1,720,974 research outputs found
Differential effects of ethanol on cerebral cortical and hippocampal allopregnanolone levels in mice and rats
No full textAcute ethanol administration to rats stimulates the hypothalamic-pituitary-adrenal (HPA) axis and increases brain and plasma levels of the potent neurosteroid allopregnanolone. Increased allopregnanolone levels contribute to the anxiolytic, anticonvulsant, sedative and pro-aggressive actions of ethanol. It is not yet known if ethanol’s effects on allopregnanolone levels generalize across species. Indeed, studies in mice have reported that ethanol does not always alter brain and plasma allopregnanolone levels. We thus explored the effects of ethanol administration on brain levels of allopregnanolone and its precursor progesterone in C57BL/6J and DBA/2J mice, two inbred strains with different sensitivity to behavioral effects of alcohol.
Male C57BL/6J and DBA/2J mice were injected with ethanol (1, 2, 3 or 4 g/kg, i.p.) or saline and were sacrificed 1 hour later or 15, 30, 60 and 120 minutes later for the time course studies. Allopregnanolone, progesterone and corticosterone levels were measured by radioimmunoassay in cerebral cortex and hippocampus.
Acute ethanol administration did not alter cerebral cortical and hippocampal levels of allopregnanolone and progesterone in both C57BL/6J and DBA/2J mice at any of the doses examined. Cerebral cortical levels of allopregnanolone and progesterone were also not altered at any of the time points examined in either strain. In contrast, as expected, acute ethanol administration dose-dependently increased cerebral cortical levels of allopregnanolone and progesterone in male Sprague-Dawley rats. Acute ethanol administration dose-dependently increased corticosterone levels in the cerebral cortex and the hippocampus of both mouse strains. In C57BL/6J mice, corticosterone levels were increased by 319%, 352% and 448% in the cerebral cortex and by 284%, 218% and 368% in the hippocampus at the doses of 2, 3 and 4 g/kg, respectively, p<0.001. In DBA/2J mice, corticosterone levels were increased by 354%, 417%, 447% and 574% in the cerebral cortex and by 259%, 434%, 567% and 629% at the doses of 1, 2, 3 and 4 g/kg, respectively, p<0.001. The effect of ethanol on cerebral cortical corticosterone levels was also time-dependent: in C57BL/6J mice it was apparent at 15 min (+155%), reached a peak at 60 min (+306%) and remained elevated at 120 min (+217%) from ethanol administration (p<0.001); in DBA/2J mice it was apparent at 30 min (+546%), reached a peak at 60 min (+1002%) and remained elevated at 120 min (+822%) from ethanol administration (p<0.001). These results suggest that ethanol administration is activating the HPA axis, as expected, and that ethanol might directly impair brain neurosteroid synthesis. Moreover, to evaluate if the effect of ethanol on allopregnanolone levels was specific to ethanol or not, we tested whether administration of morphine, which also increases cerebral cortical levels of allopregnanolone in rats, alters allopregnanolone and progesterone levels in male C57BL/6J and DBA/2J mice. Morphine administration increased cerebral cortical allopregnanolone levels in C57BL/6J mice (+77%, +93% and +88%, at the doses of 5, 10 and 30 mg/kg, respectively, p<0.01) and DBA/2J mice (+81% at the dose of 5 mg/kg, p<0.05). Morphine administration also increased progesterone levels in both strains. These results suggest that the impairment in brain neurosteroidogenesis in C57BL/6J and DBA/2J mice appears to be specific to ethanol.
