RESUMO
The balance between GABA-mediated inhibitory and glutamate-mediated excitatory synaptic transmission represents a fundamental mechanism for controlling nervous system function, and modulators that can alter this balance may participate in the pathophysiology of neuropsychiatric disorders. Pregnenolone sulfate (PS) is a neuroactive steroid that can modulate the activity of ionotropic glutamate and GABA(A) receptors either positively or negatively, depending upon the particular receptor subtype, and modulates synaptic transmission in a variety of experimental systems. To evaluate the modulatory effect of PS in vivo, we infused PS into rat striatum for 20 min via a microdialysis probe while monitoring local extracellular dopamine (DA) levels. The results demonstrate that PS at low nanomolar concentrations significantly increases extracellular DA levels. The PS-induced increase in extracellular DA is antagonized by the N-methyl-d-aspartate (NMDA) receptor antagonist, d-AP5 [d-(-)-2-amino-5-phosphonopentanoic acid], but not by the sigma receptor antagonist, BD 1063 [1(-)[2-(3,4-dichlorophenyl)-ethyl]-4-methylpiperazine]. The results demonstrate that exogenous PS, at nanomolar concentrations, is able to increase DA overflow in the striatum through an NMDA receptor-mediated pathway.
Assuntos
Corpo Estriado/metabolismo , Dopamina/metabolismo , Pregnenolona/farmacologia , Animais , Relação Dose-Resposta a Droga , N-Metilaspartato/antagonistas & inibidores , N-Metilaspartato/metabolismo , Pregnenolona/administração & dosagem , Ratos , Receptores sigma/antagonistas & inibidores , Receptores sigma/metabolismo , Transdução de SinaisRESUMO
This study explores the hypotheses that: (1) ethanol will interact with dl-Methylphenidate (MPH) to enantioselectively elevate plasma d-MPH, and primarily yield l-ethylphenidate as a transesterification metabolite; (2) women will exhibit lower relative bioavailability of MPH than men; and (3) sex-dependent differences in subjective effects will exist. dl-MPH HCl (0.3 mg/kg) was administered orally 30 min before ethanol, 30 min after ethanol (0.6 gm/kg), or without ethanol, in a randomized, normal subject three-way crossover study of 10 men and 10 women. Pharmacokinetic parameters were compared. Subjective effects were recorded using visual analog scales. One subject was a novel poor MPH metabolizer whose data were analyzed separately. Ethanol after or before MPH significantly (P<0.0001) elevated the geometric mean for the maximum d-MPH plasma concentration (C(max) (+/-SD)) from 15.3 (3.37) ng/ml to 21.5 (6.81) and 21.4 (4.86), respectively, and raised the corresponding geometric mean for the area under the concentration-time curve values from 82.9 (21.7) ng ml/h to 105.2 (23.5) and 102.9 (19.2). l-MPH was present in plasma only at 1-3% of the concentration of d-MPH, except in the poor metabolizer where l-MPH exceeded that of d-MPH. The metabolite l-ethylphenidate frequently exceeded 1 ng/ml in plasma, whereas d-ethylphenidate was detected only in low pg/ml concentrations. Women reported a significantly greater stimulant effect than men when questioned "Do you feel any drug effect?" (P<0.05), in spite of lower mean plasma d-MPH area under the response-time curves in women. Ethanol elevates plasma d-MPH C(max) and area under the concentration-time curve by approximately 40% and 25%, respectively. If the poor metabolizer of MPH proves to be a distinct phenotype, determining the genetic mechanism may be of value for individualizing drug therapy. The more pronounced stimulant effects experienced by women have sex-based abuse liability implications.
Assuntos
Depressores do Sistema Nervoso Central/farmacologia , Depressores do Sistema Nervoso Central/farmacocinética , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/farmacocinética , Etanol/farmacologia , Etanol/farmacocinética , Metilfenidato/farmacologia , Metilfenidato/farmacocinética , Adulto , Área Sob a Curva , Biotransformação , Pressão Sanguínea/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Estudos Cross-Over , Interações Medicamentosas , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Metilfenidato/análogos & derivados , Metilfenidato/metabolismo , Farmacogenética , Mecânica Respiratória/efeitos dos fármacos , Caracteres Sexuais , EstereoisomerismoRESUMO
Neuroactive steroids are synthesized de novo in brain, yet their physiological significance remains elusive. We provide biochemical, electrophysiological, and behavioral evidence that several specific actions of alcohol (ethanol) are mediated by the neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP; allopregnanolone). Systemic alcohol administration elevates 3alpha, 5alpha-THP levels in the cerebral cortex to pharmacologically relevant concentrations. The elevation of 3alpha,5alpha-THP is dose- and time-dependent. Furthermore, there is a significant correlation between 3alpha,5alpha-THP levels in cerebral cortex and the hypnotic effect of ethanol. Blockade of de novo biosynthesis of 5alpha-reduced steroids using the 5alpha-reductase inhibitor finasteride prevents several effects of ethanol. Pretreatment with finasteride causes no changes in baseline bicuculline-induced seizure threshold but reverses the anticonvulsant effect of ethanol. Finasteride pretreatment also reverses ethanol inhibition of spontaneous neural activity in medial septal/diagonal band of Broca neurons while having no direct effect on spontaneous firing rates. Thus, elevation of 3alpha,5alpha-THP levels by acute ethanol administration represents a novel mechanism of ethanol action as well as an important modulatory role for neurosteroids in the CNS.
