RESUMO
The effects of chronic elevations in circulating glucocorticoids on the expression of peptides and peptide receptors of the hypothalamic-pituitary-adrenal (HPA) axis have been studied extensively in rodents, but they have not been examined in primates. To determine the responses of the HPA axis in primates to elevated cortisol, hypothalamic and pituitary tissue from normal older pigtailed macaques (Macaca nemestrina) that had received daily oral administration of cortisol or placebo for 1 year were studied. Pro-opiomelanocortin in the anterior pituitary and corticotropin-releasing factor (CRF) mRNA expression in the hypothalamic paraventricular nucleus (PVN) were significantly reduced in cortisol-treated monkeys in comparison with controls. CRF receptor 1 (CRF-R1) expression in the anterior pituitary and arginine vasopressin mRNA expression in the PVN were unchanged by chronic cortisol administration. Sustained elevation of circulating glucocorticoids results in suppression of HPA peptide and peptide receptor expression in the PVN and anterior pituitary similar to those found in rodents. Chronic therapeutic administration of glucocorticoids in humans may have unintended consequences for hypothalamic and pituitary function.
Assuntos
Anti-Inflamatórios/farmacologia , Hidrocortisona/farmacologia , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/fisiologia , Adeno-Hipófise/efeitos dos fármacos , Adeno-Hipófise/fisiologia , Animais , Arginina Vasopressina/genética , Hormônio Liberador da Corticotropina/genética , Feminino , Expressão Gênica/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/fisiologia , Macaca nemestrina , Masculino , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/fisiologia , Receptores de Hormônio Liberador da Corticotropina/genéticaRESUMO
Seizure incidence varies significantly with age, with seizure susceptibility particularly high during the first few years of life. Of significant concern is what effects do brief, repetitive seizures have on the developing brain. We approached this issue by examining the change in seizure threshold, and related markers of neuronal activity and metabolic activity (c-fos mRNA and 2-deoxyglucose [2DG]), as a function of repetitive seizure episodes in immature and mature rats. Starting on postnatal day 15 (P15) (immature) or P60 (adult) rats were given two flurothyl seizures a day for 5 days (nine or ten seizures). The seizure latency profile, our measure of threshold, in immature versus adult rats across the 5-day testing period was different. In immature rats, threshold for the second seizure on each day was significantly lower than for the first seizure, suggesting that there was little refractoriness after the first seizure of the day. In contrast, the mature animal had a significantly longer threshold latency to the second seizure for the first 3 days of testing. The immature animal was also more likely than the adult to exhibit tonic extension as a feature of the first seizure of the day. Following repetitive seizures, more regions of the CNS showed c-fos mRNA expression in the immature animal than adults, suggesting that repetitive seizures in the immature animal activated a greater percentage of the brain. Compared with the effects of a single seizure, repetitive seizures resulted in less 2DG labeling in most regions of the brain (except the hippocampus); in the immature brain this difference was more distinct than in adults. The consequences of repetitive seizures in the immature animal results in distinctly different seizure behavior and neuronal activity pattern (c-fos expression) than that observed in the mature animal.
Assuntos
Envelhecimento/metabolismo , Comportamento Animal/fisiologia , Convulsões/metabolismo , Envelhecimento/fisiologia , Animais , Animais Recém-Nascidos , Antimetabólitos/farmacocinética , Encéfalo/metabolismo , Desoxiglucose/farmacocinética , Feminino , Masculino , Proteínas Proto-Oncogênicas c-fos/biossíntese , RNA Mensageiro/biossíntese , Ratos , Ratos Sprague-Dawley , Convulsões/fisiopatologiaRESUMO
Several lines of evidence suggest that norepinephrine (NE) can modulate seizure activity. However, the experimental methods used in the past cannot exclude the possible role of other neurotransmitters coreleased with NE from noradrenergic terminals. We have assessed the seizure susceptibility of genetically engineered mice that lack NE. Seizure susceptibility was determined in the dopamine beta-hydroxylase null mutant (Dbh -/-) mouse using four different convulsant stimuli: 2,2,2-trifluroethyl ether (flurothyl), pentylenetetrazol (PTZ), kainic acid, and high-decibel sound. Dbh -/- mice demonstrated enhanced susceptibility (i.e., lower threshold) compared with littermate heterozygous (Dbh +/-) controls to flurothyl, PTZ, kainic acid, and audiogenic seizures and enhanced sensitivity (i.e., seizure severity and mortality) to flurothyl, PTZ, and kainic acid. c-Fos mRNA expression in the cortex, hippocampus (CA1 and CA3), and amygdala was increased in Dbh -/- mice in association with flurothyl-induced seizures. Enhanced seizure susceptibility to flurothyl and increased seizure-induced c-fos mRNA expression were reversed by pretreatment with L-threo-3, 4-dihydroxyphenylserine, which partially restores the NE content in Dbh -/- mice. These genetically engineered mice confirm unambiguously the potent effects of the noradrenergic system in modulating epileptogenicity and illustrate the unique opportunity offered by Dbh -/- mice for elucidating the pathways through which NE can regulate seizure activity.
