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B E Sumner

Publications and source records attributed to B E Sumner.

At least 19 recordsLinked to original sources
PubMed1999

Effects of tamoxifen on serotonin transporter and 5-hydroxytryptamine(2A) receptor binding sites and mRNA levels in the brain of ovariectomized rats with or without acute estradiol replacement.

Estradiol-17beta (E(2)), in its positive feedback mode for gonadotropin release in the female rat, induces expression of the genes for the 5-hydroxytryptamine(2A) receptor (5-HT(2A)R) and the serotonin transporter (SERT) in the dorsal raphe nucleus (DRN) with a concomitant increase in the densities of 5-HT(2A)R and the SERT in rat forebrain. The forebrain regions affected are those which, in humans, are concerned with the control of mood, mental state, cognition and emotion. Here we have used the mixed estradiol agonist/antagonist, tamoxifen, to determine whether this action of estradiol is mediated by cytoplasmic estradiol receptors. Acute treatment ( approximately 32 h) of ovariectomized rats with estradiol benzoate (EB) increased significantly the amount of 5-HT(2A)R mRNA and SERT mRNA in the DRN and the densities of 5-HT(2A)R and SERT binding sites in the forebrain. These effects of EB were completely blocked by tamoxifen. Treatment with tamoxifen alone had no effect on either gene expression or the density of binding sites. Together, these data show that tamoxifen acts as a pure estradiol antagonist with respect to serotonergic mechanisms in brain. Detailed analysis of the effects of estradiol and tamoxifen on the DRN showed that SERT gene expression is constitutive only in the posterior DRN; in the anterior DRN, SERT gene expression appears to depend upon estrogen induction which is blocked by tamoxifen. Our findings strongly suggest that estradiol receptors are involved in mediating estradiol action on central serotonergic mechanisms and are relevant for our understanding of the effects of antiestrogens as well as estradiol on mood, mental state and cognition.

Animals↗
PubMed1999

Serotonin transporter (SERT) mRNA and binding site densities in male rat brain affected by sex steroids.

Estrogen increases serotonin transporter (SERT) mRNA and binding sites in female rat brain. In order to determine whether changes in SERT are gender- and steroid-specific we have now carried out studies on adult male Wistar rats which were either intact or castrated (under halothane anesthesia) and injected with arachis oil, estradiol benzoate (EB), testosterone propionate (TP) or the non-aromatizable androgen, 5alpha-dihydrotestosterone (5alpha-DHT). The number of SERT mRNA-expressing cells in the dorsal raphe (DR) nucleus was decreased by castration and increased by treatment (for approximately 32 h) with EB or TP, but not 5alpha-DHT. Sex steroids had no effect on the number of SERT mRNA-expressing cells in the median raphe nucleus. The density of SERT sites, assessed by autoradiography of [3H]paroxetine binding, was significantly reduced in arcuate nucleus and median raphe after castration, and increased in arcuate, basolateral amygdala and ventromedial hypothalamic nucleus by treatment with EB or TP, but not 5alpha-DHT. Estradiol, but not testosterone or 5alpha-DHT reduced the density of SERT sites in midbrain central grey. These data show that testosterone as well as estrogen affects SERT expression in male brain, and that the action of testosterone probably depends upon its enzymatic conversion, by aromatase, to estradiol. Our findings may have implications for sex steroid control of mood and behavior, and the action of neurotoxic derivatives of amphetamine, such as 3, 4-methylenedioxymethamphetamine, in the human.

Animals↗
PubMed1998

Testosterone as well as estrogen increases serotonin2A receptor mRNA and binding site densities in the male rat brain.

Our previous findings in female rats suggest that the potent effects of sex steroids on mood and mental state may be mediated, in part, by the effect of estrogen on the 5-hydroxytryptamine2A receptor (5-HT2AR) in brain. The aim of the present study was to determine the effect of acute (approximately 32h) sex steroid manipulation on central 5-HT2AR in the adult male Wistar rat. Castration (under halothane anesthesia) decreased while testosterone or estrogen, but not 5alpha-dihydrotestosterone (5alpha-DHT), increased significantly the 5-HT2AR mRNA content in dorsal raphe nucleus and the density of 5-HT2AR binding sites in frontal, cingulate and primary olfactory cortex and nucleus accumbens. The lack of effect of 5alpha-DHT, a potent androgen which cannot be converted to estrogen, suggests that the action of testosterone depends upon its conversion to estrogen by aromatase. This may also explain why estrogen, but not testosterone or 5alpha-DHT, increased the density of 5-HT2AR binding sites in the caudate-putamen, a brain region where aromatase is scarce. These findings are discussed in relation to the possible role of the 5-HT2AR in depression, schizophrenia and Alzheimer's Disease.