Assuntos
Comportamento Animal/efeitos dos fármacos , Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Fármacos Neuroprotetores/metabolismo , Pregnanolona/metabolismo , Animais , Bicuculina , Química Encefálica/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Convulsivantes , Inibidores de Ciclo-Oxigenase/farmacologia , Di-Hidrotestosterona/análogos & derivados , Di-Hidrotestosterona/farmacologia , Eletrofisiologia , Inibidores Enzimáticos/farmacologia , Epilepsia/induzido quimicamente , Epilepsia/fisiopatologia , Finasterida/farmacologia , Indometacina/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/fisiologiaRESUMO
Prolonged alcohol (ethanol) consumption leads to the development of alcohol tolerance and cross-tolerance to some benzodiazepines and barbiturates. In contrast, rats undergoing alcohol withdrawal are sensitized to the anticonvulsant effects of the endogenous GABA(A) receptor modulator, 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP). Alterations in endogenous, cerebral cortical levels of 3alpha,5alpha-THP during alcohol withdrawal could contribute to the observed sensitization to 3alpha,5alpha-THP. Therefore, this study investigated plasma and brain levels of 3alpha,5alpha-THP, progesterone, and corticosterone during alcohol dependence and withdrawal in the rat. Plasma corticosterone, progesterone (a precursor of 3alpha,5alpha-THP) and 3alpha,5alpha-THP levels were unchanged in alcohol-dependent animals. Cerebral cortical levels of 3alpha,5alpha-THP decreased in dependent male animals, but not in dependent female rats. During alcohol withdrawal, plasma corticosterone and progesterone levels increased in male, but not female rats. However, neither plasma nor cerebral cortical 3alpha,5alpha-THP levels were altered from control levels in male or female rats during alcohol withdrawal. Plasma and brain levels of 3alpha,5alpha-THP were markedly higher in female compared with male rats. Cerebral cortical levels of 3alpha,5alpha-THP during the diestrus phase of the estrus cycle were approximately 4 to 6 ng/g, a concentration that may approach physiological relevance. These findings suggest that sensitization to 3alpha,5alpha-THP during alcohol withdrawal is not mediated by elevations in brain levels of endogenous 3alpha,5alpha-THP in male or female rats. However, elevations in circulating corticosterone and progesterone levels during ethanol withdrawal in male rats may underlie gender differences in allopregnanolone sensitivity during ethanol withdrawal.
Assuntos
Delirium por Abstinência Alcoólica/sangue , Alcoolismo/sangue , Pregnanolona/sangue , Animais , Córtex Cerebral/metabolismo , Estro/efeitos dos fármacos , Feminino , Masculino , Ratos , Ratos Sprague-Dawley , Fatores SexuaisRESUMO
Our laboratory has previously shown that the synthetic neuroactive steroid 3alpha-hydroxy-5beta-pregnan-20-one hemisuccinate (3alpha5betaHS) is a negative modulator of NMDA receptors in vitro. Similarly, 3alpha5betaHS exhibits rapid sedative, analgesic, anticonvulsive, and neuroprotective effects in vivo. Here we report a study designed to investigate whether a negatively charged neuroactive steroid, 3alpha5betaHS, modulates the action of NMDA receptors in vivo. Our results indicate that peripherally administered 3alpha5betaHS enters the CNS and inhibits NMDA-mediated motor activity and dopamine release in the rat striatum. The increase in motor activity induced by intrastriatal microinjection of NMDA was blocked by the systemic administration of 3alpha5betaHS and the NMDA-induced increase in extracellular dopamine in the striatum was also attenuated by both systemically administered and intrastriatally administered (by in vivo microdialysis) 3alpha5betaHS. These data indicate that 3alpha5betaHS acts through striatal NMDA receptors in vivo. When taken together, these results suggest that neuroactive steroids may prove to be effective in the treatment of neurological and psychiatric disorders involving over-stimulation of NMDA receptors in the mesotelencephalic dopamine system.