Biomedical subjects

J D Mikkelsen

Publications and source records attributed to J D Mikkelsen.

At least 19 recordsLinked to original sources

PubMed2006

Exacerbated loss of cell survival, neuropeptide Y-immunoreactive (IR) cells, and serotonin-IR fiber lengths in the dorsal hippocampus of the aged flinders sensitive line "depressed" rat: Implications for the pathophysiology of depression?

Impairment of hippocampal neurogenesis has been proposed to provide a cellular basis for the development of major depression. Studies have shown that serotonin (5-HT) and neuropeptide Y (NPY) may be involved in stimulating cell proliferation in the dentate gyrus. The Flinders-sensitive line (FSL) rat represents a genetic model of depression with characterized 5-HT and NPY abnormalities in the hippocampus. Consequently, it could be hypothesized that hippocampal neurogenesis in the FSL rat would be impaired. The present study examined the relationship among 1) number of BrdU-immunoreactive (IR) cells, 2) NPY-IR cells in the dentate gyrus, and 3) length of 5-HT-IR fibers in the dorsal hippocampus, as well as volume and number of 5-HT-IR cells in the dorsal raphé nucleus, in adult and aged FSL rats and control Flinders-resistant line (FRL) rats. Surprisingly, adult FSL rats had significantly more BrdU-IR and NPY-IR cells compared with adult FRL rats. However, aging caused an exacerbated loss of these cell types in the FSL strain compared with FRL. The aged FSL rats also had shortened 5-HT-IR fibers in the dorsal hippocampus, indicative of an impaired 5-HT innervation of this area, compared with FRL. These results suggest that, for "depressed" FSL rats, compared with FRL rats, aging is associated with an excacerbated loss of newly formed cells in addition to NPY-IR cells and 5-HT-IR dendrites in the hippocampus. These observations may be of relevance to the depression-like behavior of the FSL rat and, by inference, to the pathophysiology of depression.

Aging↗

PubMed2006

Unaltered neuropeptide Y (NPY)-stimulated [35S]GTPgammaS binding suggests a net increase in NPY signalling after repeated electroconvulsive seizures in mice.

Although electroconvulsive seizures (ECS) are widely used as a treatment for severe depression, the working mechanism of ECS remains unclear. Repeated ECS causes anticonvulsant effects that have been proposed to underlie the therapeutic effect of ECS, and neuropeptide Y (NPY) is a potential candidate for mediating this anticonvulsant effect. Repeated ECS results in prominent increases in NPY synthesis. In contrast, NPY-sensitive receptor binding is decreased, so it is unclear whether ECS causes a net increase in NPY signalling. Agonist-stimulated [35S]GTPgammaS binding is a method for detecting functional activation of G-protein-coupled receptors. The present study in mice examined the effects of daily ECS for 14 days on NPY-stimulated [35S]GTPgammaS functional binding and compared this with gene expression of NPY and NPY receptors as well as [125I]peptide YY (PYY) binding in hippocampus of the same animals. Significant increases in NPY mRNA and concomitant reductions in NPY-sensitive binding were found in the dentate gyrus, hippocampal CA1, and neocortex of ECS treated mice, which is consistent with previous rat data. These changes remained significant 1 week after repeated ECS. Significant increases in NPY Y1, Y2, and Y5 mRNA were found in the dentate gyrus after ECS. Surprisingly, unaltered levels of functional NPY receptor binding accompanied the decreased NPY-sensitive binding. This suggests that mechanisms coupling NPY receptor stimulation to G-protein activation could be augmented after repeated ECS. Thus increased synthesis of NPY after repeated ECS should result in a net increase in NPY signalling in spite of reduced levels of NPY-sensitive binding.

Animals↗

PubMed2005

Regulation of activity-regulated cytoskeleton protein (Arc) mRNA after acute and chronic electroconvulsive stimulation in the rat.

