Biomedical subjects

C A Wilson

Publications and source records attributed to C A Wilson.

At least 37 records · Page 2Linked to original sources

PubMed2000

Melanin-concentrating hormone, melanocortin receptors and regulation of luteinizing hormone release.

Melanin-concentrating hormone (MCH) is a neuropeptide, identified by its ability to either mimic or antagonize the melanin-dispersing action of alpha-melanocyte stimulating hormone (alphaMSH) on skin melanophores. MCH and alphaMSH also have antagonistic actions in the brain affecting feeding behaviour, aggression, anxiety, arousal and reproductive function through the release of luteinizing hormone (LH). It is not clear, however, how they exert their opposite effects in the central nervous system (CNS). One possibility is that they act via a common receptor. In this study we have examined the effect of a number of MC receptor antagonists, with relative selectivity for the MC3, 4 and 5 subtypes, on the actions of MCH on LH release. We confirmed that bilateral administration of MCH (100 and 200 ng/side) into the medial preoptic area of oestrogen-primed (oestradiol benzoate 5 microgram) ovariectomized anaesthetized rats, stimulated the release of LH. This effect was blocked by the concomitant administration into the medial preoptic area of the MC4/5 antagonist ([D-Arg8]ACTH(4-10) and the MC3/5 antagonist ([Ala6]ACTH(4-10)-both at 500 ng/side-but not by the MC3/4 antagonist, SHU9119 (200 ng/side). Furthermore, the MC3 agonist [Nle3]-gamma2 MSH failed to affect LH release. These results indicate that the MC3 and MC4 receptors are not involved in mediating the action of MCH but are consistent with an action via the MC5 subtype. Preputial glands, which express MC5 receptors, were also stimulated by MCH which is in keeping with this idea. In HEK293 cells transfected with the MC5 receptor MCH increased the production of IP3. However, it was much less potent than alphaMSH and unlike alphaMSH, had no effect on the production of cAMP. MCH (10-10 to 10-5 M) also failed to displace I125NDP-MSH from cells transfected with MC5 receptors indicating that it was not acting as a competitive antagonist and its binding site was distinct from that of alphaMSH. Thus while MCH may function as an agonist at the MC5 receptor, its stimulation of LH release is more likely to be mediated via a specific MCH receptor that has common properties with the MC5 receptor.

Adrenocorticotropic Hormone↗

PubMed2000

The effect of leptin on luteinizing hormone release is exerted in the zona incerta and mediated by melanin-concentrating hormone.

The adipose hormone, leptin, not only restrains appetite, but also influences energy expenditure. One such influence is to promote sexual maturation and fertility. The neuromodulatory circuits that mediate this effect are not well known but the present study suggests that one mediator could be melanin-concentrating hormone (MCH). We show that the long-form receptor (Ob-Rb) is expressed in the zona incerta of the rat and that administration of leptin (both 0.5 microg and 1.0 microg/side) into this area of ovariectomized, oestrogen-primed rats stimulated the release of luteinizing hormone (LH) within 1 h, the effect enduring for a further 1 h. Injections of leptin into the arcuate nucleus induced a smaller, transient rise in LH while injections into the paraventricular and ventromedial nuclei were without effect. MCH neurones are present in the zona incerta and administration of this hormone into the medial preoptic area (mPOA) stimulates LH release, therefore we investigated the possibility that MCH might mediate this effect of leptin. An injection of MCH antiserum into mPOA prevented the rise in LH normally induced by leptin injected into the zona incerta. In addition, melanocortin receptor antagonists ([D-Arg8]ACTH(4-10) and [Ala6]ACTH(4-10)), previously shown to inhibit the stimulatory effect of MCH on LH release, also inhibited the effect of leptin. We propose that one route by which leptin may promote reproductive activity is by enhancing MCH release from fibres within the mPOA. Speculative mechanisms for the action of MCH include the following possibilities: MCH may be acting on the specific MCH receptor which in turn interacts with a melanocortin or melanocortin-like receptor; MCH may bind directly to one of the melanocortin receptors; or melanocortin antagonists may interact with the MCH receptor.

Alternative Splicing↗

PubMed2000

The interaction between Ran and NTF2 is required for cell cycle progression.

