Biomedical subjects

A J Douglas

Publications and source records attributed to A J Douglas.

At least 19 recordsLinked to original sources

PubMed2002

The importance of oxytocin mechanisms in the control of mouse parturition.

The role of oxytocin in parturition in mice was investigated. Pup birth profiles, blood samples and brains were collected from parturient mice observed under red light conditions in a reversed light:dark photoperiod. Peripheral administration of an oxytocin antagonist in a dose-dependent manner delayed the birth of subsequent pups, indicating that oxytocin is required for a normal pup birth profile. Oxytocin neurones were activated during birth as shown by both increased immediate early gene ( Fos) expression in oxytocin neurones in the supraoptic nucleus and increased plasma oxytocin concentrations during birth. In addition, the nucleus of the tractus solitarius and the olfactory bulbs, sites that process inputs to oxytocin neurones, become activated during parturition. Exposure to stress during parturition halted subsequent deliveries; at this stage plasma oxytocin concentrations were not higher than those of virgin mice, and birth was restored by administration of oxytocin. Administration of beta-adrenergic antagonist (propranolol) also restored stress-delayed birth, whereas administration of ritrodrine (beta-agonist) delayed birth in non-stressed mice, indicating that adrenergic mechanisms contribute to stress-delayed births in mice. Administration of morphine (mu-opioid agonist) delayed births transiently, but naloxone (opioid antagonist) did not prevent stress-delayed birth, indicating that endogenous opioids do not appear to contribute to neuroendocrine or uterine mechanisms that promote birth in mice. Therefore, despite evidence in oxytocin knockout mice that oxytocin is not essential for parturition in this species, the results of the present study indicate that oxytocin neurone activity and secretion contribute to the birth process in normal mice.

Adrenergic beta-Agonists↗

PubMed2001

Brain preparations for maternity--adaptive changes in behavioral and neuroendocrine systems during pregnancy and lactation. An overview.

Pregnancy, parturition and lactation comprise a continuum of adaptive changes necessary for the development and maintenance of the offspring. The endocrine changes that are driven by the conceptus and are essential for the maintenance of pregnancy and are involved in the preparations for motherhood are outlined. These changes include large increases in the secretion of sex steroid hormones, and the secretion of peptide hormones that are unique to pregnancy. The ability of these pregnancy hormones to alter several aspects of brain function in pregnancy is considered, and the adaptive importance of some of these changes is discussed, for example in metabolic and body fluid adjustments, and the induction of maternal behavior. The importance of sex steroids in determining the timing of the various adaptive changes in preparing for parturition and maternal behavior is emphasized, and the concept that the actions of prolactin and oxytocin, quintessential mammalian motherhood neuropeptides, can serve to coordinate a spectrum of adaptive changes is discussed. The part played by oxytocin neurons and their regulatory mechanisms is reviewed to illustrate how neural systems involved in maternity are prepared in pregnancy via changes in phenotype, synaptic organization and in the relative importance of their different inputs, to function optimally when needed. For oxytocin neurons secreting from the posterior pituitary, important in parturition and essential in lactation, these changes include mechanisms to restrain their premature activation, and adaptations to support synchronized burst firing for pulsatile oxytocin secretion in response to stimulation via afferents from the birth canal, olfactory system or suckled nipples. Within the brain, expression of oxytocin receptors permits centrally released oxytocin to facilitate the expression of maternal behavior. Changes in other neuroendocrine systems are similarly extensive, leading to lactation, suppression of ovulation, reduced stress responses and increased appetite; these changes in lactation are driven by the suckling stimulus. The possible link between these adaptations and changes in cognition and mood in pregnancy and post partum are considered, as well as the dysfunctions that lead to common problems of depression and puerperal psychoses.

Adaptation, Physiological↗

PubMed2001

Endogenous opioid regulation of oxytocin and ACTH secretion during pregnancy and parturition.

