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Biomedical subjects

C E Finch

Publications and source records attributed to C E Finch.

At least 145 records · Page 8Linked to original sources
PubMed1988

Pituitary and hypothalamic glucose-6-phosphate dehydrogenase: effects of estradiol and age in C57BL/6J mice.

Activities of glucose-6-phosphate dehydrogenase (G6PDH) and 6-phosphogluconate dehydrogenase (6-PGDH) were measured in the mediobasal hypothalamus and pituitary gland of C57BL/6J mice throughout their lifespan. Activities of pituitary G6PDH, pituitary 6-PGDH, and hypothalamic G6PDH increase with age in female mice, assayed 7 days after ovariectomy, but not in intact females or males. Pituitary G6PDH specific activity is increased by middle-age (13-14 months) in females, before the onset of acyclicity, and remains elevated throughout the acyclic phases of persistent vaginal cornification and persistent diestrus. This increase in activity is ovary dependent, because it can be prevented by long term (12-month) ovariectomy. The increased activity is not linked to pituitary tumorigenesis and does not result from trapped blood cells, as evaluated by studies with 51Cr-labeled erythrocytes. Responses to physiological levels of estradiol (E2) were analyzed with a graded series of chronic polyethylene implants or after a single sc injection in ovariectomized mice aged 5-22 months. The responsiveness of pituitary G6PDH to E2 is not altered during aging. Young cycling (6 months old) and older acyclic mice (19 months old) displaying persistent vaginal cornification show equivalent increases of about 100% in G6PDH specific activity after chronic E2 treatment and similar time courses of induction after a single E2 injection. Pituitary G6PDH is maximally induced (30% increase) by 48 h after E2 injection in all age groups. In addition, the rates of decline in pituitary G6PDH specific activity after ovariectomy are similar in young and older mice (half-life, 4 days). The specific activity of G6PDH in the mediobasal hypothalamus and blood is unaffected by E2 administration. The relatively low doses of E2 used here fail to alter 6-PGDH specific activity in pituitary or brain. These findings indicate that female reproductive senescence in mice is not associated with generalized losses of sensitivity and responsivity to E2 throughout the neuroendocrine axis.

Aging↗
PubMed1988

Rapid corticosterone-induced changes in gene expression in rat hippocampus display type II glucocorticoid receptor specificity.

Corticosteroids influence a wide range of neuronal activities by binding to either of two different glucocorticoid receptors found in rat brain. To investigate genomic responses in brain to stress levels of circulating corticosterone (CORT), we isolated hippocampal total RNA and poly(A)-containing RNA from rats treated with 10 mg/day CORT or vehicle. RNA translation products were resolved by 2-dimensional gel electrophoresis and fluorography. Select changes in four translation products after acute CORT treatment were inferred from up to 100-fold increases in three polypeptides and a 2-fold decrease in another. While adrenalectomy decreased levels of the inducible RNA sequences (adrenalectomized vs. intact controls), CORT increased the inducible sequences above their levels in intact controls. Rapid increases within 2 h of CORT treatment were seen for RNAs coding for 35, 33, and 20 kilodalton polypeptides. However, RNA coding for a 50 kilodalton polypeptide had a delayed decrease, first seen after 32 h CORT. The CORT increases displayed type II glucocorticoid receptor-specificity: RU 28362 greater than or equal to CORT greater than aldosterone greater than dihydrotestosterone = control. Since type II receptors are only substantially occupied by stress levels of CORT, these changes in gene expression are candidates for molecular stress responses in the brain.

Animals↗
PubMed1987

Hypothalamic monoamines and their catabolites in relation to the estradiol-induced luteinizing hormone surge.