The temporal profile of Arc gene expression after acute and chronic electroconvulsive stimulations (ECS) was studied using semi-quantitative in situ hybridisation in the rat cortex. A single ECS strongly and temporarily increased Arc mRNA levels in dentate granular cells with maximal induction seen up to 4 h after the stimulus, but returned to baseline at 24 h. A single ECS also increased expression of Arc mRNA in the CA1 and the parietal cortex, but the expression peaked within 1 h and returned to baseline levels within 2 h. Repeated or chronic ECS is a model of electroconvulsive therapy and it would be predicted that gene products involved in antidepressant effects accumulate after repeated ECS. However, repeated ECS reduced Arc gene expression in the CA1 24 h after the last stimulus. These results indicate that Arc is an immediate early gene product regulated by an acute excitatory stimulus, but not accumulated by long term repetitive ECS and therefore not a molecular biomarker for antidepressant properties. More likely, Arc is likely a molecular link to the decline in memory consolidation seen in depressive patients subjected to electroconvulsive therapy.

Animals↗

PubMed2005

Xylazine activates oxytocinergic but not vasopressinergic hypothalamic neurons under normal and hyperosmotic conditions in rats.

Role of central alpha2-adrenoceptors in the regulation of hypothalamic magnocellular cells was studied under hyperosmotic challenge elicited by hypertonic saline (HS). Rats pretreated with receptor agonist, xylazine (XYL), were injected intraperitoneally with different (low: 0.375, moderate: 0.75, high: 1.5 M) HS 30 min later. The activity of the paraventricular (PVN) and supraoptic (SON) vasopressin and oxytocin perikarya was established by Fos-dual-immunohistochemistry 60 min after HS administration. Results showed that 1/XYL is a potent stimulus for oxytocin but not vasopressin magnocellular cells under basal and weak hyperosmotic conditions 2/highHS completely overlaps the effect of XYL. In addition, XYL partially suppressed Fos expression in the parvocellular PVN cells activated by highHS. The data suggest that alpha2-adrenoceptors may play an important role in the regulation of oxytocinergic PVN and SON neurons under basal and weak hyperosmotic conditions and that alpha2-adrenoceptors may also participate in the control of PVN parvocellular cells under intense osmotic challenge.

Adrenergic alpha-Agonists↗

PubMed2005

Serotonergic systems associated with arousal and vigilance behaviors following administration of anxiogenic drugs.

Serotonergic systems play important roles in modulating behavioral arousal, including behavioral arousal and vigilance associated with anxiety states. To further our understanding of the neural systems associated with increases in anxiety states, we investigated the effects of multiple anxiogenic drugs on topographically organized subpopulations of serotonergic neurons using double immunohistochemical staining for c-Fos and tryptophan hydroxylase combined with topographical analysis of the rat dorsal raphe nucleus (DR). Anxiogenic drugs with diverse pharmacological properties including the adenosine receptor antagonist caffeine, the serotonin 5-HT2A/2C receptor agonist m-chlorophenyl piperazine (mCPP), the alpha2-adrenoreceptor antagonist yohimbine, and the benzodiazepine receptor partial inverse agonist N-methyl-beta-carboline-3-carboxamide (FG-7142) induced increases in behavioral arousal and vigilance behaviors consistent with an increase in anxiety state. In addition, these anxiogenic drugs, excluding yohimbine, had convergent actions on an anatomically-defined subset of serotonergic neurons within the middle and caudal, dorsal subdivision of the DR. High resolution topographical analysis revealed that at the mid-rostrocaudal level, caffeine and FG-7142 had convergent effects on c-Fos expression in serotonergic neurons that were restricted to a previously undefined region, which we have named the shell region of the dorsal part of the dorsal raphe nucleus (DRDSh), that overlaps the anatomical border between the dorsal part of the dorsal raphe nucleus, the ventral part of the dorsal raphe nucleus (DRV), and the ventrolateral part of the dorsal raphe nucleus (DRVL). Retrograde tracing methods revealed that DRDSh contains large numbers of neurons projecting to the basolateral amygdaloid nucleus, a forebrain structure important for emotional appraisal and modulation of anxiety-related physiological and behavioral responses. Together these findings support the hypothesis that there is a functional topographical organization in the DR and are consistent with the hypothesis that anxiogenic drugs have selective actions on a subpopulation of serotonergic neurons projecting to a distributed central autonomic and emotional motor control system regulating anxiety states and anxiety-related physiological and behavioral responses.