The small GTPase Ran is required for the trafficking of macromolecules into and out of the nucleus. Ran also has been implicated in cell cycle control, specifically in mitotic spindle assembly. In interphase cells, Ran is predominately nuclear and thought to be GTP bound, but it is also present in the cytoplasm, probably in the GDP-bound state. Nuclear transport factor 2 (NTF2) has been shown to import RanGDP into the nucleus. Here, we examine the in vivo role of NTF2 in Ran import and the effect that disruption of Ran imported into the nucleus has on the cell cycle. A temperature-sensitive (ts) mutant of Saccharomyces cerevisiae NTF2 that does not bind to Ran is unable to import Ran into the nucleus at the nonpermissive temperature. Moreover, when Ran is inefficiently imported into the nucleus, cells arrest in G(2) in a MAD2 checkpoint-dependent manner. These findings demonstrate that NTF2 is required to transport Ran into the nucleus in vivo. Furthermore, we present data that suggest that depletion of nuclear Ran triggers a spindle-assembly checkpoint-dependent cell cycle arrest.

Animals↗

PubMed2000

Extended analysis of the in vitro tropism of porcine endogenous retrovirus.

We previously reported that mitogenic activation of porcine peripheral blood mononuclear cells resulted in production of porcine endogenous retrovirus(es) (PERV[s]) capable of productively infecting human cells (C. Wilson et al., J. Virol. 72:3082-3087, 1998). We now extend that analysis to show that additional passage of isolated virus, named here PERV-NIH, through a human cell line yielded a viral population with a higher titer of infectious virus on human cells than the initial isolate. We show that in a single additional passage on a human cell line, the increase in infectivity for human cells is accounted for by selection against variants carrying pig-tropic envelope sequences (PERV-C) as well as by enrichment for replication-competent genomes. Sequence analysis of the envelope cDNA present in virions demonstrated that the envelope sequence of PERV-NIH is related to but distinct from previously reported PERV envelopes. The in vitro host range of PERV was studied in human primary cells and cell lines, as well as in cell lines from nonhuman primate and other species. This analysis reveals three patterns of susceptibility to infection among these host cells: (i) cells are resistant to infection in our assay; (ii) cells are infected by virus, as viral RNA is detected in the supernatant by reverse transcription-PCR, but the cells are not permissive to productive replication and spread; and (iii) cells are permissive to low-level productive replication. Certain cell lines were permissive for efficient productive infection and spread. These results may prove useful in designing appropriate animal models to assess the in vivo infectivity properties of PERV.

Amino Acid Sequence↗

PubMed2000

Serotonin inhibits luteinizing hormone release via 5-HT1A receptors in the zona incerta of ovariectomised, anaesthetised rats primed with steroids.

The zona incerta (ZI), an area in the dorsal hypothalamus, contains neuronal systems that appear to control gonadotropin release. Previous findings show that there is an inverse relationship between serotonin (5-HT) activity in the ZI and plasma luteinizing hormone (LH) levels, indicating that the 5-HT system in this area has an inhibitory effect on LH release. Employing anaesthetised, ovariectomised rats primed with 5 microg oestradiol benzoate followed at 48 h by 0.5 mg progesterone, we have shown that 2 microg/side 5-HT in the ZI inhibits the LH surge that normally occurs 4 h after the progesterone treatment. This effect was mimicked by 2 microg/side 8-OH-DPAT, a 5-HT1A agonist, but not by DOI, a 5-HT2 agonist, BMY7378, a presynaptic 5-HT1A agonist or MCPP, a 2B & 2C agonist. The inhibitory effect of 5-HT and 8-OH-DPAT was prevented by pretreatment, 1 h before, with either 2 mg/kg i.p. WAY100135, a 5-HT1A antagonist or 0.25 mg/kg i.p. ritanserin, a 5-HT2 antagonist. These results indicate that 5-HT in the ZI exerts its inhibitory effect on LH release via 5-HT1A receptors but that another 5-HT subtype may also be involved.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2000

Rare case of naso-oral fistula with extensive osteocartilaginous necrosis secondary to cocaine abuse: review of otorhinolaryngological presentations in cocaine addicts.

