Biomedical subjects

M E Meyer

Publications and source records attributed to M E Meyer.

At least 19 recordsLinked to original sources

PubMed1992

A limiting factor mediates the differential activation of promoters by the human progesterone receptor isoforms.

The two transcription activation functions (TAFs) of the human progesterone receptor (hPR) have been characterized. TAF-1, located in the N-terminal region A/B, has been narrowed down to a 91-amino acid sequence, which is sufficient for transcription activation in chimeras with the GAL4 DNA binding domain. Both hPR TAF-1 and TAF-2 activate a minimal promoter in yeast. No autonomous TAF could be found in the N-terminal 164 amino acids (designated AB3) which are responsible for the differential activation of promoters by the hPR isoforms A and B. Reduction of the target gene promoter complexity did not alter this differential activation, indicating that AB3 does not require additional promoter-bound factors to exert its effect. Instead, the cell specificity of AB3 and its ability to squelch hPR-induced transcription suggest that this differential isoform activity is due to the effect of a limiting factor which binds to region AB3.

Amino Acid Sequence↗

PubMed1992

Effects of intracerebral quinpirole on locomotion in rats.

The effects of the dopamine D2 receptor agonist quinpirole (LY 171555) on locomotor activity and margin time (thigmotaxis or wall-hugging) were measured for 2 h in rats injected either s.c. (vehicle, 0.02, 2.0 mg/kg) or directly into either the dorsal striatum or nucleus accumbens (vehicle, 0.1, 1.0, 10, 20 or 40 micrograms bilaterally in each site). In all groups, margin time decreased as drug dose increased. As in previous research, quinpirole given s.c. decreased locomotor activity at a low dose and had a biphasic effect on locomotor activity at the high dose. Both of these effects were also elicited by quinpirole injected directly into the dorsal striatum; 10 and 20 micrograms decreased locomotion immediately, while 40 micrograms led to both the immediate decrease and a later increase. In contrast, the lowest doses of quinpirole (0.1 and 1.0 microgram) injected into the nucleus accumbens led to an increase in locomotion from 20 to 60 min, while the higher doses led only to the early decrease. Thus, both the locomotor activating and inhibiting effects of quinpirole are found in both the nucleus accumbens and the dorsal striatum, but the differing dose-response relationships indicate that the mechanisms are not the same in these two brain regions.

Animals↗

PubMed1992

The effects of bilateral and unilateral vibrissotomy on behavior within aquatic and terrestrial environments.

Introducing an untreated rat to a novel environment typically results in thigmotaxis or wall-seeking behavior and the unilateral removal of the vibrissae induces an asymmetry in thigmotaxis. The present study investigated the effects of bilateral and unilateral removal of the vibrissae (vibrissotomy) upon the rat exhibiting thigmotaxis within aquatic and terrestrial environments. Unilateral vibrissotomy resulted in directional thigmotaxis asymmetry toward the intact vibrissae side within both environments. Within the aquatic environment, the unilateral vibrissotomy group swam a significantly longer distance than the other two groups. The data are discussed in terms of activation and sensory information.

Animals↗

PubMed1992

Potentiation of the dorsal immobility response following intrastriatal injections of enkephalins.

The effects of bilateral intrastriatal injections (1.0 microgram/side) of leucine5- and methionine5-enkephalins and their related nonopiate fragments upon three measures of immobility over a time course were investigated. Both leucine5-enkephalin and des-Tyr1-leucine-enkephalin potentiated the duration of the dorsal immobility response (DIR) 15 min postinjection and over a 1-h time course. On the other hand, methionine5-enkephalin and des-Tyr1-methionine-enkephalin potentiated the duration of the DIR at 5 and 15 min. These enkephalins and their fragments had no effect upon vertical cling and bar catalepsy. In a second study, an SC injection of 4 mg/kg naloxone 15 min prior to the central injections blocked the potentiation of the DIR effects of the enkephalins.

Animals↗

PubMed1992

Dopamine D1 antagonists potentiate the durations of bar and cling catalepsy and the dorsal immobility response in rats.

The effects of dopamine D1 antagonists SCH 23390 or SK&F 83566 (at SC doses of 0.00, 0.01, 0.05, and 0.1 mg/kg) were tested for 2 h on bar and cling catalepsy and the dorsal immobility response. Each of the drugs potentiated the duration of each of the three measures of immobility in a dose- and time-dependent manner. Each of the drugs had rapid but brief effects on all three response measures; the peak effect of SK&F 83566 took place at 20 min and that for SCH 23390 at 40 min for each behavior. At each effective drug dose, SCH 23390 had a greater effect than SK&F 83566 on each behavior. Dopamine D1 antagonists potentiated three different immobility responses, as do dopamine D2 antagonists.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1992

Differential effects of dopamine D2 agonist quinpirole upon the dorsal immobility response in rats.