Adrenergic alpha-Antagonists↗

PubMed2005

Retigabine: chemical synthesis to clinical application.

Retigabine [D23129; N-(2-amino-4-(4-fluorobenzylamino)-phenyl)carbamic acid ethyl ester] is an antiepileptic drug with a recently described novel mechanism of action that involves opening of neuronal K(V)7.2-7.5 (formerly KCNQ2-5) voltage-activated K(+) channels. These channels (primarily K(V)7.2/7.3) enable generation of the M-current, a subthreshold K(+) current that serves to stabilize the membrane potential and control neuronal excitability. In this regard, retigabine has been shown to have a broad-spectrum of activity in animal models of electrically-induced (amygdala-kindling, maximal electroshock) and chemically-induced (pentylenetetrazole, picrotoxin, NMDA) epileptic seizures. These encouraging results suggest that retigabine may also prove useful in the treatment of other diseases associated with neuronal hyperexcitability. Neuropathic pain conditions are characterized by pathological changes in sensory pathways, which favor action potential generation and enhanced pain transmission. Although sometimes difficult to treat with conventional analgesics, antiepileptics can relieve some symptoms of neuropathic pain. A number of recent studies have reported that retigabine can relieve pain-like behaviors (hyperalgesia and allodynia) in animal models of neuropathic pain. Neuronal activation within several key structures within the CNS can also be observed in various animal models of anxiety. Moreover, amygdala-kindled rats, which have a lowered threshold for neuronal activation, also display enhanced anxiety-like responses. Retigabine dose-dependently reduces unconditioned anxiety-like behaviors when assessed in the mouse marble burying test and zero maze. Early clinical studies have indicated that retigabine is rapidly absorbed and distributed, and is resistant to first pass metabolism. Tolerability is good in humans when titrated up to its therapeutic dose range (600-1200 mg/day). No tolerance, dependence or withdrawal potential has been reported, although adverse effects can include mild dizziness, headache, nausea and somnolence. Thus, retigabine may prove to be useful in the treatment of a diverse range of disease states in which neuronal hyperexcitability is a common underlying factor.

Animals↗

PubMed2001

Modulation of the degree and pattern of methyl-esterification of pectic homogalacturonan in plant cell walls. Implications for pectin methyl esterase action, matrix properties, and cell adhesion.

Homogalacturonan (HG) is a multifunctional pectic polysaccharide of the primary cell wall matrix of all land plants. HG is thought to be deposited in cell walls in a highly methyl-esterified form but can be subsequently de-esterified by wall-based pectin methyl esterases (PMEs) that have the capacity to remove methyl ester groups from HG. Plant PMEs typically occur in multigene families/isoforms, but the precise details of the functions of PMEs are far from clear. Most are thought to act in a processive or blockwise fashion resulting in domains of contiguous de-esterified galacturonic acid residues. Such de-esterified blocks of HG can be cross-linked by calcium resulting in gel formation and can contribute to intercellular adhesion. We demonstrate that, in addition to blockwise de-esterification, HG with a non-blockwise distribution of methyl esters is also an abundant feature of HG in primary plant cell walls. A partially methyl-esterified epitope of HG that is generated in greatest abundance by non-blockwise de-esterification is spatially regulated within the cell wall matrix and occurs at points of cell separation at intercellular spaces in parenchymatous tissues of pea and other angiosperms. Analysis of the properties of calcium-mediated gels formed from pectins containing HG domains with differing degrees and patterns of methyl-esterification indicated that HG with a non-blockwise pattern of methyl ester group distribution is likely to contribute distinct mechanical and porosity properties to the cell wall matrix. These findings have important implications for our understanding of both the action of pectin methyl esterases on matrix properties and mechanisms of intercellular adhesion and its loss in plants.

Antibodies, Monoclonal↗

PubMed2001

Intrahippocampal infusion of antisense oligodeoxynucleotide to the GABA(A) receptor gamma2 subunit enhances neuropeptide Y gene expression.