Overall, these results show important species differences in the effects of ethanol on brain neurosteroidogenesis. Given that ethanol does not alter cerebral cortical and hippocampal concentrations of allopregnanolone and progesterone in the two mouse strains examined, the differential sensitivity to some of the behavioral effects of ethanol cannot be directly correlated to hormonal changes in C57BL/6J and DBA/2J mice
Decreased allopregnanolone induced by hormonal contraceptives is associated with a reduction in social behavior and sexual motivation in females rats
No full textFailure of acute ethanol administration to alter cerebral cortical and hippocampal allopregnanolone levels in C57BL/6J and DBA/2J mice
No full textAcute ethanol administration to rats stimulates the hypothalamic-pituitary-adrenal (HPA) axis and increases brain and plasma levels of the potent neurosteroid allopregnanolone. Increased allopregnanolone levels contribute to the anxiolytic, anticonvulsant, sedative and pro-aggressive actions of ethanol. It is not yet known if ethanol’s effects on allopregnanolone levels generalize across species. Indeed, studies in mice have reported that ethanol does not always alter brain and plasma allopregnanolone levels We thus explored the effects of ethanol administration on brain levels of allopregnanolone and its precursor progesterone in C57BL/6J and DBA/2J mice, two inbred strains with different sensitivity to behavioral effects of alcohol.
Male C57BL/6J and DBA/2J mice were injected with ethanol (1, 2, 3 or 4 g/kg, i.p.) or saline and were sacrificed 1 hour later or 15, 30, 60 and 120 minutes later for the time course studies. Allopregnanolone, progesterone and corticosterone levels were measured by radioimmunoassay in cerebral cortex and hippocampus.
Acute ethanol administration did not alter cerebral cortical and hippocampal levels of allopregnanolone and progesterone in both C57BL/6J and DBA/2J mice at any of the doses examined. Cerebral cortical levels of allopregnanolone and progesterone were also not altered at any of the time points examined in either strain. Acute ethanol administration dose-dependently increased corticosterone levels in the cerebral cortex and the hippocampus of both mouse strains. In C57BL/6J mice, corticosterone levels were increased by 319%, 352% and 448% in the cerebral cortex and by 284%, 218% and 368% in the hippocampus at the doses of 2, 3 and 4 g/kg, respectively, p<0.001. In DBA/2J mice, corticosterone levels were increased by 354%, 417%, 447% and 574% in the cerebral cortex and by 259%, 434%, 567% and 629% in the hippocampus at the doses of 1, 2, 3 and 4 g/kg, respectively, p<0.001. The effect of ethanol on cerebral cortical corticosterone levels was also time-dependent: in C57BL/6J mice it was apparent at 15 min (+155%), reached a peak at 60 min (+306%) and remained elevated at 120 min (+217%) from ethanol administration (p<0.001); in DBA/2J mice it was apparent at 30 min (+546%), reached a peak at 60 min (+1002%) and remained elevated at 120 min (+822%) from ethanol administration (p<0.001). These results suggest that ethanol administration is activating the HPA axis, as expected, and that ethanol might directly impair brain neurosteroid synthesis. Moreover, to evaluate if the effect of ethanol on allopregnanolone levels was specific to ethanol or not, we tested whether administration of morphine, which also increases cerebral cortical levels of allopregnanolone in rats, alters allopregnanolone and progesterone levels in male C57BL/6J and DBA/2J mice. Morphine administration increased cerebral cortical allopregnanolone levels in C57BL/6J mice (+77%, +93% and +88%, at the doses of 5, 10 and 30 mg/kg, respectively, p<0.01) and DBA/2J mice (+81% at the dose of 5 mg/kg, p<0.05). Morphine administration also increased progesterone levels in both strains. These results suggest that the impairment in brain neurosteroidogenesis in C57BL/6J and DBA/2J mice appears to be specific to ethanol.
Overall, these results show important species differences in the effects of ethanol on brain neurosteroidogenesis. Given that ethanol does not alter cerebral cortical and hippocampal concentrations of allopregnanolone and progesterone in the two mouse strains examined, the differential sensitivity to some of the behavioral effects of ethanol cannot be directly correlated to hormonal changes in C57BL/6J and DBA/2J mice
Decreased allopregnanolone induced by hormonal contraceptives is associated with a reduction in social behavior and sexual motivation in female rats
No full textRATIONALE:
Allopregnanolone is a neurosteroid involved in depression, memory, social, and sexual behavior. We have previously demonstrated that treatment with a combination of ethinylestradiol (EE) and levonorgestrel (LNG), two compounds frequently used in hormonal contraception, decreased brain allopregnanolone concentrations. These changes may contribute to some of the emotional and sexual disorders observed in hormonal contraceptive users.