Progress of parturition in the rat is optimal when there is increased oxytocin secretion, thus ensuring quick birth and otherwise risking adverse neonatal health. To ensure that the mechanisms for this are available, oxytocin neurons adapt in pregnancy and this includes development of a tonic inhibition by endogenous opioids. Endogenous opioid inhibition of oxytocin secretion increases in pregnancy, initially acting on the nerve terminals in the posterior pituitary and later on oxytocin cell bodies and their inputs. This inhibition enhances stores of oxytocin and enables restraint of oxytocin neuron responsiveness to selected excitatory inputs. The hypothalamic neurons which mediate stress also adapt in late pregnancy so that hypothalamo-pituitary-adrenal axis and oxytocin secretory responses to stressor exposure are attenuated. This is also partly due to endogenous opioid inhibition. Thus, in pregnancy oxytocin and hypothalamo-pituitary-adrenal axis secretion in response to stimulation is restrained, protecting the unborn fetus(es) from premature delivery and glucocorticoid exposure and preparing the oxytocin neurons for their important secretory role during parturition. In parturition itself, endogenous opioids continue to inhibit these neurons. Stress exposure during parturition delays births, probably due to endogenous opioid inhibition of pulsatile oxytocin secretion. On the other hand, basal ACTH and corticosterone secretion are reduced in parturition through inhibition by endogenous opioids. So, opioids continue to regulate the activity of oxytocin and hypothalamo-pituitary-adrenal mechanisms in labor; inhibition of oxytocin neurons at this time may control the spacing of pup births.

Adrenocorticotropic Hormone↗

PubMed2001

The N-terminal region of the VP1 protein of swine vesicular disease virus contains a neutralization site that arises upon cell attachment and is involved in viral entry.

The N-terminal region of VP1 of swine vesicular disease virus (SVDV) is highly antigenic in swine, despite its internal location in the capsid. Here we show that antibodies to this region can block infection and that allowing the virus to attach to cells increases this blockage significantly. The results indicate that upon binding to the cell, SVDV capsid undergoes a conformational change that is temperature independent and that exposes the N terminus of VP1. This process makes this region accessible to antibodies which block virus entry.

Amino Acid Sequence↗

PubMed2000

Single amino acid differences are sufficient for CD4(+) T-cell recognition of a heterologous virus by cattle persistently infected with bovine viral diarrhea virus.

Cattle that are persistently infected (PI) with one strain of bovine viral diarrhea virus (BVDV) can resolve infection with a second, antigenically heterologous strain but not the homologous strain. Since CD4(+) T cells are thought to be critical for the resolution of acute BVDV infection (Howard et al., 1992, Vet. Immunol. Immunopathol. 32, 303-314), we have examined the recognition of a heterologous virus (NADL) by CD4(+) T cells from Pe515-PI animals. The immune response of non-PI control cattle challenged with NADL or Pe515ncp was strain cross-reactive, whereas Pe515-PI animals responded to NADL only. The immune repertoire of both groups included NS3, which differs by approximately 1% (9/683) amino acids between these two viruses. Lymphoproliferative responses to proteins and synthetic peptides corresponding to three nonconservative differences in NS3 demonstrated that CD4(+) T cells from non-PI control animals responded well to proteins but poorly to the peptides from both viruses. In contrast, PI animals were responsive to heterologous proteins and peptides but nonresponsive to the homologous equivalents. A single amino acid difference between the two sequences was sufficient to allow responsiveness.

Amino Acid Sequence↗

PubMed2000

Nitric oxide and the oxytocin system in pregnancy.

We examined the functional role of the nitric oxide (NO)-producing system in magnocellular neurons and how this changes at the end of pregnancy, using a combination of blood sampling and oxytocin radioimmunoassay, electrophysiology, immunocytochemistry for Fos expression, and in situ hybridization histochemistry. In urethane-anesthetized virgin rats, systemic administration of NO synthase (NOS) inhibitors led to a facilitation of oxytocin release evoked by hyperosmotic stimulation. Direct application of the NO donor sodium nitroprusside to the supraoptic nucleus by in vivo microdialysis inhibited the electrical activity of both oxytocin neurons and vasopressin neurons, whereas direct application of an NOS inhibitor increased electrical activity, indicating that endogenous NO acts within the supraoptic nucleus to inhibit neuronal activity. However, during late pregnancy, the influence of endogenous NO is dramatically downregulated, reflected by a reduced expression of neuronal NOS mRNA in these neurons and a loss of efficacy of NOS inhibitors on stimulus-evoked oxytocin release. This downregulation may cause the oxytocin system to become more excitable at term, resulting in the capacity for greater release of oxytocin during parturition.

Animals↗

PubMed2000

Sex-steroid induction of endogenous opioid inhibition on oxytocin secretory responses to stress.