The effects of various dose levels of systemically injected quinpirole upon the dorsal immobility response (DIR) over a time course was investigated in male rats. A low dose of quinpirole (0.01 mg/kg) significantly attenuated the duration of the DIR following the 10-min interval, whereas the highest dose (1.0 mg/kg) had a biphasic effect so that at the 10-min interval the duration of the DIR was significantly potentiated and at the 60-min interval the duration of the DIR was significantly attenuated. The intermediate dose (0.1 mg/kg) had intermediate behavioral effects. The data support the growing evidence that quinpirole has differential effects upon behavior over time as a function of the dose levels. The present data were discussed in reference to presynaptic and postsynaptic dopamine D2 receptor theory.

Animals↗

PubMed1992

Differential effects of intrastriatal estradiol on the dorsal immobility response in male rats.

The effects of implants of 17 beta-estradiol and cholesterol in four regions of the dorsal striatum were tested on the duration of the dorsal immobility response in gonadectomized male rats. The dorsal immobility response was significantly potentiated by 4-h implants of 17 beta-estradiol in the dorsomedial and dorsolateral regions of the dorsal striatum but not in the ventromedial and ventrolateral regions. These data further support the growing evidence that estradiol acts directly but differentially on the striatum to affect behaviors in the rat.

Animals↗

PubMed1992

Mechanisms of antihormone action.

The mechanisms of action of two types of anti-hormones is discussed. Type I anti-hormones comprise the antiestrogen hydroxy-tamoxifen and the antiprogestin RU486, both of which promote DNA binding of the cognate receptors and, due to the activity of one of the two transcription activation functions of the estrogen and progesterone receptors, act as mixed agonist/antagonists. Evidence supporting that ICI 164,384 is also a member of the same group is presented. Type II antagonists impair DNA binding of the corresponding receptor in vitro and, in some cases, also in vivo. Ligand-mapping, an approach to identify the site of interaction of a steroid substitution within the hormone-binding domain of the receptor has been used to identify the 11 beta-pocket of the progesterone receptor and revealed that a single amino acid is responsible for the differential antagonistic effect of RU486 in man, chicken and hamster.

Animals↗

PubMed1991

Control of transcription of the chicken progesterone receptor gene. In vitro and in vivo studies.

To study the promoter of the chicken progesterone receptor (cPR) gene and the relevance of several progestin-responsive elements therein, chimeric genes were constructed which contained the 5'-flanking region of the cPR gene linked to promoterless globin or chloramphenicol acetyltransferase sequences. Cell-specific initiation of transcription was observed in transiently transfected chicken embryo fibroblasts when using 876 base pairs of the cPR gene upstream region. Transcription from these reporter genes could be induced by progestins in the presence of cPR form A but not of form B. In keeping with these data, three in vitro progesterone receptor (PR)-binding sites were identified in the cPR promoter region by DNase I protection assays. However, in vivo, nuclear run-on transcription demonstrated that neither primary stimulation with progestins, nor treatment of secondarily estrogen-stimulated chicks with progestins, glucocorticoids, or androgens resulted in any significant change of cPR gene transcription in the oviduct, thus suggesting a cell- and/or development-specific role for these progestin-responsive elements. Although estrogen is known to increase PR levels in the chick oviduct, this effect does not involve stimulation of PR gene transcription, as demonstrated here by nuclear run-on experiments, the analysis of DNase I hypersensitive sites, and transient cotransfection studies. Since acute withdrawal from estrogen-stimulation markedly decreased the level of cPR mRNAs in chick oviduct when analyzed by Northern blotting, we conclude that estrogen-dependent stimulation of PR levels in the oviduct is a post-transcriptional process.

Animals↗

PubMed1991

Sex differences in locomotor activity after acute and chronic cocaine administration.