The effects of hippocampal treatment with a phosphorothioate oligodeoxynucleotide (ODN) antisense to the gamma-aminobutyric acid (GABA)A receptor gamma2 subunit on neuropeptide Y (NPY) were studied. Adult male Wistar rats were treated with unilateral intrahippocampal infusion of gamma2 subunit antisense ODN for 5 days. Rats infused with mismatch ODN and naïve rats served as controls. Brain sections were analysed for levels of NPY mRNA by in situ hybridisation, NPY-immunoreactivity (NPY-ir) by means of immunocytochemistry, and specific NPY binding sites by in vitro receptor autoradiography. Following infusion of antisense ODN, a marked increase in cytoplasmic NPY-ir was observed in hilar neurones of the fascia dentata. Further, intense NPY-ir was visualised in the mossy fibres and in cell bodies of the entorhinal cortex and throughout the neocortex. High levels of NPY mRNA were detected in the same cortical areas of antisense treated rats. A very large increase was observed in the piriform and parietal areas. NPY gene expression also occurred in the granular cell layer, in which no NPY mRNA could be detected in normal animals. The level and distribution of cells displaying high levels of NPY mRNA differed among animals, perhaps as a result of the distinct anatomical location of ODN infusion. Finally, hippocampal levels of NPY specific binding increased, suggesting that NPY neurotransmission is markedly increased. These findings are reminiscent of reported changes in the expression of NPY mRNA and immunoreactivity in conditions of increased neuronal excitation and support the usefulness of the present animal model for the study of epileptic phenomena.

Animals↗

PubMed2001

Hypocretin (orexin) in the rat pineal gland: a central transmitter with effects on noradrenaline-induced release of melatonin.

Hypocretin-1 (HCRT-1) and hypocretin 2 (HCRT-2), also known as orexin-A and orexin-B, are two neuropeptides derived from the same precursor. Hypocretinergic neurons have been found exclusively in the hypothalamic dorsolateral area. These neurons are implicated in sleep and feeding through activation of specific G-protein-coupled orexin-1 and orexin-2 receptor (OR-R1 and OR-R2). The purpose of this study was to determine the existence of the HCRT peptides in the central input of the rat pineal gland. Further, OR-R1 and OR-R2 expression was determined in the pineal gland and the effect of HCRT-2 on melatonin synthesis and secretion was analysed in dissociated rat pinealocytes. A large contingent of HCRT-positive nerve fibres and terminals were observed in the epithalamus, many of which entered into the pineal parenchyma. A significant number of nerve fibres endowed with positive boutons were identified in the pineal stalk, though the number of positive fibres decreased along the extension of the stalk. So far, no positive fibres have been found in the superficial pineal gland. RT-PCR analysis revealed the expression of OR-R2 mRNA, whereas OR-R1-receptor mRNA was not detected. When tested alone, HCRT-2 had no effect on secretion of melatonin from cultured rat pinealocytes. However, HCRT-2 partially inhibited (by a maximum of 30%) the beta-adrenergic-induced melatonin secretion. The same effect was seen on activation of N-acetyltransferase activity. The distribution and the large number of HCRT-positive fibres together with the effect on noradrenaline-mediated melatonin release through specific receptors suggests that these peptides may be significant central transmitters in pineal function, probably mediating homeostatic signals to the pineal gland.

Acetyltransferases↗

PubMed2001

Chronic antidepressant treatments decrease pro-opiomelanocortin mRNA expression in the pituitary gland: effects of acute stress and 5-HT(1A) receptor activation.

Consistent findings in depressed patients are hyperactivity in the hypothalamic-pituitary-adrenal (HPA) axis with high plasma concentrations of adrenocorticotropic hormone and cortisol. Long-term antidepressant treatments seem to normalize this hyperactivity, suggesting a link between the HPA axis and the action of antidepressant treatments. The present study was carried out to study the effects of antidepressant treatments on pro-opiomelanocortin (POMC) mRNA expression, with a focus on interaction with acute stress and 5-HT(1A) receptor activation. Male rats were treated for 21 days with saline, citalopram, fluoxetine, moclobemide or desipramine, and the expression of POMC mRNA in the anterior pituitary was analysed by semi-quantitative in situ hybridization. All antidepressants, but not saline, cocaine and haloperidol, reduced POMC mRNA expression. The decrease in POMC mRNA was not observed until 9 days of citalopram treatment. Decreased POMC mRNA levels were also observed after 14 days of repeated electroconvulsive stimulation. The decreased POMC mRNA levels did not affect the stress-induced POMC mRNA increase, measured following swim stress and restraint stress. Finally, using Fos as a marker for neural activity, we showed attenuation of 8-OH-DPAT-stimulated activity in the paraventricular nucleus following 21 days of citalopram treatment. In conclusion, antidepressant treatments decrease basal POMC mRNA expression without affecting the acute stress response, and the reduced POMC mRNA may be related to reduced 5-HT(1A)-stimulated hypothalamic output.