In pregnancy, endogenous opioids inhibit enhanced basal and stressor-stimulated oxytocin neurone activity and secretion. By contrast, stress responses of the hypothalamo-pituitary-adrenal (HPA) axis are reduced in pregnancy. We investigated whether the high levels of oestradiol and progesterone of pregnancy could induce these changes. Silastic capsules containing oestradiol or progesterone (or control capsules) were implanted s.c. in virgin female rats for 16 or 17 days, with or without progesterone removal on day 15 to mimic the progesterone withdrawal seen at the end of pregnancy. Plasma concentrations of oxytocin, adrenocorticotrophic hormone (ACTH) and corticosterone were measured in jugular vein blood samples from conscious rats. Under basal conditions, naloxone (5 mg/kg) increased oxytocin secretion in all groups, but had no greater effect in sex-steroid treated rats, and did not induce Fos expression in the supraoptic nucleus. Forced swimming, a stressor, increased oxytocin secretion at 5 min in vehicle-injected controls, and this response was slightly attenuated in the sex-steroid treated groups. Pretreatment with naloxone greatly enhanced the response in the sex-steroid treated rats, and was less effective in the controls. In rats treated with oestradiol alone, naloxone prolonged the response. Thus, the combined sex-steroid treatment enhanced the responsiveness of oxytocin neurones to the stressor, while simultaneously restraining oxytocin secretion via endogenous opioid inhibition. In the same rats, ACTH and corticosterone secretion was also stimulated by the stressor, but the hypothalamo-pituitary-adrenal (HPA) axis response was not attenuated in sex-steroid treated rats. Naloxone weakly reduced the HPA axis response in controls and was ineffective in the sex-steroid treated rats. We conclude that oestradiol and progesterone may be responsible for inducing the opioid restraint and enhanced oxytocin neurone responsiveness in pregnancy.

Animals↗

PubMed2000

Attenuation of hypothalamic-pituitary-adrenal axis stress responses in late pregnancy: changes in feedforward and feedback mechanisms.

The hypothalamic-pituitary-adrenal axis is hyporesponsive to stress in late pregnancy, exemplified as reduced adrenocorticotropic hormone (ACTH) and corticosterone responses to restraint, but the mechanisms are unknown. We investigated forward drive and negative feedback upon the hypothalamic-pituitary-adrenal axis in pregnant rats. Corticotropin-releasing hormone (CRH) and vasopressin mRNA expression in the parvocellular paraventricular nucleus and mineralocorticoid and glucocorticoid receptor expression in the paraventricular nucleus and hippocampus were quantified with in situ hybridization. Because it can enhance the corticosterone negative feedback signal, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) bioactivity in these brain regions and anterior pituitary was measured in vitro, and ACTH and corticosterone stress responses were measured after intracerebroventricular glycyrrhetinic acid, an 11beta-HSD inhibitor. Changes in corticosterone feedback on ACTH secretion were examined after pharmacological adrenalectomy by metyrapone and aminoglutethimide. Parvocellular paraventricular nucleus CRH mRNA content was reduced on day 21 and the CRH mRNA : vasopressin mRNA ratio was unaltered, indicating decreased production of both CRH and vasopressin. An increase in glucocorticoid receptor mRNA expression in the dentate gyrus (mineralocorticoid receptor mRNA expression was unaltered) and increased 11beta-HSD1 activity in the paraventricular nucleus and anterior pituitary suggest an increase in slow negative feedback mechanisms in pregnancy, but glycyrrhetinic acid did not modify the stress response. After metyrapone/aminoglutethimide treatment, corticosterone decreased ACTH secretion more slowly in pregnancy, indicating a decrease in rapid feedback sensitivity. Thus, reduced forward drive rather than increased effectiveness of glucocorticoid negative feedback may underlie stress hyporesponsiveness of the hypothalamic-pituitary-adrenal axis in pregnancy.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗

PubMed2000

Quo vadis neurohypophysial hormone research?