Adult, intact and gonadectomized male and female Wistar rats (n = 9) were exposed to an automated open field to assess the behavioral effects of acute cocaine administration (saline, 1.0 and 10.0 mg/kg subcutaneous). The subjects were exposed to the open field for 10 min, removed to be injected and returned to the open field for another 30 min. Three saline and two drug sessions were run in counterbalanced order. Locomotor activity in intact and castrated male rats and ovariectomized female rats decreased following injection, irrespective of the dose of cocaine. The locomotor activity of intact female rats was higher than that of any other group of subjects. It decreased during the session after saline and 1.0 mg/kg cocaine, but increased towards the end of the 30 min session after 10.0 mg/kg. Rearing measures paralleled the observations on locomotor activity. To determine the effects of chronic, home-cage, cocaine administration, five of the subjects in each group were injected with 10.0 mg/kg cocaine for 9 consecutive days. The remaining four subjects received saline injections. On day 10, all subjects were re-exposed to the open-field for 10 min, removed, injected with 10.0 mg/kg cocaine and returned to the open field for another 30 min. Chronic home cage cocaine administration produced an increase in cocaine's effects on locomotor activity and rearing in intact female rats only. However, behavioral sensitization was also observed in intact female rats who had been treated with saline for 9 consecutive days, suggesting that behavioral sensitization to cocaine in intact female rats may develop very rapidly and independent of environmental context.

Animals↗

PubMed1991

Progestin receptors: isoforms and antihormone action.

We present evidence that the two isoforms of A and B of the chicken (cPR) and human progesterone receptor (hPR) originate from two different mRNA populations. One of these encodes the isoforms A which originate by initiation of translation at an in-frame AUG found 127 (cPR) and 165 (hPR) codons downstream of the AUG which gives rise to the isoforms B. Two estrogen-inducible hPR promoters were identified which are responsible for the generation of these two classes of transcripts. Characterization of the cPR promoter suggested the possible existence of cell-type and isoform-specific auto-regulation of cPR transcription and provided evidence that estrogen-induction of cPR expression occurs at a post-transcriptional level. Finally, we demonstrate promoter-specific transcriptional activation by the hPR isoforms A and B, and we discuss the mechanism of action of the anti-progestin RU486.

Animals↗

PubMed1991

[Nuclear receptors. Hormones, anti-hormones and regulation of the transcription].

Nuclear receptors are ligand-inducible transcription factors which respond to endocrine, paracrine and, possibly, autocrine signals, thus triggering key events in early embryonal development, differentiation and homeostasis. Here we discuss recent results which may lead to an understanding of the molecular mechanisms of transcriptional activation by a given transcription activation function (TAF) of these activators and of the receptor isoform-specific activation of transcription. In addition, we present a concept of the mechanism of action of two different types of antihormones.

Animals↗

PubMed1990

Labyrinthine and visual involvement in the dorsal immobility response of adult rats.

The dorsal immobility response (DIR) is typically seen in the infants of many altricial mammalian species. Lifting the animal into the air by the nape of the neck is the primary releasing stimulus. Functionally, this response appears to facilitate carrying of the infants by the adults. When grasped by the nape and lifted into the air, adult rats will also exhibit the DIR. In this paper, the role of the labyrinths in the DIR of adult male rats was examined. Vestibular stimulation produced by vertical circular acceleration increased the duration of the DIR, while labyrinthectomy greatly diminished the DIR. In rats with intact labyrinths, visual occlusion greatly potentiated the DIR, whereas, in labyrinthectomized rats, visual occlusion had little effect. These data indicate that the vestibular system plays a major role in mediating the DIR of adult rats. The retention of the DIR into adulthood and the possible increased role of the labyrinths in the control of the adult DIR, are discussed with respect to the possible role of the DIR as an anti-predator mechanism.

Animals↗

PubMed1990

Agonistic and antagonistic activities of RU486 on the functions of the human progesterone receptor.

