Asunto(s)
Alprazolam/farmacología , Conducta Animal/efectos de los fármacos , Química Encefálica/efectos de los fármacos , Compuestos Bicíclicos Heterocíclicos con Puentes , Síndrome de Abstinencia a Sustancias/metabolismo , Animales , Compuestos Bicíclicos con Puentes/farmacología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Cloruros/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Tolerancia a Medicamentos , Canales Iónicos/efectos de los fármacos , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Muscimol/farmacología , Receptores de GABA-A/metabolismo , Radioisótopos de AzufreRESUMEN
Chronic benzodiazepine administration is associated with neurochemical alterations in the GABAergic system, as determined in a variety of animal models and tissue culture systems. In animals, effects of chronic benzodiazepine agonists on receptor binding are uncertain, but several studies indicate a decrease in GABA-dependent chloride uptake. In contrast, limited data indicate that chloride uptake is increased after chronic antagonist administration, and results of inverse agonist administration are uncertain. Most animal studies are limited by lack of attention to drug choice and to pharmacokinetic variables, and by failure to determined delivered drug concentrations. More limited data in tissue culture systems are conflicting with regard to effects on benzodiazepine binding, but recent studies indicate that GABA-dependent chloride uptake may be decreased after chronic agonist exposure, and increased after chronic antagonist and inverse agonist administration. Data from these systems may complement results obtained in intact animals, and cultures may allow more detailed examination of the kinetics and specificity of drug effects.
Asunto(s)
Ansiolíticos/administración & dosificación , Receptores de GABA-A/efectos de los fármacos , Animales , Benzodiazepinas , Células Cultivadas , Antagonistas de Receptores de GABA-A , Factores de TiempoRESUMEN
Behavioral and neurochemical evidence indicates links between the opioid and GABA neurotransmitter systems. To assess effects of chronic opiates on the major site of postsynaptic GABAergic activity, the GABAA receptor, we administered chronic morphine and naltrexone to mice and evaluated binding at the benzodiazepine and t-butylbicyclophosphorothionate (TBPS) sites and GABA-dependent chloride uptake. After morphine (3 days), benzodiazepine receptor binding in vivo but not in vitro was increased in cortex compared to placebo-treated mice. TBPS binding was unchanged in cortex, but muscimol-stimulated chloride uptake was increased at low doses of muscimol. Benzodiazepine and TBPS binding and muscimol-stimulated chloride uptake were unchanged in naltrexone-(8 days) compared to placebo-treated mice. When naltrexone was administered previously to block opiate sites, the increases in benzodiazepine binding and chloride uptake observed with chronic morphine were reversed. These results indicate that chronic morphine but not naltrexone enhances benzodiazepine binding and GABAA receptor function, perhaps by an action at opioid receptors.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes , Morfina/farmacología , Receptores de GABA-A/metabolismo , Animales , Química Encefálica/efectos de los fármacos , Compuestos Bicíclicos con Puentes/farmacología , Cloruros/metabolismo , Cloro , Flunitrazepam/farmacología , Técnicas In Vitro , Canales Iónicos/efectos de los fármacos , Canales Iónicos/metabolismo , Masculino , Ratones , Muscimol/farmacología , Naltrexona/farmacología , Radioisótopos , Receptores de GABA-A/efectos de los fármacos , Radioisótopos de AzufreRESUMEN
1. The effects of lorazepam discontinuation on responses to benzodiazepine agonists and antagonists were studied in mice. 2. The convulsant dose of pentylenetetrazol was decreased after an acute dose of lorazepam (0.5 mg kg-1) at 4 days after drug discontinuation, compared to 1 or 7 days after discontinuation or to vehicle treatment. 3. The percentage of mice undergoing convulsions after an acute dose of FG 7142 (40 mg kg-1) was increased at 4 days after lorazepam discontinuation, compared to 1 or 7 days after discontinuation or to vehicle treatment. 4. After an acute dose (0.5 mg kg-1), lorazepam concentrations in cortex tended to be greater in lorazepam-treated compared to vehicle-treated mice at 4 days after discontinuation compared to 1 and 7 days. 5. These data indicate a shift toward reduced agonist sensitivity and increased inverse agonist sensitivity in mice 4 days after lorazepam discontinuation.