Here we highlight just a few of the outstanding questions in the field of neurohypophysial hormones that we envisage will be addressed successfully in the new millennium. To begin, we focus on the regulation of receptors. Despite intensive investigation with new drugs, molecular modelling and transgenic models, the determinants of receptor selectivity remain elusive; there may even be more vasopressin or oxytocin receptor subtypes to be discovered. We discuss the controversy over the interesting studies that indicate modulation of oxytocin receptor-binding by steroids. Oxytocin and vasopressin release and action in the brain are discussed from several aspects. Dendritically released oxytocin acting locally is important for the milk ejection reflex, and similarly released vasopressin is important in regulating patterning of vasopressin neurone activity. Such dendritically released oxytocin and vasopressin is likely to be important in paracrine modulation of neural circuitry involved in neuroendocrine control, and for a range of behaviours. Is it possible that the whole range of behaviours that comprise 'social' (or 'anti-social') or 'maternal' behaviour can be engineered by modifying the expression of just these one or two peptides and their receptors? However, whether gene expression and knockout approaches will answer all the open questions about the real functions of oxytocin and vasopressin remains to be shown.

Animals↗

PubMed2000

Effect of progesterone on the activation of neurones of the supraoptic nucleus during parturition.

Parturition is driven by a pulsatile pattern of oxytocin secretion, resulting from burst firing activity of supraoptic oxytocin neurones and reflected by induction of Fos expression. Rats were injected with progesterone on day 20 of pregnancy to investigate the role of the decreasing progesterone:ratio oestrogen ratio, which precedes delivery, in the activation of supraoptic neurones. Progesterone delayed the onset of birth by 28 h compared with vehicle (control) and prolonged the duration of delivery, which was overcome by pulsatile injections of oxytocin, indicating that the slow delivery may reflect impaired oxytocin secretion. Parturient rats pretreated with progesterone had fewer Fos immunoreactive nuclei in the supraoptic nucleus than did parturient rats pretreated with vehicle. The number of Fos immunoreactive nuclei was not restored after oxytocin injection, indicating that appropriate activation of oxytocin neurones is impaired by progesterone and also that there is a lack of stimulatory afferent drive. Fos expression increased in the nucleus of the tractus solitarius during parturition in rats pretreated with either vehicle or progesterone, but not in rats that had been pretreated with progesterone and induced with oxytocin, indicating that this input was inhibited. Endogenous opioids inhibit oxytocin neurones in late pregnancy and the opioid antagonist, naloxone, increases Fos expression in supraoptic nuclei by preventing inhibition. However, progesterone attenuated naloxone-induced Fos expression in the supraoptic nucleus in late pregnancy and naloxone administered during parturition did not accelerate the duration of births delayed by progesterone administration, indicating that progesterone does not act by hyperactivation of endogenous opioid tone. RU486, a progesterone receptor antagonist, enhanced supraoptic neurone Fos expression in late pregnancy, indicating progesterone receptor-mediated actions. Thus, progesterone withdrawal is necessary for appropriate activation of supraoptic and tractus solitarius neurones during parturition.

Analysis of Variance↗

PubMed1999

Discrimination of granulocyte colony-stimulating factor isoforms by high-performance capillary electrophoresis.

Granulocyte colony-stimulating factor (G-CSF) is a glycoprotein which acts primarily to stimulate the proliferation, differentiation and activation of committed progenitor cells of the neutrophil-granulocyte lineage into functionally mature neutrophils. The traditional biological assays employed to detect G-CSF are a myeloid bone marrow colony assay, a factor-dependent cell line specific for G-CSF and commercially available immunoassays. However, these methods will not distinguish between glycosylated and non-glycosylated forms of the molecule. In this study high-performance capillary electrophoresis (HPCE) was used to analyse glycosylated and non-glycosylated recombinant human granulocyte colony-stimulating factor (r-met-hG-CSF). Glycosylated G-CSF preparations contained human serum albumin (HSA), added as a protein carrier. Glycosylated and non-glycosylated G-CSFs were prepared in 40 mM Na2HPO4 buffer, pH 2.5, containing hydroxypropylmethylcellulose (HPMC) or 50 mM Na2HPO4 buffer, pH 9.0. Glycosylated G-CSF could be separated into two distinct glycoform populations at the lower pH studied. Differences in migration time and peak shape between glycosylated and non-glycosylated G-CSF were demonstrated. HPCE analysis of G-CSF produced using a baculovirus expression vector system revealed a further distinct G-CSF glycoform and demonstrated the resolving power of the technique.

Electrophoresis, Capillary↗

PubMed1998

Attenuated neuroendocrine responses to emotional and physical stressors in pregnant rats involve adenohypophysial changes.