We report what we believe to be only the 10th case of palatal necrosis secondary to cocaine abuse in a 33-year-old female patient. Extensive necrosis also involved the cartilaginous and bony septum and paranasal sinuses. Following exclusion of other mid-line destructive diseases her treatment involved saline douches and cessation of cocaine. She remains under review within the department with no evidence of progressive disease. We present a review of the other nine cases of palatal necrosis reported in the world literature and demonstrate a greater incidence in female users. The various presenting conditions of cocaine abuse encountered within the head and neck region by the otorhinolaryngologist are then discussed.

Adult↗

PubMed2000

Heterogeneity in the bioactivity of LH secreted by peripubertal rats.

Treatment of immature rats with 5 iu equine chorionic gonadotrophin (eCG) on day 25 typically stimulates a preovulatory surge of LH on day 27 and ovulation on day 28. In rats weighing > 60 g at the time of treatment, an LH surge and ovulation occurred in 75% of the animals but, in rats weighing < 60 g, only 13% ovulated even though 69% showed an LH surge. Previous findings have shown that exogenous LH can stimulate ovulation in the rats < 60 g, indicating that the anovulation was not due to ovarian immaturity, but rather to an abnormal form of LH. Thus, it was important to determine whether the bioactivity of LH released at the time of the surge differs in rats < 60 g compared with rats > 60 g. Experiments showed that LH from both groups of eCG-treated animals were equipotent in stimulating testosterone production from incubated Leydig cells and progesterone production from cultured granulosa cells. Similarly the surge of progesterone in vivo, which occurs co-incident with the LH surge, was of similar magnitude in both groups of animals. Since prostaglandin synthesis increases at the time of ovulation and is also stimulated by LH, it was investigated whether the activity of ovarian phospholipase A2, the rate limiting enzyme in prostaglandin synthesis, and ovarian prostaglandin E2 concentrations differed in the animals > 60 g and < 60 g. Phospholipase A2 activities were similar in both groups of animals at the time of the LH surge, as were the prostaglandin E2 concentrations. However, in all animals that ovulated (15/20 in rats > 60 g and 2/15 in rats < 60 g), there was a threefold increase in ovarian prostaglandin E2 concentrations. The results show that, in underweight animals, the bioactivity of LH, in terms of its ability to stimulate steroidogenesis and phospholipase A2 activity, is similar to that released by animals > 60 g; however, the LH produced by the underweight animals fails to induce ovulation by failing to increase, either directly or indirectly, prostaglandin E2 production. Comparison of the profiles of plasma LH collected at the time of the LH surge on an anionic ion exchange column indicates that the LH from rats < 60 g possesses significantly less of the neutral or basic glycoform of LH than that from rats > 60 g. This finding provides a further index that the biopotency of LH produced by underweight animals is different from that of rats > 60 g.

Animals↗

PubMed2000

Less hypoglycemia with insulin glargine in intensive insulin therapy for type 1 diabetes. U.S. Study Group of Insulin Glargine in Type 1 Diabetes.

OBJECTIVE: Insulin glargine (21A-Gly-30Ba-L-Arg-30Bb-L-Arg-human insulin) is a biosynthetic insulin analog with a prolonged duration of action compared with NPH human insulin. This study compared insulin glargine with NPH human insulin in subjects with type 1 diabetes who had been previously treated with multiple daily injections of NPH insulin and regular insulin. RESEARCH DESIGN AND METHODS: This study was a multicenter randomized parallel-group study in which subjects were randomized to receive premeal regular insulin and either insulin glargine (at bedtime) or NPH insulin (at bedtime for patients on once-daily therapy and at bedtime and in the morning for patients on twice-daily therapy) for up to 28 weeks. Dose titration of both basal insulins was based on capillary fasting whole blood glucose (FBG) levels; the goal was a premeal blood glucose concentration of 4.4-6.7 mmol/l. RESULTS: A total of 534 well-controlled type 1 diabetic subjects (mean GHb 7.7%, mean fasting plasma glucose [FPG] 11.8 mmo/l) were treated. A small decrease in GHb levels was noted with both insulin glargine (-0.16%) and NPH insulin (-0.21%; P > 0.05). Significant reductions in median FPG levels from baseline (-1.67 vs. -0.33 mmol/l with NPH insulin, P = 0.0145) and a trend for a reduction in capillary FBG levels were achieved with insulin glargine. After the 1-month titration phase, significantly fewer subjects receiving insulin glargine experienced symptomatic hypoglycemia (39.9 vs. 49.2%, P = 0.0219) or nocturnal hypoglycemia (18.2 vs. 27.1%, P = 0.0116) with a blood glucose level <2.0 mmol/l compared with subjects receiving NPH insulin. CONCLUSIONS: Lower FPG levels with fewer episodes of hypoglycemia were achieved with insulin glargine compared with once- or twice-daily NPH insulin as part of a basal-bolus regimen in patients with type 1 diabetes.