Monoamines and non-conjugated catabolites (serotonin (5-HT), 5-hydroxyindole acetic acid (5-HIAA), 3,4-dihydroxyphenyl-acetic acid (DOPAC), homovanillic acid (HVA), 4-hydroxy-3-methoxyphenylethyleneglycol (MHPG), norepinephrine (NE), and dopamine (DA] were measured in the medial basal hypothalamus (MBH) and preoptic area (POA) of ovariectomized (OVX) and OVX estradiol (E2)-treated rats using high-performance liquid chromatography with electrochemical detection. These E2 treatments were sufficient to induce an LH surge. The use of MHPG/NE ratios as estimates of NE release was validated in the rat hypothalamus by the major decreases of MHPG after injection of the alpha 2-adrenergic agonist, clonidine, and by MHPG increases after the alpha 2-antagonist, yohimbine. The ratio, MHPG/NE, decreased between morning and afternoon in the MBH but not in the POA; there were no differences between OVX and E2-treated rats. Previous studies using a variety of methods indicate that NE turnover increases during LH surges. The present data suggest that unconjugated MHPG is not a sensitive measure of NE release in the rat hypothalamus, but can detect the large changes produced by stimulating or inhibiting the alpha 2-adrenergic autoreceptor. The ratios of DOPAC/DA and 5-HIAA/5-HT in the MBH decreased consistently between morning and afternoon in OVX rats, with or without E2 treatment. This suggests that the release of DA and 5-HT decreases during the day regardless of steroidal milieu.

Animals↗
PubMed1987

Alteration of calmodulin distribution does not accompany dopaminergic supersensitization of the mouse striatum.

Membrane-bound calmodulin increases following dopaminergic supersensitization of the rat striatum. To assess the generality of this relationship, mice were treated with two different supersensitization paradigms. Calmodulin levels and subcellular distribution were determined by radioimmunoassay. Chronic haloperidol treatment increased striatal D2 dopamine receptor density by 25% but had no effect on membrane-bound calmodulin levels. Similarly, 6-hydroxy-dopamine (6-OHDA) lesions depleted striatal dopamine content greater than 95% without affecting membrane-bound calmodulin. In contrast, soluble calmodulin levels decreased by 15% in the 6-OHDA-lesioned striatum, suggesting that soluble calmodulin is enriched in presynaptic dopaminergic terminals. We conclude that dopaminergic supersensitization can occur in the mouse striatum in the absence of any change in calmodulin distribution.

Animals↗
PubMed1987

Genotypic influences on pituitary responsiveness to haloperidol in mice.

Previous studies from this laboratory demonstrated that CBA/J mice have impaired striatal dopaminergic supersensitivity in response to subchronic haloperidol administration. Others have speculated that the peripheral hyperprolactinemia produced by haloperidol is necessary for the striatal dopamine receptor supersensitization produced by dopamine antagonists. In the present experiments, we tested the hypothesis that the impaired supersensitization response to haloperidol in CBA/J mice was secondary to an impaired hyperprolactinemic response by comparing the CBA/J mice with other mice that show normal supersensitization responses: the BALB/cJ and C57BL/6J strains. Acute haloperidol treatments increased serum prolactin levels 60 min later in all three strains, with the greatest response in CBA/J mice. After longer haloperidol treatment (2 or 21 days), serum prolactin remained elevated in CBA/J and, to a lesser extent, in C57BL/6J mice; levels remained low throughout treatment in BALB/cJ mice. Although, the basal density of pituitary dopamine receptors [( 3H]spiperone or D-2 binding sites) was greater in CBA/J than BALB/cJ mice, only BALB/cJ mice showed increased pituitary D-2 binding sites following chronic haloperidol administration. Taken together with previous studies of dopamine and noradrenaline receptors in these mouse strains, we conclude that CBA/J mice have a generalized impairment in their supersensitization responses to pharmacologic blockade of receptors. These data do not support the involvement of prolactin in haloperidol-induced dopamine receptor up-regulation.

Animals↗
PubMed1987

Transient shortening of estrous cycles in aging C57BL/6J mice: effects of spontaneous pseudopregnancy, progesterone, L-dihydroxyphenylalanine, and hydergine.