Animals↗
PubMed1998

Sex steroid control of mood, mental state and memory.

1. Sex steroid hormones exert profound effects on mood and mental state. Thus, in women, oestrogen is thought to protect against depression and delay the onset of schizophrenia and Alzheimer's disease. 2. Our studies in the female rat show that oestradiol, in its positive feedback mode for gonadotrophin release, increases the expression of genes for the 5-hydroxytryptamine 5-HT2A receptor and the serotonin transporter (SERT) in the dorsal raphe nucleus and the density of 5-HT2A receptor and SERT sites in regions of the forebrain that, in the human, are concerned with cognition, mental state, emotion and memory. 3. In the male rat, castration decreases while oestrogen and testosterone, but not 5 alpha-dihydrotestosterone (5 alpha-DHT), increase the density of 5-HT2A receptors in forebrain. The fact that 5 alpha-DHT has no effect suggests that the action of testosterone depends on its conversion to oestradiol by aromatase. 4. In intact rats, the density of 5-HT2A receptors in cerebral cortex is significantly higher in pro-oestrous female than in male and dioestrous female rats, showing that the spontaneous, preovulatory surge of oestradiol that reaches a peak at 12.00 h of pro-oestrus also increases the density of 5-HT2A receptors in cortex. 5. Oestrogen and testosterone (by way of its conversion to oestrogen) also stimulate the expression of the arginine vasopressin gene in the bed nucleus of the stria terminalis of the rodent, a mechanism that plays a key role in olfactory memory. 6. These actions of sex steroid hormones are discussed in the context of genomic versus non-genomic mechanisms, the recent discovery that there are two oestradiol receptors with different distributions in brain, the significance of our findings for our understanding of the control of mood, mental state and memory and the mechanism by which oestrogen stimulation of the 5-HT2A receptor could delay the onset of Alzheimer's disease.

Affect↗
PubMed1997

The density of 5-hydoxytryptamine2A receptors in forebrain is increased at pro-oestrus in intact female rats.

We have shown previously that in ovariectomised rats, oestradiol-17beta, in its positive-feedback mode for luteinizing hormone (LH) release, induces a significant increase in the density of 5-hydroxytryptamine2A (5-HT2A) receptors in the forebrain. Here we investigated whether there are any changes in 5-HT2A receptor density in relation to the spontaneous surge of oestradiol-17beta in female COB Wistar rats between dioestrus and pro-oestrus. Using [3H]RP62203-binding and autoradiography, we found that 5-HT2A binding sites were significantly increased at 1630-1800 h on pro-oestrus compared with 0900-1130 h on dioestrus in frontal and cingulate cortex, olfactory tubercle and nucleus accumbens. The densities of 5-HT2A binding sites in male rats were similar to dioestrous female values in cortex, and to pro-oestrous female values in nucleus accumbens. The changes in the density of 5-HT2A binding sites in the forebrain of female rats may be relevant to oestrogen effects on mood and mental state.

Animals↗
PubMed1996

Estrogen control of central neurotransmission: effect on mood, mental state, and memory.