Adult↗

PubMed2000

Quantitative MR imaging study of intravitreal sustained release of VEGF in rabbits.

PURPOSE: To determine whether sustained elevation of vascular endothelial growth factor (VEGF) in the vitreous cavity causes retinal hyperpermeability [blood-retinal barrier (BRB) breakdown] before the development of retinal neovascularization (NV) and to document the kinetics of the integrity of BRB breakdown versus time. METHODS: Poly(L-lactide-co-glycolide)based devices loaded with VEGF were implanted intravitreally in rabbit eyes. Contrast-enhanced magnetic resonance imaging (MRI) methods were used to identify and quantitate the retinal permeability at various time points after implantation. This was done with the newly developed MR tracer AngioMARK (Epix Medical, Boston, MA). After the MRI measurements, fundus photography and fluorescein angiography (FA) also were performed on the same set of animals. RESULTS: At 3 days after implantation, the MR images showed a significant retinal leakage into the vitreous cavity (BRB breakdown) of the VEGF-implanted eyes. To quantitate this leakage, the permeability surface area product (PS) was measured. At 3 days, the mean PS product was 1.25 +/-0.25 x 10(-5) cm3/min. Based on the VEGF in vitro release study, this 3-day BRB breakdown corresponded to a total sustained release of 7.42 +/- 0.54 microg/ml of VEGF. The fundus and FA photographs of these VEGF-implanted eyes taken at 4 days after implantation also showed a considerable level of retinal vascular dilation and tortuosity. By 12 days after implantation, the mean PS product decreased to 5.83 +/- 1.38 x 10(-6) cm3/min. However, the retinal NV was observed only after the second week after implantation. By this time, a total of 10.70 +/- 0.92 microg/ml of VEGF was released in a sustained fashion. Also, after the retinal NV development, retinal detachment also was observed. The control eyes, however, which were implanted with blank devices, remained unchanged and normal during the entire course of this study (PS = 5.57 +/- 0.66 x 10(-7) cm3/min). CONCLUSIONS. The findings indicate that sustained delivery of elevated amounts of VEGF in the vitreous cavity induces a BRB breakdown even earlier than 3 days after implantation. This was achieved after a total sustained release of 7.42 +/- 0.54 microg/ml of VEGF. This retinal leakage regressed by more than half by the time the retinal NV developed. Furthermore, a retinal detachment occurred after this retinal NV. These results are similar to proliferative diabetic retinopathy (PDR). The sustained elevation of VEGF in the vitreous cavity of rabbit eyes is potentially a good model to test VEGF antagonists to treat or prevent PDR in humans. The quantifiable change of BRB breakdown by the contrast-enhanced MRI method is ideal to assess the therapeutic intervention in vivo without killing the animal and may prove to be clinically useful in humans.

Animals↗

PubMed1999

Factor analysis shows that female rat behaviour is characterized primarily by activity, male rats are driven by sex and anxiety.

This experiment explored sex differences in behaviour using factor analysis to describe the relationship between different behavioral variables. A principal component solution with an orthogonal rotation of the factor matrix was used, ensuring that the extracted factors are independent of one another, and thus reflect separate processes. In the elevated plus-maze test of anxiety, in male rats factor 1 accounted for 75% of the variance and reflected anxiety, factor 2 represented activity, and accounted for 24% of the variance. This contrasted with the finding in female rats in which factor 1 was activity, accounting for 57% of the variance, with the anxiety factor accounting for only 34% of the variance. When behaviour in both the plus-maze and holeboard were analysed, a similar sex difference was found with anxiety emerging as factor 1 in males and holeboard activity as factor 1 in females. Locomotor activity in the inner portion of the holeboard loaded on the anxiety factor for males, but on activity for females. When behaviours in the plus-maze and sexual orientation tests were analysed, anxiety emerged as factor 1 in males, sexual preferences factor 2, and activity factor 3. In females, activity was factor 1, sexual preference factor 2, anxiety factor 3, and social interest factor 4. These results suggest caution should be exercised in interpreting the results from female rats in tests validated on males because the primary controlling factor may be different.

