RESUMO
Recent studies have shown that anesthetic agents alter the physical properties of lipid rafts on model membranes. However, if this destabilization occurs in brain membranes, altering the lipid raft-protein interaction, remains unknown. We analyzed the effects produced by pentobarbital (PB) on brain plasma membranes and lipid rafts in vivo. We characterized for the first time the thermotropic behavior of plasma membranes, synaptosomes, and lipid rafts from rat brain. We found that the transition temperature from the ordered gel to disordered liquid phase of lipids is close to physiological temperature. We then studied the effect of PB on protein composition of lipid rafts. Our results show a reduction of the total protein associated to rafts, with a higher reduction of the NMDAR compared to the GABAA receptor. Both receptors are considered the main targets of PB. In general, our results suggest that lipid rafts could be plausible mediators in anesthetic action.
Assuntos
Encéfalo/efeitos dos fármacos , Hipnóticos e Sedativos/farmacologia , Microdomínios da Membrana/efeitos dos fármacos , Pentobarbital/farmacologia , Receptores de GABA-A/genética , Receptores de N-Metil-D-Aspartato/genética , Anestesia , Animais , Encéfalo/metabolismo , Expressão Gênica , Hipnóticos e Sedativos/metabolismo , Masculino , Microdomínios da Membrana/química , Microdomínios da Membrana/metabolismo , Pentobarbital/metabolismo , Ratos , Ratos Wistar , Receptores de GABA-A/biossíntese , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/biossíntese , Sinaptossomos/química , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo , Temperatura de TransiçãoRESUMO
The central nervous system is severely affected by hypoxic conditions, which produce alterations in neural cytoarchitecture and neurotransmission, resulting in a variety of neuropathological conditions such as convulsive states, neurobehavioral impairment and motor CNS alterations. Some of the neuropathologies observed in hypobaric hypoxia, corresponding to high altitude conditions, have been correlated with a loss of balance between excitatory and inhibitory neurotransmission, produced by alterations in glutamatergic and GABAergic receptors. In the present work, we have studied the effect of chronic hypobaric hypoxia (506 hPa, 18 h/day x 21 days) applied to adult male mice on GABA(A) receptors from cerebral cortex, to determine whether hypoxic exposure may irreversibly affect central inhibitory neurotransmission. Saturation curves for [3H]GABA specifically bound to GABA(A) receptors in isolated synaptic membranes showed a 30% decrease in maximal binding capacity after hypoxic exposure (Bmax control, 4.70+/-0.19, hypoxic, 3.33+/-0.10 pmol/mg protein), with no effect on GABA binding sites affinity (Kd control: 159.3+/-13.3 nM, hypoxic: 164.2+/-15.1 nM). Decreased B(max) values were observed up to the 10th post-hypoxic day, returning to control values by the 15th post-hypoxic day. Pharmacological properties of GABA(A) receptor were also affected by hypoxic exposure, with a 45 to 51% increase in the maximal effect by positive allosteric modulators (pentobarbital and 5alpha-pregnan-3alpha-ol-20-one). We conclude that long-term hypoxia produces a significant but reversible reduction on GABA binding to GABA(A) receptor sites in cerebral cortex, which may reflect an adaptive response to this sustained pathophysiological state.
Assuntos
Córtex Cerebral/metabolismo , Desoxicorticosterona/análogos & derivados , Hipóxia Encefálica/metabolismo , Receptores de GABA-A/metabolismo , Animais , Ansiolíticos/metabolismo , Bicuculina/metabolismo , Desoxicorticosterona/metabolismo , Antagonistas GABAérgicos/metabolismo , Moduladores GABAérgicos/metabolismo , Masculino , Camundongos , Pentobarbital/metabolismoRESUMO
Evidence that beta-myrcene (MYR) interferes with the metabolic activation of premutagens has been provided by in vitro studies. In order to determine whether MYR also interferes with the in vivo metabolism of xenobiotics, thereby modifying pharmacological responses to drugs, we investigated the effects of this monoterpene on pentobarbital (PT) sleeping time in rats. Two experiments were carried out. In the first, a single dose of MYR (0.25, 0.5 or 1.0 g/kg po) was given 1 h before PT (40 mg/kg ip). No effect was observed with the two lowest doses, but the highest MYR dose given 1 h before PT increased the PT-induced sleeping time (131 +/- 15 min vs 64 +/- 15 min for controls, mean +/- SD). In the second experiment, male rats were treated with MYR (1.0 g/kg po once a day) for 14 days and injected with PT (40 mg/kg ip) 24 h after the last dose of MYR. Repeated treatment with MYR markedly reduced PT sleeping time compared to the vehicle-treated control group (21 +/- 13 min vs 35 +/- 19 min for controls, mean +/- SD). These results indicate that MYR interferes with the in vivo barbiturate metabolism and support the view that MYR induces the phenobarbital-inducible cytochrome P-450 (P-450 2B subfamily) enzymes in the rat.