1. Estrogen exerts profound effects on mood, mental state and memory by acting on both "classical" monoamine and neuropeptide transmitter mechanisms in brain. Here we review an example of each type of action. 2. With respect to the effect of estrogen on central monoamine neurotransmission, low levels of estrogen in women are associated with the premenstrual syndrome, postnatal depression and post-menopausal depression. Sex differences in schizophrenia have also been attributed to estrogen. Previous studies have shown that estrogen stimulates a significant increase in dopamine2 (D2) receptors in the striatum. Here we show for the first time that estrogen also stimulates a significant increase in the density of 5-hydroxytryptamine2A (5-HT2A) binding sites in anterior frontal, cingulate and primary olfactory cortex and in the nucleus accumbens, areas of the brain concerned with the control of mood, mental state, cognition, emotion and behavior. These findings explain, for example, the efficacy of estrogen therapy or 5-HT uptake blockers such as fluoxetine in treating the depressive symptoms of the premenstrual syndrome. and suggest that the sex differences in schizophrenia may also be due to an action of estrogen mediated by way of 5-HT2A receptors. 3. With respect to the effect of estrogen on central neuropeptide transmission, estrogen stimulates the expression of the arginine vasopressin (AVP) gene in the bed nucleus of the stria terminalis (BNST) in rodents. This results in a 100-fold increase in AVP mRNA in the BNST and a massive increase in AVP peptide in the BNST and its projections to the lateral septum and lateral habenula. The BNST-AVP system enhances and/or maintains "social" or "olfactory" memory, and thus provides a powerful model for correlating transcriptional control of neuropeptide gene expression with behavior. Whether similar mechanisms operate in the human remain to be determined. 4. These two examples of the action of estrogen on central neurotransmission are discussed in terms of their immediate clinical importance for the treatment of depressive symptoms, their use as powerful models for investigations on the steroid control of central neurotransmitter mechanisms, and the role of estrogen as "Nature's" psychoprotectant.

Affect↗
PubMed1994

An alpha 1 adrenergic mechanism mediates estradiol stimulation of LHRH mRNA synthesis and estradiol inhibition of POMC mRNA synthesis in the hypothalamus of the prepubertal female rat.

We showed previously that the surge of luteinizing hormone-releasing hormone (LHRH) induced by estradiol-17 beta (E2) in the female rat can be blocked by an alpha 1 adrenergic antagonist. The aim of the present study was to determine whether this was due to a direct action of E2 on noradrenergic projections to LHRH neurons or whether it also involved other systems such as the arcuate pro-opiomelanocortin (POMC) neurons which are thought to inhibit LHRH biosynthesis and release. The experimental preparation was the prepubertal female rat in which an LHRH surge is induced by pregnant mare serum gonadotropin. Prazosin was used as a specific alpha 1 adrenergic antagonist and LHRH and POMC mRNA concentrations and cell numbers, in the medial preoptic area and rostral arcuate nucleus, respectively, were determined by in situ hybridization. Prazosin significantly reduced the total number of LHRH mRNA expressing cells, and increased the total number of POMC mRNA expressing cells and the concentration of POMC mRNA per cell. These results suggest that the inhibition of E2-stimulated LHRH biosynthesis and release by alpha 1 adrenergic blockade may be mediated by two mechanisms; (i) increased POMC synthesis leading to inhibition of LHRH neurons and (ii) direct inhibition of a stimulatory alpha 1 adrenergic/LHRH mechanism.

Animals↗
PubMed1992

Pregnancy alters the density of opioid binding sites in the supraoptic nucleus and posterior pituitary gland of rats.

Opioid receptor binding was measured in cryostat sections of supraoptic nucleus (SON) and posterior pituitary of virgin and pregnant rats by quantitative receptor autoradiography after in vitro incubation with [3H]etorphine or [3H](-)-bremazocine in the presence of unlabelled sub-type-selective agonists. Mu-selective [3H]etorphine-binding in the SON was reduced on the last day (21) of pregnancy vs. virgin controls (9.9 +/- 2.2 vs. 31.7 +/- 6.5 fmol/mg). Kappa-selective [3H](-)-bremazocine binding to the SON was not altered by pregnancy. Kappa-selective [3H](-)-bremazocine-binding to the posterior pituitary was less on day 16 of pregnancy vs. virgin females (19.1 +2- 5.2 vs. 74.4 +/- 16.2 fmol/mg). The results suggest mechanisms for the changes in actions of opioids on oxytocin neurones in pregnancy.

Analgesics↗
PubMed1991

Rapid changes in the content of proenkephalin A and corticotrophin releasing hormone mRNAs in the paraventricular nucleus during morphine withdrawal in urethane-anaesthetized rats.