1. The responsiveness of the rat hypothalamo-pituitary-adrenal (HPA) axis and hypothalamo-neurohypophysial system (HNS) to emotional (elevated plus-maze) and physical (forced swimming) stressors and to administration of synthetic corticotrophin-releasing hormone (CRH) was investigated during pregnancy and lactation. In addition to pregnancy-related adaptations at the adenohypophysial level, behavioural responses accompanying the neuroendocrine changes were studied. 2. Whereas basal (a.m.) plasma corticosterone, but not corticotrophin (adrenocorticotrophic hormone; ACTH), levels were increased on the last day (i.e. on day 22) of pregnancy, the stress-induced rise in both plasma hormone concentrations was increasingly attenuated with the progression of pregnancy beginning on day 15 and reaching a minimum on day 21 compared with virgin control rats. A similar attenuation of responses to both emotional and physical stressors was found in lactating rats. 3. Although the basal plasma oxytocin concentration was elevated in late pregnancy, the stress-induced rise in oxytocin secretion was slightly lower in day 21 pregnant rats. In contrast to vasopressin, oxytocin secretion was increased by forced swimming in virgin and early pregnant rats indicating a differential stress response of these neurohypophysial hormones. 4. The blunted HPA response to stressful stimuli is partly due to alterations at the level of corticotrophs in the adenohypophysis, as ACTH secretion in response to CRH in vivo (40 ng kg-1, i.v.) was reduced with the progression of pregnancy and during lactation. In vitro measurement of cAMP levels in pituitary segments demonstrated reduced basal levels of cAMP and a lower increase after CRH stimulation (10 nM, 10 min) in day 21 pregnant compared with virgin rats, further indicating reduced corticotroph responsiveness to CRH in pregnancy. 5. The reduced pituitary response to CRH in late pregnancy is likely to be a consequence of a reduction in CRH receptor binding as revealed by receptor autoradiography. [125I] CRH binding in the anterior pituitary was significantly reduced in day 11, 17 and 22 pregnant rats compared with virgin controls. 6. Anxiety-related behaviour of the animals as revealed by the time on and entries into the open arms of the elevated plus-maze was different between virgin and pregnant rats with decreased number of entries indicating increased anxiety with the progression of pregnancy (except on pregnancy day 18). The emotional behaviour, however, was not correlated with the neuroendocrine responses. 7. The results indicate that the reduced response of the HPA axis to stressors described previously during lactation is already manifested around day 15 of pregnancy in the rat and involves physiological adaptations at the adenohypophysial level. However, alterations in stressor perception at higher brain levels with the progression of pregnancy may also be involved.

Acclimatization↗

PubMed1998

Stimulation of expression of the oxytocin gene in rat supraoptic neurons at parturition.

We measured expression of the oxytocin gene in the supraoptic nucleus (SON) during pregnancy, parturition and lactation to examine its relationship to states of accumulation or depletion of oxytocin stores and to conditions of strong excitation of oxytocin neurons. The primary transcript (heterogeneous nuclear RNA, hnRNA) of the oxytocin gene was measured using a 3H-cDNA probe against intron 1 for in situ hybridisation. Autoradiographs of the SON showed the hnRNA as discrete clumps of silver grains within the nucleus of each neuron. The number of cells expressing oxytocin hnRNA did not change during pregnancy but increased during parturition; 10-day lactating animals showed similar increases. Oxytocin mRNA was also measured by in situ hybridisation using a 3H- or 35S-labelled oligonucleotide probe against exon C: hybridisation was seen over the cytoplasm of supraoptic neurons, but no differences were measured between virgin, mid-pregnant, preparturient, parturient or 2-day lactating rats. The data suggest that enhanced oxytocin gene transcription is not necessary to increase oxytocin stores in pregnancy. However, acute stimulation of magnocellular oxytocin neurons at parturition, which strongly increases neuron activity and secretion, results in a rapid increase in the number of cells expressing oxytocin hnRNA, and increased expression is sustained in lactation.

Animals↗

PubMed1998

Serological evidence for pneumovirus infections in pigs.