Animals↗

PubMed1999

The influence of gender and age on neonatal rat hypothalamic 5-HT1A and 5-HT2A receptors.

1. Rat hypothalamic 5-hydroxytryptamine (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) concentrations are transiently sexually differentiated in the second week postpartum (pp), with higher levels in the female. In this report we investigate the possibility that 5-HT receptors may also exhibit sexual dimorphism in the neonatal period. 2. 5-HT1A and 5-HT2A receptors were quantitated by radioligand binding of [3H]ketanserin and [3H]8-OH DPAT, respectively, in hypothalamus and amygdala from male and female rats at days 8-16 pp. 3. There was no sexual dimorphism or change in the density of 5-HT2A binding in hypothalamus or amygdala over days 8-16 pp. There was also no sexual dimorphism of 5-HT1A receptors. 4. There was an increase in 5-HT1A receptor density in both the hypothalamus and the amygdala. In the hypothalamus, but not the amygdala, this increase was interrupted on day 14 by a decrease in 5-HT1A receptors, which we suggest may be of physiological significance in modifying the eventual pattern of adult agonistic activity. 5. The results suggest that the sexual dimorphism in 5-HT turnover is predominantly presynaptic, relating to altered synthesis and/or release, and is not of sufficient magnitude or duration to produce adaptive responses in postsynaptic 5-HT1A or 5-HT2A receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1999

Localization of human BRCA1 and its loss in high-grade, non-inherited breast carcinomas.

Although the link between the BRCA1 tumour-suppressor gene and hereditary breast and ovarian cancer is established, the role, if any, of BRCA1 in non-familial cancers is unclear. BRCA1 mutations are rare in sporadic cancers, but loss of BRCA1 resulting from reduced expression or incorrect subcellular localization is postulated to be important in non-familial breast and ovarian cancers. Epigenetic loss, however, has not received general acceptance due to controversy regarding the subcellular localization of BRCA1 proteins, reports of which have ranged from exclusively nuclear, to conditionally nuclear, to the ER/golgi, to cytoplasmic invaginations into the nucleus. In an attempt to resolve this issue, we have comprehensively characterized 19 anti-BRCA1 antibodies. These reagents detect a 220-kD protein localized in discrete nuclear foci in all epithelial cell lines, including those derived from breast malignancies. Immunohistochemical staining of human breast specimens also revealed BRCA1 nuclear foci in benign breast, invasive lobular cancers and low-grade ductal carcinomas. Conversely, BRCA1 expression was reduced or undetectable in the majority of high-grade, ductal carcinomas, suggesting that absence of BRCA1 may contribute to the pathogenesis of a significant percentage of sporadic breast cancers.

Antibodies↗

PubMed1999

Development of sizing systems for protective clothing for the adult male.

The aim of the study was to obtain comprehensive anthropometric data from which to develop a sizing system appropriate for inclusion in specifications for protective clothing; and for purchases of other selected equipment. Fifty-five body dimensions on a male sample of the New Zealand Fire Services (n = 691, approximately 7% of employees) were obtained by direct measurement. Descriptive statistics and selected percentiles (5th, 50th, 95th) are given. The body dimensions accounting for most of the variance in the data were established by factor analysis and are reported here. Size groups for various body sections based on the relevant measurements of that section were established by cluster analysis around a control variable.

Adult↗

PubMed1999

Terminally differentiated human neurons survive and integrate following transplantation into the traumatically injured rat brain.