Assuntos
Norepinefrina/deficiência , Convulsões/induzido quimicamente , Convulsões/etiologia , Estimulação Acústica , Animais , Convulsivantes , Suscetibilidade a Doenças , Flurotila , Camundongos , Camundongos Knockout/genética , Norepinefrina/genética , Proteínas Proto-Oncogênicas c-fos/genética , RNA Mensageiro/metabolismoRESUMO
To study the effect of PRL deficiency on the onset of puberty, PRL release was chronically inhibited by treating immature female rats with the dopaminergic receptor agonist, bromoergocriptine (CB-154). The resulting alterations in the time of puberty onset, and in other associated parameters, such as serum levels of pituitary hormones, ovarian responsiveness to gonadotropins and ovarian hCG receptor content were then evaluated. CB-154 was provided in the drinking water from day 22 onward at the concentration of 20 and 100 micrograms/ml. The treatment resulted in almost complete suppression of serum PRL levels throughout the entire period studied (day 22 to first diestrus). In contrast, serum GH, FSH, and LH levels were not depressed. Likewise, pulsatile release of FSH was not affected and only a subtle alteration in pulsatile LH release was apparent. The onset of puberty, as determined by the age at vaginal opening, and at first diestrus after the first estrus and by the presence of corpora lutea at sacrifice (first diestrus), was markedly delayed in the hypoprolactinemic (HPO) rats. This inhibitory effect of CB-154 was completely prevented by concomitant administration of PRL. Ovarian weight was significantly decreased in HPO rats at the three ages studied (27, 32, and 36 days of age). By day 36, 50% of the control animals had already ovulated, as compared with only 9% of the HPO rats. Microscopic examination of ovaries from HPO rats revealed a retarded follicular development. In vitro ovarian progesterone response to hCG studied at day 32 and 36 of age was reduced in the HPO rats. Uterine growth was also depressed in HPO rats, the ovaries of which, when incubated in vitro, failed to show the prepubertal increase in estrogen response to hCG seen in control rats between day 32 ad 36. Aromatase activity, as measured by the in vitro release of estradiol from ovaries incubated in the presence of an excess of androgen substrate, was depressed in HPO rats. hCG receptor content in the ovaries from HPO rats (counts per min [125]hCG bound per micrograms DNA) was also lower than that of control animals at day 32 and 34 but not at day 36. However, at this later time the hCG receptor content per milligram of ovary was still significantly reduced in HPO rats. The results support the view that PRL plays an important role in the process of ovarian development that leads to the onset of puberty in the female rat and that this effect is, at least in part, exerted through a positive influence of PRL on ovarian LH receptor content.
Assuntos
Bromocriptina/farmacologia , Prolactina/metabolismo , Maturidade Sexual/efeitos dos fármacos , Animais , Feminino , Hormônio Foliculoestimulante/sangue , Hormônio do Crescimento/sangue , Hormônio Luteinizante/sangue , Ovário/efeitos dos fármacos , Ovário/fisiologia , Prolactina/sangue , Prolactina/farmacologia , Ratos , Receptores de Superfície Celular/fisiologia , Receptores do LHRESUMO
Implantation of GH in the median eminence of the hypothalamus of 23-day-old female rats tonically inhibited serum GH levels throughout prepubertal development (days 23-36) and depressed GH diurnal pulsatile release. Puberty was significantly delayed in GH-deficient animals, a delay associated with a blunted in vitro ovarian steroidal responsiveness to gonadotropins (particularly estradiol) and a marked decrease in prepubertal uterine weight, as evaluated 4, 7, and 13 days after GH implantation. The prepubertal body weight increase was also depressed. Neither ovarian weight nor serum levels of LH, FSH, PRL, or TSH were consistently altered by the GH implant. In addition, evaluation of pulsatile PRL release in 33-day-old rats revealed no difference between control and GH-deficient animals. Ovarian LH receptor content was lower in GH-implanted rats than in controls, suggesting that a decrease in LH receptors may be one of the mechanisms by which a chronic decrease in serum gH depressed the prepubertal ovarian estradiol and, to a lesser extent, the progesterone response to gonadotropins. A direct ovarian site of action for GH was indicated by the results of experiments in which GH was administered to immature hypophysectomized estrogen-treated rats. The in vitro ovarian progesterone response of the GH-treated animals to both hCG and human FSH was distinctly increased by prior in vivo GH treatment. This effect of GH was not reproduced either by the in vivo administration of LH at a dose calculated by RIA to be contaminating the GH preparation or by FSH at a dose that induced a marked increase in aromatase activity in the same ovaries. GH treatment of hypophysectomized rats failed to affect either aromatase activity or hCG-induced estradiol release, indicating that GH does not directly facilitate the production of estradiol by the ovary. The fact that intact rats with GH implants did not actually show a decrease in the ovarian estradiol response to hCG but, rather, failed to show an increased response at the same time as control animals strongly suggests that ovarian maturation was delayed in GH-deficient rats. It is suggested that, in addition to PRL, GH may also play a role in the process of prepubertal reproductive development by enhancing the steroidal response of the ovary to gonadotropins.