OBJECTIVES:
We thus examined whether the reduction in allopregnanolone concentrations induced by long-term EE/LNG administration was associated with altered emotional, learning, social, and sexual behaviors.
METHODS:
Rats were orally treated with a combination of EE (0.030 mg) and LNG (0.125 mg) once a day for 4 weeks and were subjected to behavioral tests 24 h after the last administration.
RESULTS:
EE/LNG treatment reduced immobility behavior in the forced swim test, without affecting sucrose preference and spatial learning and memory. In the resident-intruder test, EE/LNG-treated rats displayed a decrease in dominant behaviors associated with a reduction in social investigation. In the paced mating test, EE/LNG treated rats showed a reduction in proceptive behaviors, while the lordosis quotient was not affected. Progesterone, but not estradiol, administration to EE/LNG-treated rats increased sexual activity and cerebrocortical allopregnanolone concentrations. Prior administration of finasteride decreased allopregnanolone concentrations and abolished the increase in proceptivity induced by progesterone administration.
CONCLUSIONS:
The decrease in brain allopregnanolone concentrations induced by EE/LNG treatment is associated with a reduction in social behavior and sexual motivation in female rats. These results might be relevant to the side effects sometimes exhibited by women taking hormonal contraceptives
Failure of acute ethanol administration to alter cerebrocortical and hippocampal allopregnanolone levels in C57BL/6J and DBA/2J mice
No full textBackground: Ethanol (EtOH) administration increases brain allopregnanolone levels in rats, and this increase contributes to sensitivity to EtOH's behavioral effects. However, EtOH's effects on allopregnanolone may differ across species. We investigated the effects of acute EtOH administration on allopregnanolone, progesterone, and corticosterone levels in cerebral cortex and hippocampus of C57BL/6J and DBA/2J mice, 2 inbred strains with different alcohol sensitivity. Methods: Naïve male C57BL/6J and DBA/2J mice received EtOH (1, 2, 3, or 4 g/kg, intraperitoneally [i.p.]) or saline and were euthanized 1 hour later. For the time-course study, mice received EtOH (2 g/kg, i.p.) and were euthanized 15, 30, 60, and 120 minutes later. Steroids were measured by radioimmunoassay. Results: Acute EtOH administration did not alter cerebrocortical and hippocampal levels of allopregnanolone and progesterone in these strains at any of the doses and time points examined. Acute EtOH dose-dependently increased cerebrocortical corticosterone levels by 319, 347, and 459% in C57BL/6J mice at the doses of 2, 3, and 4 g/kg, and by 371, 507, 533, and 692% in DBA/2J mice at the doses of 1, 2, 3, and 4 g/kg, respectively. Similar changes were observed in the hippocampus. EtOH's effects on cerebrocortical corticosterone levels were also time dependent in both strains. Moreover, acute EtOH administration time-dependently increased plasma levels of progesterone and corticosterone. Finally, morphine administration increased cerebrocortical allopregnanolone levels in C57BL/6J (+77, +93, and +88% at 5, 10, and 30 mg/kg, respectively) and DBA/2J mice (+81% at 5 mg/kg), suggesting that the impairment in brain neurosteroidogenesis may be specific to EtOH. Conclusions: These results underline important species differences on EtOH-induced brain neurosteroidogenesis. Acute EtOH increases brain and plasma corticosterone levels but does not alter cerebrocortical and hippocampal concentrations of allopregnanolone and progesterone in naïve C57BL/6J and DBA/2J mice
Immunochemical localization of GABAA receptor subunits in the freshwater polyp Hydra vulgaris (Cnidaria, Hydrozoa)
No full textγ-aminobutyric acid (GABA) receptors, responding to GABA positive allosteric modulators, are present in the freshwater polyp Hydra vulgaris (Cnidaria, Hydrozoa), one of the most primitive metazoans to develop a nervous system. We examined the occurrence and distribution of GABAA receptor subunits in Hydra tissues by western blot and immunohistochemistry. Antibodies against different GABAA receptor subunits were used in Hydra membrane preparations. Unique protein bands, inhibited by the specific peptide, appeared at 35, 60, ∼50 and ∼52 kDa in membranes incubated with α3, β1, γ3 or δ antibodies, respectively. Immunohistochemical screening of whole mount Hydra preparations revealed diffuse immunoreactivity to α3, β1 or γ3 antibodies in tentacles, hypostome, and