The present study evaluated the survival and integration of human postmitotic neurons (hNT) following transplantation into the traumatically injured rodent brain. Anesthetized male Sprague-Dawley rats (n = 47) were subjected to lateral fluid percussion brain injury of moderate severity (2.4-2.6 atm). Sham animals (n = 28) were surgically prepared, but did not receive brain injury. At 24 h following injury or sham surgery, the rats were re-anesthetized and approximately 100,000 hNT cells (freshly cultured or previously frozen) or vehicle were stereotactically injected into the ipsilateral cortex. Animals were examined for neuromotor function at 48 h, 7 days, and 14 days posttransplantation using a standard battery of motor tests. Animals were sacrificed at 2 weeks postinjury and viability of hNT grafts was assessed by Nissl staining and MOC-1 immunohistochemistry, which recognizes human neural cell adhesion molecules (NCAM) expressed on hNT cells. Transplanted hNT grafts remained viable in 83% of brain-injured animals at 2 weeks following transplantation of either fresh or frozen hNT cells. Glial fibrillary acidic protein (GFAP) immunohistochemistry revealed a marked increase in the number of reactive astrocytes following brain injury in both vehicle and hNT implanted animals. These reactive astrocytes appeared not to impede grafted cells from sending projections into host tissue. Despite the survival of transplanted cells in the traumatically injured brain, hNT cells had no significant effect on posttraumatic neurologic motor function during the acute posttraumatic period. Since hNT cells are transfectable, prolonged survival of these transplanted cells in the posttraumatic milieu suggests that grafted hNT cells may be a suitable means for delivery of therapeutic, exogenous proteins into the CNS for treatment of traumatic brain injury.

Animals↗

PubMed1999

Intracellular APP processing and A beta production in Alzheimer disease.

Senile plaques composed of A beta peptides are a histopathological hallmark of Alzheimer disease (AD). A role for A beta in the etiology of AD has been argued from analysis of mutations associated with a subset of early-onset familial AD (FAD). Expression of autosomal dominant mutations in the genes for the amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2) in affected patients, cultured cells, or transgenic mice leads to increased production of total A beta or increased production of A beta ending at residue 42 (A beta42). Since A beta42 is the more amyloidogenic and toxic species in vitro and is the major component of amyloid senile plaques in vivo, overproduction of this peptide may play a crucial role in the pathogenesis of AD. Thus, an understanding of the production of A beta within the cell in normal and pathological conditions is critical to understanding early events in AD. Studies in cell culture have established that processing of APP to form A beta can occur at multiple locations within the cell and leads to the production of 2 pools of A beta: a secreted pool composed predominantly of A beta40 and a nonsecreted, intracellular pool composed preferentially of more amyloidogenic A beta42. The purpose of this review is to provide a summary of our current understanding of APP processing in the generation of the secreted and intracellular pools of A beta and to propose a model linking the intracellular pool to the formation of extracellular plaques and neuronal pathology in AD.

Alzheimer Disease↗

PubMed1999

Mothers' perceptions of factors influencing violence in schools.

This study investigated mothers' perceptions of factors contributing to school violence. Of 345 mothers, 225 (65%) from urban public schools and 120 (35%) from suburban public schools, significant differences in perceptions of school violence were found on the enabling factors subscale for school location. Urban school mothers were significantly more likely than suburban mothers to attribute violence problems at their child's school to the lack of dress codes, violent messages in rap music, and poor parent/teacher communication. Significant differences in perceptions of school violence were found on the reinforcing factor subscale for school location, income, family structure, and race. Mothers of low- and middle-income, single parents, and African Americans were much more optimistic about the possibility that violence prevention programs for students, parents, and teachers would work well to stop or reduce school violence than were higher-income, married, and White mothers. These mothers also were more likely to believe it was acceptable for their child to fight at school than were their counterparts.

Adult↗

PubMed1999

Receptors and neurotransmitters involved in the dual modulation of prolactin release by the serotoninergic system in pregnant and lactating rats.