Regular estrous cycles can be reinitiated in old acyclic female rats by pharmacologic, hormonal, and environmental manipulations. The most responsive acyclic states are persistent vaginal cornification (PVC) and spontaneous pseudopregnancy (SP). However, it is not known if the irregular cyclicity that precedes acyclicity during aging can also be alleviated. We found that transient shortening of estrous cycles follows smear sequences indicative of pseudopregnancy in C57BL/6J mice, aged 9-15 mo, suggesting a role for progesterone. This phenomenon was investigated through a limited model of pseudopregnancy in which intact aging mice with lengthened cycles were given progesterone implants (yielding 70 ng progesterone/ml plasma) that suppressed estrous cycles; upon removal of the implants, cycles were transiently shortened in aging mice. Therefore, we hypothesize that withdrawal from the progesterone elevations associated with SP is the mechanism in shortening subsequent estrous cycles. Effects of central-acting drugs, similar to those used to reinitiate cyclicity in acyclic old rats, were also examined. Hydergine, an ergot mixture with partial dopaminergic and serotonergic agonist activities, suppressed SP when fed to 10- to 12-mo-old, middle-aged mice. Hydergine did not otherwise affect estrous cycle length, prevent PVC, or reinitiate cycling in acyclic PVC mice. Feeding L-dihydroxyphenylalanine to middle-aged mice did not suppress SP, affect estrous cycle lengths, or reinitiate cycles from PVC.

Aging↗
PubMed1987

Supernumerary ovarian grafts in aging C57BL/6J mice reveal complexities in the neuroendocrine impairments of acyclic mice.

Determinants of the age-related acyclic state, persistent vaginal cornification (PVC), were studied in reproductively senescent mice using a 2-stage ovarian transplantation procedure, whereby ovaries from young mice were grafted to older mice without removing their autogenous ovaries until 8 wk later. In contrast to the usual ("1-stage") procedure, in which the autogenous ovaries are removed at the time of grafting, the 2-stage approach is postulated to circumvent potential effects of the reduction in steroids during the ovariprival phase prior to vascularization of the grafted ovary, which may reverse age-related hypothalamic-pituitary impairments. The 2-stage transplantation procedure was validated in young C57BL/6J mice. Estrous cycles were not disrupted by removal of the autogenous ovaries 8 wk after the grafting, indicating that grafted ovaries began functioning before or within days after ovariectomy. No difference in estrous cycle frequency or distribution was detected between the young mice with 2-stage and those with 1-stage transplants for at least 3 mo after removal of the autogenous ovaries. Most older (15- to 18-mo-old) mice with PVC (70%) remained acyclic after receiving young ovaries by either the 1-stage or the 2-stage procedure, indicating that extra-ovarian, presumably neuroendocrine, impairments are sufficient to maintain acyclicity in most older mice once it is initiated. However, 30% of the older mice from each transplantation group began cycling after receiving young ovaries by either the 1-stage or 2-stage procedure, as observed before 1-stage transplants. Therefore, cycle reactivation was not a result of the transient ovariprival phase incurred during 1-stage transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1987

Dopamine and serotonin systems in human and rodent brain: effects of age and neurodegenerative disease.

The nonpathological age-related changes in the dopamine- and serotonin-containing neurotransmitter systems in human and rodent brain are reviewed. The dopamine system exhibits age-related declines both presynaptically and postsynaptically. Presynaptically, both the levels of dopamine and the number of midbrain dopamine-containing neurons decline by up to 50% at advanced ages in the absence of neurological disease. Postsynaptically, the density of D-2 dopamine receptors decreases by 40%, while D-1 dopamine receptors either increase (man) or remain stable (rodents). Additional reductions of dopamine levels and D-2 receptors have been reported in Alzheimer's disease (AD), but these changes are relatively small, and not consistently observed. The levels of serotonin appear stable during normal aging, and presynaptic markers such as (3H)imipramine binding may actually increase. In human brain, the two major classes of serotonin receptor (S-1 and S-2) decrease by 30 to 50% over the lifespan. In AD, both presynaptic and postsynaptic markers of the serotonin system are reduced, including a loss of the serotonin-containing raphe neurons. The additional loss of serotonin receptors in AD approaches 80% when compared with young normals. A hypothesis is presented to explain the typically young age at onset of schizophrenia (usually before 30 years of age) and the older age at onset of parkinsonism (rarely before 50 years of age) within the context of normal age-related declines in the dopamine system occurring in the absence of neurological disorders. The possibility that chronic cocaine abuse might accelerate the development of parkinsonism is discussed.