Assuntos
Monoterpenos , Pentobarbital/antagonistas & inibidores , Sono/efeitos dos fármacos , Terpenos/farmacologia , Monoterpenos Acíclicos , Animais , Sistema Enzimático do Citocromo P-450/biossíntese , Indução Enzimática/efeitos dos fármacos , Masculino , Pentobarbital/metabolismo , Ratos , Ratos Wistar , Terpenos/administração & dosagemRESUMO
Evidence that beta-myrcene (MYR) interferes with the metabolic activation of premutagens has been provided by in vitro studies. In order to determine whether MYR also interferes with the in vivo metabolism of xenobiotics, thereby modifying pharmacological responses to drugs, we investigated the effects of this monoterpene on pentobarbital (PT) sleeping time in rats. Two experiments were carried out. In the first, a single dose of MYR (0.25, 0.5 or 1.0 g/kg po) was given 1 h before PT (40 mg/kg ip). No effect was observed with the two lowest doses, but the highest MYR dose given 1 h before PT increased the PT-induced sleeping time (131 +/- 15 min vs 64 +/- 15 min for controls, mean +/- SD). In the second experiment, male rats were treated with MYR (1.0 g/kg po once a day) for 14 days and injected with PT (40 mg/kg ip) 24 h after the last dose of MYR. Repeated treatment with MYR markedly reduced PT sleeping time compared to the vehicle-treated control group (21 +/- 13 min vs 35 +/- 19 min for controls, mean +/- SD). These results indicate that MYR interferes with the in vivo barbiturate metabolism and support the view that MYR induces the phenobarbital-inducible cytochrome P-450 (P-450 2B subfamily) enzymes in the rat
Assuntos
Animais , Masculino , Ratos , Pentobarbital/antagonistas & inibidores , Sono/efeitos dos fármacos , Terpenos/farmacologia , Sistema Enzimático do Citocromo P-450/biossíntese , Indução Enzimática , Pentobarbital/metabolismo , Ratos Wistar , Terpenos/administração & dosagemRESUMO
A single dose of calcitonin (150 mIU/100 g body weight, sc) produced a significant decrease in liver antipyrine hydroxylase and aminopyrine demethylase activities. By contrast, pentobarbital sleeping time was not altered by calcitonin treatment. The present results indicate that acute calcitonin administration depresses the metabolism of substrates of the mixed function oxidase system of rat liver.
Assuntos
Aminopirina N-Desmetilase/metabolismo , Calcitonina/farmacologia , Fígado/enzimologia , Oxigenases de Função Mista/metabolismo , Animais , Antipirina/metabolismo , Masculino , Pentobarbital/metabolismo , Ratos , Ratos Endogâmicos , Sono/efeitos dos fármacosRESUMO
The effect of the duration of isolation periods on the development of tolerance to sodium barbital was studied in mice. The HD50 values for pentobarbital-induced hypnosis were higher in all mice that were long-term treated with sodium pentobarbital, whether or not they were isolated or in groups. Diazepam HD50s were higher in mice isolated and long-term treated with sodium barbital for 38 days and in grouped animals treated with the barbiturate for 20 and 30 days. Social isolation for 8 weeks plus 23 days increased the pentobarbital hypnotic dose (HD50). These data show that social isolation increased the rate of tolerance acquisition to sodium barbital by mice.