Quantitative in situ hybridization was used to measure corticotrophin-releasing hormone (CRH) and proenkephalin A mRNA in the medial parvocellular paraventricular nucleus (PVN) 4 h after test procedures. Urethane anaesthesia alone resulted in a significant increase in both CRH and proenkephalin transcripts. The additional stimulus of i.p. hypertonic saline, however, resulted in a further significant increase in both mRNA species. Female rats were given intracerebroventricular (i.c.v.) infusion for 5 days of either morphine sulphate to induce tolerance and dependence, or vehicle, via a subcutaneous osmotic minipump implanted under ether anaesthesia. The rats were then anaesthetized with urethane, fitted with an intravenous cannula for injections and 65 min later either naloxone (5 mg/kg) or vehicle was injected. Naloxone alone in the i.c.v. vehicle rats had no effect on CRH or proenkephalin A mRNA. In i.c.v. morphine-infused rats proenkephalin a mRNA in the PVN was significantly less than in controls. Naloxone given to i.c.v. morphine-infused rats resulted in a doubling of hybridization to proenkephalin mRNA in the PVN which was significantly greater than that seen in the i.c.v. vehicle group. CRH mRNA in the PVN was not altered either by naloxone in control rats, or by chronic i.c.v. morphine infusion. By contrast, naloxone did increase CRH mRNA by ca. 40% in morphine-infused rats. The results show that stress-induced increases in CRH and enkephalin mRNAs in the PVN do not require conscious appreciation of the stress.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia, General↗
PubMed1990

Opioid receptor subtypes in the supraoptic nucleus and posterior pituitary gland of morphine-tolerant rats.

Morphine, given acutely, inhibits oxytocin secretion in adult female rats, but chronic intracerebroventricular infusion for five to six days induces tolerance and dependence in the mechanisms regulating oxytocin secretion. One explanation for tolerance could be that there is a loss of opioid receptors. To test this hypothesis cryostat sections of selected brain regions and the pituitary, from six control and six intracerebroventricular morphine-infused rats, were processed for quantitative in vitro receptor autoradiography. [3H]Etorphine or [3H](-)-bremazocine were used as ligands, and DAGO, DPDPE and U50,488H as selective displacers from mu-, delta-, and kappa-receptors, respectively. Control incubations had naloxone determined specificity. The supraoptic nucleus (site of oxytocin-secreting magnocellular perikarya) contained both mu- and kappa-receptors in control rats (mean +/- S.E.M. binding of mu-selective [3H]etorphine was 91.8 +/- 25.4 fmol/mg of tissue, and of kappa-selective [3H](-)-bremazocine was 130.4 +/- 25.6 fmol/mg). Chronic morphine treatment caused a 83.9% decrease in binding in mu-selective conditions (P less than 0.05), but no significant change in kappa-selective binding. In the median preoptic nucleus (which projects to the supraoptic nucleus) mean +/- S.E.M. binding of [3H]etorphine decreased by 77.0% (P less than 0.01) in chronic morphine-treated rats, from the control value of 76.2 +/- 9.8 fmol/mg of tissue. In the posterior pituitary gland (site of the terminals of the oxytocin-secreting magnocellular perikarya) binding with [3H](-)-bremazocine in controls was over 90% lower than in the supraoptic nucleus. No changes followed chronic morphine treatment. Thus chronic morphine exposure reduces the numbers of available mu-receptors in the supraoptic nucleus, and of opioid receptors in the median preoptic nucleus, perhaps accounting for morphine-tolerance in relation to oxytocin secretion.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1989

Does acute, intense stimulation of oxytocin neurones in the supraoptic nucleus increase their content of oxytocin mRNA?