Aging↗
PubMed1987

Hormonal influences on the estradiol-induced and age-related increases of pituitary dopamine in C57BL/6J mice. Effects of gonadal steroids, gender, and prolactin.

Estradiol (E2) produces many-fold increases in the dopamine (DA) content of the anterior pituitary and also plays a role in the age-related increase in pituitary DA in female C57BL/6J mice. These studies address the following questions: (1) What are the time and dose characteristics of the E2-induced increase in pituitary DA and can other gonadal steroids - such as progesterone (P) and 5 alpha-dihydrotestosterone - also influence pituitary DA? (2) Is the age-related increase in pituitary DA due entirely to an increase in the E2:P ratio seen in aging female mice, or can extra-ovarian factors also play a role? (3) Is the E2-induced (and therefore possibly the age-related) increase in pituitary DA secondary to an E2-induced increase in serum prolactin? In ovariectomized (OVX) mice, E2 implants increased pituitary DA in a time- and dose-dependent fashion. P implants administered to OVX mice simultaneously with E2 antagonized the E2-induced increase in pituitary DA. Daily injections of 5 alpha-dihydrotestosterone given in conjunction with E2 implants had no effect on basal or E2-increased pituitary DA in OVX mice. Thus, E2 is the only gonadal steroid examined which increases anterior pituitary DA. In intact aging mice, P attenuates the age-related increase in pituitary DA, supporting the hypothesis that the increased ratio of E2:P secreted by the ovaries of aging female mice is responsible for the age-related increase in pituitary DA. However, at advanced ages, intact male mice also showed modest increases in anterior pituitary DA.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1986

Regional serotonin receptor studies: chronic methysergide treatment induces a selective and dose-dependent decrease in serotonin-2 receptors in mouse cerebral cortex.

Compared with the well described supersensitization responses of dopaminergic and beta-adrenergic receptors to pharmacologic antagonists and denervation, the regulation of serotonin-1 (S-1) and serotonin-2 (S-2) receptors is poorly understood. In an effort to modulate S-1 and S-2 receptors in mouse brain, male C57BL/6J mice were treated chronically with methysergide, a serotonin antagonist with nanomolar affinity for both S-1 and S-2 receptors. Methysergide treatment had no influence on the affinity or density of S-1 receptors as measured by binding of (3H)-5-HT in cerebral cortex, hippocampus or hypothalamus. In contrast, the S-2 receptor specific binding of (3H)-spiperone in the cerebral cortex decreased in a dose dependent fashion, a direction of change opposite to that usually seen in catecholamine pathways chronically exposed to antagonists. The effect was selective for the S-2 serotonergic receptor since the D-2 dopaminergic receptor specific binding of (3H)-spiperone in the caudate nucleus was unaffected by drug treatment. These results suggest that either serotonin receptors respond atypically to chronic receptor blockade by antagonist or that in vivo, methysergide may have additional pre-synaptic effects on serotonin uptake or release.

Animals↗
PubMed1986

Extensive postmortem stability of RNA from rat and human brain.

The postmortem stability of brain RNA was measured in rat and human samples for up to 48 hr. Whole rat brains, cooled at a rate approximating that of human brains awaiting autopsy, were collected at intervals from 0 to 48 hr after death and frozen. These samples were compared with freshly obtained, unfrozen rat brains. Two potentially independent characteristics of these RNA populations were measured: the recovery or yield of RNA/gram tissue (quantity) and the integrity or extent of degradation (quality). Total RNA yields were similar after all postmortem delays. Hybridization of [32P]-labeled cDNA probes to nitrocellulose filter blots of electrophoretically separated rat brain RNA failed to reveal degradation of the specific rat brain mRNAs during the postmortem period. Similarly, in vitro translation of these same rat total RNA samples produced high molecular weight translation products with no differences between long and short postmortem times. Human cerebral cortex RNA was prepared by the same methods as those used for rat brain from a neurosurgical sample and four other donors with postmortem intervals from 7 to 36 hr. Typically, the yield of total RNA from human brain was 40-50% of the yield from rat brain. When analyzed by RNA gel blot hybridization studies, as for rat brain RNA, human cortical RNA appeared slightly degraded. However, the degree of apparent RNA degradation was not related to the postmortem interval. In vitro translation products of human cortical RNA revealed high molecular weight peptides at all postmortem intervals, but slightly less [35S]incorporation into these bands was found at the longer postmortem intervals relative to the shorter times. Together, these results demonstrate an extensive stability of brain RNA that invites aggressive use of molecular genetic techniques for the study of human neurodegenerative diseases.