upper part of the gastric region; immunoreactive fibers were also present in the lower peduncle. By contrast, δ antibodies revealed a strong labeling in the lower gastric region and peduncle, as well as in tentacles. Double labeling showed colocalization of α3/β1, α3/γ3 and α3/δ immunoreactivity in granules or cells in tentacles and gastric region. In the peduncle, colocalization of both α3/β1 and α3/γ3 immunoreactivity was found in fibers running horizontally above the foot. These data indicate that specific GABAA receptor subunits are present and differentially distributed in Hydra body regions. Subunit colocalization suggests that Hydra GABA receptors are heterologous multimers, possibly sub-serving different physiological activitie
Morphine withdrawal produces ERK-dependent and ERK-independent epigenetic marks in neurons of the nucleus accumbens and lateral septum
No full textEpigenetic changes such as covalent modifications of histone proteins represent complex molecular signatures that provide a cellular memory of previously experienced stimuli without irreversible changes of the genetic code. In this study we show that new gene expression induced in vivo by morphine withdrawal occurs with concomitant epigenetic modifications in brain regions critically involved in drug-dependent behaviors. We found that naloxone-precipitated withdrawal, but not chronic morphine administration, caused a strong induction of phospho-histone H3 immunoreactivity in the nucleus accumbens (NAc) shell and core and in the lateral septum (LS), a change that was accompanied by augmented H3 acetylation (lys14) in neurons of the NAc shell. Morphine withdrawal induced the phosphorylation of the epigenetic factor methyl-CpG-binding protein 2 (MeCP2) in Ser421 both in the LS and the NAc shell. These epigenetic changes were accompanied by the activation of members of the ERK pathway as well as increased expression of the immediate early genes (IEGs) c-fos and activity-regulated cytoskeleton-associated protein (Arc/Arg3.1). Using a pharmacological approach, we found that H3 phosphorylation and IEG expression were partially dependent on ERK activation, while MeCP2 phosphorylation was fully ERK-independent. These findings provide new important information on the role of the ERK pathway in the regulation of epigenetic marks and gene expression that may concur to regulate in vivo the cellular changes underlying the onset of the opioid withdrawal syndrome
Decreased level of allopregnanolone induced by oral contraceptives are associated with a reduction in social behaviour and sexual motivation in rats
No full textNeonatal exposure to estradiol decreases hypothalamic allopregnanolone concentrations and alters agonistic and sexual but not affective behavior in adult female rats.
No full textExposure of developing female rats to estradiol during the perinatal period induced long-lasting dysregulation
of gonadal axis and decreased cerebrocortical and plasma concentrations of allopregnanolone. We have now
examined the effects of neonatal estradiol administration in female rats on hypothalamic allopregnanolone concentrations
and on exploratory, affective, agonistic and sexual behaviors as well as social learning. A single
administration of β-estradiol 3-benzoate (EB, 10 μg) on the day of birth resulted in a delay of vaginal opening,
acyclicity and ovarian failure. These alterations were associated with a significant decrease in the concentrations
of allopregnanolone in the hypothalamus at 21 and 60 days, but not at 7 days, after birth. Neonatal administration
of EB also increased agonistic behaviors in adult rats, such as dominant behaviors and following of an ovariectomized
intruder, while living attacks unaffected. EB-treated rats showed also an increase in anogenital
investigation, associated with a drastic reduction in spontaneous and induced female sexual behaviors (receptivity
and proceptivity). In contrast, neonatal administration of EB did not affect locomotor activity, anxiety- andmoodrelated
behaviors, the social transmission of flavor preferences, and seizures sensitivity. These effects of estradiol
suggest that it plays a major role in regulation of both the abundance of allopregnanolone and the expression
of agonistic and sexual behaviors, while failing to influence affective behaviors and social learning. Thus, the
pronounced and persistent decrease in hypothalamic allopregnanolone concentration may be related to themanifestation
of agonistic and sexual behaviors
- …