A serological survey was carried out on pig sera from herds in Northern Ireland to investigate the incidence of reactivity to bovine respiratory syncytial virus (BRSV) antigens. A total of 529 pig sera from 61 herds were tested and 219 (41 per cent) were found to be reactive with BRSV-infected cell cultures in an indirect immunofluorescence test. None of the BRSV-reactive sera immunostained turkey rhinotracheitis virus-infected cell cultures, indicating specificity for BRSV epitopes. The specificity of this reactivity for BRSV antigen was confirmed by double immunolabelling, using monoclonal antibodies to BRSV and two pig sera with different reactivities to BRSV antigens. A longitudinal serological investigation of two litters of pigs indicated that BRSV-serum reactivity developed between six and 11 weeks after birth. The immunofluorescent staining pattern observed with the majority (73 per cent) of the BRSV-reactive pig sera was typical of that observed with known BRSV-reactive bovine sera. The other immunoreactive pig sera stained BRSV-infected cell cultures in an atypical staining pattern. These different reactivity patterns, combined with the results of the serum neutralisation tests, suggest that more than one serotype of a porcine pneumovirus may exist.

Animals↗

PubMed1998

Cancer mortality in relation to monitoring for radionuclide exposure in three UK nuclear industry workforces.

Cancer mortality in 40,761 employees of three UK nuclear industry facilities who had been monitored for external radiation exposure was examined according to whether they had also been monitored for possible internal exposure to tritium, plutonium or other radionuclides (uranium, polonium, actinium or other unspecified). Death rates from cancer were compared both with national rates and with rates in radiation workers not monitored for exposure to any radionuclides. Among workers monitored for tritium exposure, overall cancer mortality was significantly below national rates [standardized mortality ratio (SMR) = 83, 165 deaths; 2P = 0.02] and none of the cancer-specific death rates was significantly above either the national average or rates in non-monitored workers. Although the overall death rate from cancer in workers monitored for plutonium exposure was also significantly low relative to national rates (SMR = 89, 581 deaths; 2P = 0.005), mortality from pleural cancer was significantly raised (SMR = 357, nine deaths; 2P = 0.002); none of the rates differed significantly from those of non-monitored workers. Workers monitored for radionuclides other than tritium or plutonium also had a death rate from all cancers combined that was below the national average (SMR = 86, 418 deaths; 2P = 0.002) but prostatic cancer mortality was raised both in relation to death rates in the general population (SMR = 153, 37 deaths; 2P = 0.02) and to death rates in radiation workers who had not been monitored for exposure to any radionuclide [rate ratio (RR) = 1.65; 2P = 0.03]. Mortality from cancer of the lung was also significantly increased in workers monitored for other radionuclides compared with those of radiation workers not monitored for exposure to radionuclides (RR = 1.31, 164 deaths; 2P = 0.01). For cancers of the lung, prostate and all cancers combined, death rates in monitored workers were examined according to the timing and duration of monitoring for radionuclide exposure, with rates of radiation workers not monitored for any radionuclide forming the comparison group. In tritium-monitored workers, RRs for prostatic cancer varied significantly according to the number of years in which they were monitored (2P = 0.03). In workers monitored for plutonium exposure, RRs for all cancers combined increased with the number of years in which they were monitored (2P = 0.04) and with the number of years since first monitoring (2P = 0.0003). There was little suggestion of systematic variation in RRs for workers monitored for other radionuclides in relation to the timing or duration of monitoring, nor did it appear that their raised rates of cancer of the lung and prostate were explained by external radiation dose. These analyses of cancer mortality in relation to monitoring for radionuclide exposure reported in a large cohort of nuclear industry workers suggest that certain patterns of monitoring for some radionuclides may be associated with higher death rates from cancers of the lung, pleura, prostate and all cancers combined. Some of these findings may be due to chance. Moreover, because of the paucity of related data and lack of information about other possible exposures, such as whether plutonium workers are more likely to be exposed to asbestos, firm conclusions cannot be drawn at this stage. Further investigations of the relationship between radionuclide exposure and cancer in nuclear industry workers are needed.

Adolescent↗

PubMed1998

Substrates of energy metabolism attenuate methamphetamine-induced neurotoxicity in striatum.