We investigated whether a sustained increase in oxytocin secretion, with or without enhanced electrical activity of the cell-bodies of oxytocin neurones, leads to a rapid increase in oxytocin mRNA content in these neurones. To stimulate oxytocin release, naloxone (2.5 mg/kg i.v. twice, 30 min apart) was given to urethane-anaesthetized female rats after intracerebroventricular (i.c.v.) morphine or vehicle infusion for 5 days; in the latter, naloxone acts on the neurohypophysis to increase oxytocin release without affecting the electrical activity of oxytocin neurone cell-bodies, but in the former, naloxone acts both on the neucohypophysis and on the cell-bodies to excite them electrically. Oxytocin content in peripheral plasma was measured intermittently by radioimmunoassay for 4 h after i.v. naloxone or vehicle, then the brain was removed and cryostat sections were cut through the supraoptic nucleus (SON). Oxytocin mRNA content in individual neurones (25-50 per rat) was measured semiquantitatively by in situ hybridisation histochemistry, using a tritiated synthetic cDNA 25-mer oligonucleotide probe, autoradiographical visualisation, and computer-assisted image-analysis to measure silver grain density. Nalaxone increased oxytocin content in plasma 7-fold for at least 40 min in i.c.v. vehicle-infused rats, and 40-fold for at least 40 min in i.c.v. morphine-infused rats. Naloxone had no significant effect on the oxytocin mRNA content in labelled cells in the SON, and no effect on the proportion of labelled cells, in either the i.c.v. morphine- or i.c.v. vehicle-infused rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1979

Ultrastructural data, with special reference to bouton/glial relationships, from the hypoglossal nucleus after a second axotomy of the hypoglossal nerve.

The left hypoglossal nerve of adult male albino rats was prevented from regenerating to the tongue after a distal axotomy by implanting the proximal stump into normally innervated left sternomasoid muscle. Eighty-four days after implantation, the hypoglossal nerve was transected again and its regeneration to the tongue unimpeded. From 8 to 70 days after this second axotomy the left hypoglossal nuclei were processed for quantitative ultrastructural analysis. The first aim of this study was to compare regeneration success in the hypoglossal nucleus after second axotomy with that accompanying outgrowth of the hypoglossal nerve into denervated sternomastoid muscle. During quantitative analysis a second aim developed, of elucidating bouton/glial relationships. The second axotomy induced loss and return of subsurface cisterns, dispersal and reassembly of Nissl substance, increase and decrease of microglial numbers, slight further loss and partial return of boutons with clear spherical vesicles and symmetrical synapses, slight increase and decrease of boutons with clear flat vesicles and symmetrical synapses, regrowth of retracted dendrites and restoration of their synapses, and gradual diminution of numbers of electron-dense neurones and dendrites. Astrocytes remained hypertrophied throughout. When compared with events in the hypoglossal nucleus accompanying innervation of denervated sternomastoid muscle by the hypoglossal nerve, the results suggest (1) that regeneration of the hypoglossal nerve to its own tongue muscle instead of to a foreign muscle caused no acceleration of recovery in the hypoglossal nucleus, and (2) that the microglial response is dependent on nerve integrity and not on bouton behaviour.

Accessory Nerve↗
PubMed1978

Membrane-associated adenosine triphosphatase in normal and injured hypoglossal nuclei.

The hypoglossal nuclei of adult male albino rats, either normal, or from 1 to 70 days after left hypoglossal nerve transection, were studied cytochemically with a lead method for sodium- and potassium-activated membrane ATP-ase, using light and electron microscopy. Reaction product was measured at the light microscopical level by microdensitometry, and significance determined statistically. Light microscopy revealed a brown reaction product in the neuropil, but none in cell bodies. Blood vessel walls were more strongly coloured. Reaction product was undiminished by ouabain pre-incubation, or by incubation without sodium or potassium, or by incubation with calcium instead of magnesium. Reaction product was diminished by absence of magnesium if calcium was also absent, and abolished if sections were boiled before incubation, or if substrate was absent. Axotomy caused a statistically significant increase in neuropil reaction product in injured nuclei, maximal at 35 days postoperatively, and subsequently decreasing to normal at 70 days. Electron microscopy showed a predominantly surface membrane reaction product, with occasional positive intracellular cisternae. Basal lamina and intra-endothelial vacuoles were also positive. Axotomy resulted in the arrival and disappearance of microglis (2 to 35 days), followed by astrocyte hypertrophy (35 days), and increase in thickness and homogeneity of surface membrane reaction product. The results suggest the presence of one or more calcium- or magnesium-dependent membrane ATP-ases. The peak of the increase after axotomy is probably partly attributable to hypertrophic astrocytes, and partly to the surfaces of neuronal processes. Increase of membrane movements might explain such enzyme activity.