Animals↗
PubMed1986

Prolongation and cessation of estrous cycles in aging C57BL/6J mice are differentially regulated events.

The relative contributions of ovarian failure and hypothalamic-pituitary dysfunction to the prolongation and cessation of estrous cycles were assessed by measuring the ability of acutely ovariectomized (OVX) middle-aged (12 mo) mice to cycle after receiving grafts (under the renal capsule) of ovaries from young (2 mo) mice. The potentially disruptive effect of the acyclic state on the cycling response to grafted, young ovaries was avoided restricting grafting to middle-aged hosts that were still cycling. The effect of chronic exposure to ovarian secretions before the cessation of cyclicity on age-related hypothalamic-pituitary dysfunction was also assessed. The cycling ability of long-term OVX middle-aged mice (i.e., OVX at 3 mo) bearing grafts of young ovaries was compared to that of age-matched acutely OVX controls. Grafted young ovaries extended the cycling lifespan of acutely OVX middle-aged hosts by 60%. The length of this extended cycling lifespan, however, was only 80% of that achieved by young hosts bearing grafts of young ovaries. Young ovaries in middle-aged mice markedly lowered the incidence of long cycles (greater than 5 days), shifting the modal cycle length to 5 days. However, young ovaries in middle-aged mice failed to increase the incidence of 4-day cycles, the modal cycle of young controls. Middle-aged ovaries grafted into young hosts lengthened their cycles and shortened their cycling lifespan to middle-aged values. Long-term ovariectomy failed to increase the cycling lifespan of middle-aged hosts bearing grafts of young ovaries beyond that achieved in acutely OVX mice. Long-term ovariectomy did shorten the modal cycle length of middle-aged mice to 4 days, although the duration of 4-day cycling was only one-third (2 mo) that of young controls. These results indicate that the relative contributions of ovarian and neuroendocrine factors to three major events of reproductive aging vary with each event. Whereas the hypothalamic-pituitary unit appears to play an important role in the initial shift from 4- to 5-day cycles, the aging ovary plays the major role in the subsequent shift to longer cycles and in the ultimate cessation of cyclicity. Although chronic exposure to ovarian secretions during the period of cyclicity does not play a major role in the cessation of cyclicity, it appears to contribute to the hypothalamic-pituitary changes responsible for the initial shift from 4- to 5-day cycles.

Aging↗
PubMed1986

Effective oral administration of 17 beta-estradiol to female C57BL/6J mice through the drinking water.

17 beta-Estradiol (E2) was dissolved in the drinking water of female C57BL/6J mice and presented ad libitum. The oral administration of E2 produced expected responses in E2-sensitive target tissues. Vaginal smear cytology changed from the thin leukocytic smears characteristic of ovariectomized controls to thicker smears containing only cornified epithelial cells. Uterine weight and the specific activities of uterine glucose-6-phosphate dehydrogenase and alkaline phosphatase were elevated, while the postovariectomy elevation in serum luteinizing hormone (LH) was suppressed. However, oral E2 did not influence the specific activity of uterine acid phosphatase. During oral administration of E2 through the drinking water, serum estrone and E2 were elevated during the night and returned to low baseline levels during the day, in parallel with the circadian patterns of drinking. Similar transient elevations of serum E2 levels were observed after subcutaneous injections of E2. The oral administration of E2 has advantages over the widely utilized parenteral routes of E2 administration (i.e., injection or surgical implantation of E2-containing capsules), particularly for long-term experiments, and may be more analogous to the usual oral route of estrogen administration in women as contraceptives or as postmenopausal estrogen-replacement therapy.

Administration, Oral↗
PubMed1986

[3H]Fluphenazine binding to brain membranes: simultaneous measurement of D-1 and D-2 receptor sites.