High doses of methamphetamine (METH) produce a long-term depletion in striatal tissue dopamine content. The mechanism mediating this toxicity has been associated with increased concentrations of dopamine and glutamate and altered energy metabolism. In vivo microdialysis was used to assess and alter the metabolic environment of the brain during high doses of METH. METH significantly increased extracellular concentrations of lactate in striatum and prefrontal cortex. This increase was significantly greater in striatum and coincided with the greater vulnerability of this brain region to the toxic effects of METH. To examine the effect of supplementing energy metabolism on METH-induced dopamine content depletions, the striatum was perfused directly with decylubiquinone or nicotinamide to enhance the energetic capacity of the tissue during or after a neurotoxic dosing regimen of METH. When decylubiquinone or nicotinamide was perfused into striatum during the administration of METH, there was no significant effect on METH-induced striatal dopamine efflux, glutamate efflux, or the long-term dopamine depletions measured 7 days later. However, a delayed perfusion with decylubiquinone or nicotinamide for 6 h beginning immediately after the last METH injection attenuated the METH-induced striatal dopamine depletions measured 1 week later. These results support the hypothesis that the compromised metabolic state produced by METH administration predisposes dopamine terminals to the neurotoxic effects of glutamate, dopamine, and/or free radicals.

Animals↗

PubMed1998

The role of endogenous opioids in neurohypophysial and hypothalamo-pituitary-adrenal axis hormone secretory responses to stress in pregnant rats.

Endogenous opioid regulation of neurohypophysial and hypothalamo-pituitary-adrenal (HPA) axis hormone secretion in response to forced swimming (90 s in deep water at 19 degrees C) was investigated in virgin and 21-day-pregnant rats. There was no difference in basal plasma oxytocin concentrations between pregnant and virgin rats, but the opioid antagonist, naloxone, increased basal oxytocin secretion in the pregnant rats. Forced swimming increased oxytocin secretion similarly in pregnant and virgin rats, and this response was enhanced by naloxone. In pregnant rats naloxone had a greater effect (by 3.1-fold) than in virgins, showing stronger endogenous opioid restraint of an enhanced oxytocin secretory response to stress in pregnancy. Vasopressin secretion was not increased with forced swimming in virgin or pregnant rats, and naloxone had no effect. ACTH and corticosterone secretion in response to forced swimming was attenuated in pregnant rats compared to virgin rats, measured at 5 min. Naloxone had no effect on basal plasma ACTH or corticosterone concentration, but it reduced ACTH secretion in virgin rats 5 min after forced swimming; in pregnant rats naloxone had no such effect. Naloxone removed the pregnancy-related attenuation in corticosterone secretion measured at 5 min after forced swimming. Fifteen minutes after forced swimming, plasma corticosterone concentrations were not different between groups. In the late-pregnant rats, the increases in plasma ACTH and corticosterone induced by forced swimming were significantly prolonged compared to virgins. The results show that endogenous opioid inhibition emerges in pregnancy to restrict the responses of oxytocin neurones to a stressor. In contrast, the endogenous opioid enhancement of mechanisms regulating HPA axis secretory responses in virgin rats is not evident during pregnancy.

Adrenal Cortex Hormones↗

PubMed1997

Profile of monoamine and excitatory amino acid release in rat supraoptic nucleus over parturition.

The magnocellular oxytocin neurons of the hypothalamic supraoptic (SON) and paraventricular nuclei play an important role in the initiation and maintenance of parturition in the rat. As little is known about the neural inputs responsible for activating oxytocin neuron activity at this time, we used the technique of microdialysis to examine the profile of monoamine and excitatory amino acid neurotransmitter release within the SON before and during parturition. Microdialysis probes were implanted into the SON of anesthetized pregnant rats (n = 8) on the morning of the day preceding parturition (day 20), and 15-min dialysate samples were collected from freely moving animals over the following 2 days until 3 h after birth of the last pup. On the day of parturition (day 21), dialysate concentrations of norepinephrine were significantly increased (P < 0.05) in the hour leading up to the expulsion of the first pup and, compared with those on the previous day, remained at significantly (P < 0.05) elevated levels throughout the course of parturition. A significant (P < 0.01) increase in glutamate concentrations was also detected, although in this case, it was only elevated transiently in the 15-min period immediately before the onset of pup expulsion. Mean levels of dopamine were not different between days 20 and 21, but a significant increase in dopamine release was detected specifically during the second half of parturition. No significant changes in serotonin and aspartate concentrations were observed on days 20 and 21 or in relation to parturition. This study provides an analysis of neurotransmitter release in the SON over parturition and indicates that norepinephrine concentrations are elevated well in advance of the onset of pup expulsion, whereas a burst of glutamate release occurs immediately before the birth of the first pup. Such changes are likely to reflect activity in afferent inputs to the SON and may represent neurochemical events involved in the initiation and maintenance of parturition.

Animals↗