The receptors and neurotransmitter pathways that may participate in the inhibitory action of 5-hydroxytryptamine (5HT) on prolactin release during late pregnancy and lactation in rats were studied. Administration of the 5HT synthesis inhibitor, p-chlorophenylalanine, to late pregnant rats induced a significant increase in serum prolactin concentrations at 17:00 h on day 19 of pregnancy that was partially blocked by injections of the 5HT precursor, 5-hydroxytryptophan, or the 5HT agonists, 8-hydroxy-2-(di-n-propylamino)-tetralin hydrobromide (S1a), 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (S2) and N-(3-chlorophenyl)imidodicarbonimide diamide HCl (S3), but not by RU 24969 (S1b) or 1-meta-(chlorophenyl)-piperazine-2-HCl (S1a-2c). The 5HT neurotoxins, fenfluramine and p-chloroamphetamine, which selectively destroy fine axon serotoninergic fibres but not coarse ones, prevented the increase in circulating prolactin observed at 18:00 h on pro-oestrus and on day 21 of pregnancy, but did not modify serum prolactin concentrations at 17:00 h on day 19 of pregnancy. Administration of the adrenergic antagonists, metoprolol or prazosin, also prevented the stimulatory effects of p-chlorophenylalanine or ketanserin in pregnant rats on day 19 (17:00 h) or on days 10-12 (16:30 h) in lactating rats separated from their litters. Administration of p-chlorophenylalanine to pregnant rats on day 19 reduced dopamine concentrations in the arcuate nucleus and in the anterior hypothalamus and noradrenaline concentrations in the anterior hypothalamus and the suprachiasmatic nucleus. These results indicate that the inhibitory actions of 5HT on prolactin release in pregnant and lactating rats are mediated by S1a, S2a and S3 receptors and by the coarse axon serotoninergic fibres. In addition, the inhibitory actions of 5HT may modulate the action of a stimulatory adrenergic pathway, as well as the concentrations of noradrenaline and dopamine in different hypothalamic areas, which, in turn, particularly arcuate nucleus dopamine, regulate prolactin release.

5-Hydroxytryptophan↗

PubMed1999

Effect of gonadal steroids and gamma-aminobutyric acid on LH release and dopamine expression and activity in the zona incerta in rats.

A dopaminergic system in the zona incerta stimulates LH release and may mediate the positive feedback effects of the gonadal steroids on LH release. In this study the mechanisms by which steroids might increase dopamine activity in the zona incerta were investigated. In addition, experiments were conducted to determine whether the inhibitory effects of gamma-aminobutyric acid (GABA) on LH release in the zona incerta are due to suppression of dopamine activity in this area or conversely whether the stimulatory effects of dopamine on LH release are due to suppression of a tonic inhibitory GABAergic system. Ovariectomized rats were treated s.c. with oil, 5 micrograms oestradiol benzoate or 5 micrograms oestradiol benzoate followed 48 h later by 0.5 mg progesterone, and killed 54 h after the oestradiol benzoate injection. At this time the LH concentrations were suppressed in the oestradiol benzoate group and increased in the group treated with oestradiol benzoate and progesterone. The ratio of tyrosine hydroxylase:beta-actin mRNA in the zona incerta was significantly increased by the oestradiol benzoate treatment, but the addition of progesterone resulted in values similar to those in the control group. At the same time, the progesterone treatment increased tyrosine hydroxylase activity in the zona incerta as indicated by an increase in L-dihydroxyphenylalanine (L-DOPA) accumulation after 100 mg 3-hydroxybenzylhydrazine hydrochloric acid (NSD1015) kg-1 and an increase in dopamine release as indicated by a increase in dihydroxyphenylacetic acid (DOPAC) concentrations (one of the major metabolites of dopamine). Ovariectomized rats treated with oestradiol benzoate plus progesterone were also injected i.p. with 75 mg gamma-acetylenic GABA kg-1 (a GABA transaminase inhibitor) to increase GABA concentrations in the brain. This treatment had no effect on the ratio of tyrosine hydroxylase:beta-actin mRNA but decreased L-DOPA accumulation and DOPAC concentrations in the zona incerta, indicating a post-translational inhibition of dopamine synthesis and release. Treatment of ovariectomized rats with oestradiol benzoate followed by 100 mg L-DOPA i.p. to increase dopamine concentrations in the whole brain had no effect on glutamic acid decarboxylase mRNA expression in the zona incerta, although it increased the glutamic acid decarboxylase:beta-actin mRNA ratio in other hypothalamic areas (that is, the medical preoptic area, ventromedial nucleus and arcuate nucleus). In conclusion, the steroids act to increase dopamine activity in different ways: oestrogen increases tyrosine hydroxylase mRNA expression and progesterone acts after translation to increase tyrosine hydroxylase activity and dopamine release (as indicated by increases in DOPAC concentrations). This latter effect may be due to progesterone removing a tonic GABAergic inhibition from the dopaminergic system.

3,4-Dihydroxyphenylacetic Acid↗