[3H]Fluphenazine was used to label both D-1 and D-2 dopamine receptors in mouse striatal membranes. The D-1 and D-2 specific binding of [3H]fluphenazine was discriminated by the dopamine antagonists SCH-23390 (D-1 selective) and spiperone (D-2 selective). Saturation analyses of these two sites yielded a D-1 receptor density in mouse striatum of 1,400 fmol/mg of protein and a D-2 receptor density of 700 fmol/mg of protein. The affinity of [3H]fluphenazine for the D-2 site was slightly greater than for the D-1 site; the equilibrium dissociation constant (KD) was 0.7 versus 3.2 nM, respectively. Assay conditions are described that reduce nonspecific binding of [3H]fluphenazine to acceptable levels (35% of total binding at 1 nM [3H]fluphenazine). By comparison of displacement curves from a series of dopaminergic and nondopaminergic ligands, the pharmacological specificity of [3H]fluphenazine binding in mouse striatum was demonstrated to be dopaminergic. Only small amounts of dopamine-specific (apomorphine-sensitive) [3H]fluphenazine binding were found in other brain regions. However, chlorpromazine displaced considerable [3H]fluphenazine from all brain regions, including cerebellum, suggesting the presence of a [3H]fluphenazine binding site with a phenothiazine specificity.

Animals↗
PubMed1986

The increase of anterior pituitary dopamine in aging C57BL/6J female mice is caused by ovarian steroids, not intrinsic pituitary aging.

We describe how the increase of anterior pituitary dopamine (DA) during aging in female mice is related to altered secretion of ovarian steroids during reproductive senescence. A number of age-correlated neuroendocrine changes in female rodents result from cumulative exposure to ovarian steroids over a lifetime of estrous cycles, or from the altered pattern of ovarian steroid secretion concomitant with reproductive senescence. Pituitary DA has been shown to increase with age in female rats. To examine how the age-correlated increase of pituitary DA may depend on estradiol (E2), we measured pituitary DA and serum prolactin (PRL) in the following groups of female mice: young (7 months) cycling, middle-aged (14 months) cycling and non-cycling, old (17 months) non-cycling, old (17 months) ovariectomized (OVX) at 4 months, and young mice given 0.2 mg E2 valerate or E2 implants. Mice from some of these groups were OVX 1, 4 or 8 weeks before sacrifice. Compared with young controls, 14-month-old cycling or non-cycling mice had 3-fold higher pituitary DA, and 17-month-old non-cycling mice had 5-fold higher pituitary DA. OVX for 2 or 13 months before sacrifice abolished the effect of age; OVX of young mice had no effect on pituitary DA. Three weeks after implantation of E2 into OVX young mice or 7 weeks after injection of E2 valerate in intact young mice, pituitary DA was elevated. The E2-sensitive fraction of pituitary DA does not appear to decrease PRL secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1986

Genetic influence on the regulation of beta adrenergic receptors in mice.

The regulation of beta adrenergic receptors was investigated in inbred mouse strains in which previous studies revealed differences in the regulation of dopamine receptors. The density of beta adrenergic receptors in the cerebral cortex of BALB/J mice was about one-third of that in CBA/J and C57BL/6J mice. Strain differences in the binding of [125I]iodohydroxypindolol to beta adrenergic receptors were due to changes in the density of beta-1 adrenergic receptors. Chronic administration of propranolol did not result in an increase in the density of beta adrenergic receptors receptors in cortices of C57BL/6J and BALB/cJ mice were observed. In contrast, pretreatment with 6-hydroxydopamine resulted in increases in the density of beta adrenergic receptors in the cerebral cortex of all three strains. Analysis of the effects of these treatments on the subtypes of beta adrenergic receptors revealed that the changes were restricted to changes in the density of beta-1 receptors. The failure to observe a response to propranolol in CBA/J mice expands the extent of deficits reported previously in this strain for striatal dopamine receptor supersensitivity after chronic treatment with haloperidol (Severson et al., Brain Res. 210: 201-215, 1981). CBA/J mice may be a useful model for genetic analysis of mechanisms for the control of receptor sensitivity and to investigate the impairments of the regulation of catecholaminergic receptors observed in aged rodents.

Age Factors↗