RU486 induced the binding to a palindromic progestin responsive element (PRE) in vitro of homo- and heterodimers of the human progesterone receptor (hPR) isoforms A and B, present in T47D breast cancer cells or in HeLa cells transiently expressing the recombinant proteins. The resulting complexes were indistinguishable from those induced with the agonist R5020 with respect to specificity, affinity and stability. Ligand exposure was a necessary prerequisite to observe PR/PRE complexes. Antagonist-induced complexes migrated more rapidly during electrophoresis than agonist-induced ones, and no 'mixed' PR/RU486-PR/R5020 complexes were observed, suggesting that the dimerization interfaces of agonist- and antagonist-bound molecules are non-compatible. The analysis of a series of deletion mutants and chimeric receptors revealed the presence of two transcription activation functions (TAFs), located in the N-terminal region A/B (TAF-1) and the hormone binding domain (TAF-2). In the presence of agonists, both TAFs were active in HeLa cells. In the presence of RU486 TAF-2 was inactive, while TAF-1 within the hPR form B/RU486 complex activated transcription from a reporter gene containing a single palindromic PRE. We consider this to be the most convincing evidence that the receptor/RU486-complex does in fact bind to PREs in vivo. No transcriptional activation was observed in the presence of RU486 from a reporter gene containing the complex MMTV-LTR PRE. In contrast to hPR form B, form A was not able to activate transcription from PRE/GRE-tk-CAT in the presence of RU486. In vivo competition between hPR/RU486 and either cPR/R5020 or the human glucocorticoid receptor/dexamethasone (hGR/Dex) complex further supported that hPR/RU486 bound in vivo to its cognate responsive element. Indeed, the observed inhibition of transcription was shown to be due to competition for the MMTV PRE, since no transcriptional interference by the hPR/RU486 was observed, and since no heterodimers were formed between hPR/RU486 and cPR/R5020 or hGR/Dex. That the ligand-free hPR, however, was unable to compete, demonstrated that ligand binding is the prerequisite for DNA binding of hPR in vivo.

Animals↗

PubMed1990

Dorsal pressure potentiates the duration of tonic immobility and catalepsy in rats.

This study tested the generalizations that cutaneous pressure will elicit immobility, that there is a relationship between the intensity of cutaneous pressure and the duration of immobility, and that the localization or body surfaces, particularly the upper dorsal area or the nape of the neck, is more susceptible to immobility. Immobility was measured by the duration in sec of tonic immobility, bar grasp and vertical cling behaviors or catalepsy. It was shown in the first experiment that dorsal pressure immobility can be elicited in the adult rat. The application of a 9-kg pressure elicited a significant potentiation of the duration of tonic immobility and the bar grasp catalepsy and both 5 and 9 kg of pressure potentiated the duration of vertical cling catalepsy. In the second experiment, only pressure applied to the midline of the dorsal surface at the nape of the neck significantly potentiated the duration of these measures. These results were compared with other experimentally and naturally occurring immobilities.

Animals↗

PubMed1990

Dorsal pressure differentially affects patterning of locomotor activity in rats.

This study tested the generalizations that cutaneous pressure will induce immobility effecting various patterns of locomotor activity and that various intensities of pressure will effect those activities. Dorsal pressure (5 and 9 kg) resulted in immobility and suppressed various measures of horizontal and vertical locomotor activities, as well as margin and corner time, but has no effect upon various measures of stereotypy. The differential intensity of dorsal pressure was related to only measures of rearing behaviors.

Animals↗

PubMed1990

An open-field activity analysis of labyrinthectomized rats.

A detailed behavioral analysis was performed on rats that received bilateral labyrinthectomies. They were placed in a walled activity monitor (39 x 39 cm) that allowed the animal to move freely within the enclosure. Their behavioral activities were automatically recorded. These activities were placed into twelve different categories. The results show a lower rate of habituation for the labyrinthectomized animal as well as an overall increase in activity over all dimensions as compared to the control. This increase in behavior may be exploratory and a necessary feature in the formation of spatial maps.

Animals↗

PubMed1990

Effects of intrastriatal hormones on the dorsal immobility response in male rats.

Previous research has shown that estradiol administered either peripherally or directly into the striatum potentiates the dorsal immobility response (DIR) in ovariectomized female rats. Male rats are even more responsive than females to intrastriatal estradiol, and furthermore respond to the effects of catecholestrogens while females do not. In order to determine whether the heightened effects of estrogens in males are due to conversion to catecholestrogens, castrated male rats were given bilateral intrastriatal implants of moxestrol, which cannot be readily converted to a catecholestrogen, and diethylstilbestrol, which can. To determine whether the effects of intrastriatal estradiol in male rats might be related to the effects of androgens on the striatum, castrated male rats were given bilateral intrastriatal implants of testosterone, which can be aromatized to estrogen, and 5 alpha-dihydrotestosterone, which cannot. The effects of each of the hormones tested were measured against those of cholesterol (an inactive control substance) and 17 beta-estradiol. In each case the DIR was measured four hours after the hormone implant. Both synthetic estrogens and 17 beta-estradiol significantly potentiated the DIR, while neither of the androgens had an effect. Thus, the effects of estradiol, synthetic estrogens and catecholestrogens on the male striatum appear to be due to the estrogenic properties of these hormones.

Animals↗