Adenosine Triphosphate↗
PubMed1977

Ultrastructural responses of the hypoglossal nucleus to the presence in the tongue of botulinum toxin, a quantitative study.

The ultrastructural effects of local injection of botulinum toxin into the left half of the tongue of the rat, were studied quantitatively 35 days postoperatively in the left hypoglossal nucleus. The results showed (1) a decrease in somatic and neuropil bouton numbers because of loss of boutons with symmetrical synapses and clear spherical synaptic vesicles, (2) a decrease in the numbers of dendrite profiles in the neuropil, (3) an increase in the proportion of dendrites and boutons with unusual inclusions, suggestive of profile retraction, (4) an increase in the proportion of profiles which were unusually electron-dense, (5) an increase in the amount of astrocyte, and a growth of astrocyte sheaths around bouton-free neurone surfaces, (6) the presence of occasional microglia, and (7) subastrocytic subsurface cisterns. Control rats injected with boiled toxin had no responses except (3) and (4) above, and then only to a modest extent, possibly due to mechanical damage of a few axons or terminals at the time of injection, or to insufficient inactivation of the toxin by boiling. The results were compared with those at 35 days after axotomy, and it was concluded that botulinum toxin, which interrupts neuromuscular transmission, elicits the same responses in the hypoglossal neurones, as does transection of the hypoglossal nerve, even though earlier studies had discovered no glial replication after botulinum toxin, in contrast to axotomy.

Animals↗
PubMed1977

Responses in the hypoglossal nucleus to delayed regeneration of the transected hypoglossal nerve, a quantitative ultrastructural study.

Electron micrographs of the left hypoglossal nucleus of adult male albino rats were quantitatively analyzed from 9-70 days after allowing the transected left hypoglossal nerve to regenerate after an 84 day delay. Delay was achieved by implanting the proximal stump into already innervated sternomastoid muscle, where no regeneration occurred. Regeneration was then allowed by denervating the sternomastoid. During the regenerative period the initially high number of abnormally electron dense perikarya and dendrites decreased to almost normal values, but no cell removal was seen. This suggested that the degenerate appearance of many profiles after prolonged prevention of regeneration, was reversible. The neuropil bouton and dendrite counts, and the numbers of synapsing boutons per dendrite, increased steadily to normal values from the low values of suppressed regeneration. Somatic bouton frequencies, even though already low, decreased further at 32 days, and later increased but not to normal values. The decrease at 32 days coincided with the loss of many subsurface cisterns, and dispersion of Nissl substance, all suggestive of chromatolysis. Later the subsurface cisterns and Nissl substance returned. It was suggested that the delay of complete recovery of somatic bouton frequencies might be because of lack of sensory information from the denervated muscle into which the hypoglossal nerve was regenerating, or because of abnormally low starting values for the recovery phase. Astrocyte (or, occasionally microglial) sheaths persisted along bouton-free perikaryal surfaces.

Animals↗
PubMed1976

Quantitative ultrastructural observations on the inhibited recovery of the hypoglossal nucleus from the axotomy response when regeneration of the hypoglossal nerve is prevented.

Electron micrographs of the left hypoglossal nucleus were quantitatively analyzed in adult rats 52 to 98 days after transection of the left hypoglossal nerve and implantation of the proximal stump into the already innervated ipsilateral sternomastoid muscle, a procedure which prevented the transected nerve from regenerating. Many presynaptic boutons with clear spherical synaptic vesicles and symmetrical synapses were lost from the injured perikarya and dendrites. Some perikarya and dendrites (and, rarely, boutons) became electron dense, and astrocyte or microglial sheaths partly surrounded them. Numbers of dendrite profiles in the neuropil decreased. These statistically significant effects persisted throughout the postoperative period, whereas after axotomy with unimpeded nerve regeneration, these features would have returned to normal by 84 days postoperatively. It was therefore suggested that their recovery depended upon successful regeneration and reconnection of the hypoglossal nerve with the tongue. Subsurface cisterns, and profiles containing unusual inclusions, were numerically normal 52 to 98 days postoperatively, so it was suggested that their early response and recovery after simple axotomy might be entirely dependent on nerve disconnection and not on nerve reconnection.

Animals↗