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

PubMed2000

Analysis of pectic epitopes recognised by hybridoma and phage display monoclonal antibodies using defined oligosaccharides, polysaccharides, and enzymatic degradation.

The structure of epitopes recognised by anti-pectin monoclonal antibodies (mAbs) has been investigated using a series of model lime-pectin samples with defined degrees and patterns of methyl esterification, a range of defined oligogalacturonides and enzymatic degradation of pectic polysaccharides. In immuno-dot-assays, the anti-homogalacturonan (HG) mAbs JIM5 and JIM7 both bound to samples with a wide range of degrees of methyl esterification in preference to fully de-esterified samples. In contrast, the anti-HG phage display mAb PAM1 bound most effectively to fully de-esterified pectin. In competitive inhibition ELISAs using fully methyl-esterified or fully de-esterified oligogalacturonides with 3-9 galacturonic acid residues, JIM5 bound weakly to a fully de-esterified nonagalacturonide but JIM7 did not bind to any of the oligogalacturonides tested. Therefore, optimal JIM5 and JIM7 binding occurs where specific but undefined methyl-esterification patterns are present on HG domains, although fully de-esterified HG samples contain sub-optimal JIM5 epitopes. The persistence of mAb binding to epitopes in pectic antigens, with 41% blockwise esterification (P41) and 43% random esterification (F43) subject to fragmentation by endo-polygalacturonase II (PG II) and endo-pectin lyase (PL), was also studied. Time course analysis of PG II digestion of P41 revealed that JIM5 epitopes were rapidly degraded, but a low level of PAM1 and JIM7 epitopes existed even after extensive digestion, indicating that some HG domains were more resistant to cleavage by PG II. The chromatographic separation of fragments produced by the complete digestion of P41 by pectin lyase indicated that a very restricted population of fragments contained the PAM1 epitope while a (1-->4)-beta-D-galactan epitope occurring on the side chains of pectic polysaccharides was recovered in a broad range of fractions.

Antibodies, Monoclonal↗

PubMed2000

Analysis of different de-esterification mechanisms for pectin by enzymatic fingerprinting using endopectin lyase and endopolygalacturonase II from A. niger.

A series of pectins with different distribution patterns of methyl ester groups was produced by treatment with either plant (p-PME) or fungal pectin methyl esterases (f-PME) and compared with those obtained by base catalysed de-esterification. The products generated by digestion of these pectins with either endopectin lyase (PL) or endopolygalacturonase II (PG II) from Aspergillus niger were analysed using matrix assisted laser desorption ionisation mass spectrometry (MALDIMS) and high-performance anion-exchange chromatography with pulsed amperometric or UV detection (HPAEC-PAD/UV). Time course analysis using MALDIMS was used to identify the most preferred substrate for each enzyme. For PL, this was shown to be fully methyl esterified HG whereas for PG II, long regions of HG without any methyl esterification, as produced by p-PME was the optimal substrate. The blockwise de-esterification caused by p-PME treatment gave a decrease of partly methylated oligomers in PL fingerprints, which did not effect the relative composition of partly methylated oligomers. PG II fingerprints showed a constant increase of monomers and oligomers without any methyl ester groups with decreasing degree of esterification (DE), but almost no change in the concentration of partly methylated compounds. PL fingerprints of f-PME and chemically treated pectins showed decreasing amounts of partly methyl esterified oligomers with decreasing DE, together with a relative shift towards longer oligomers. PG II fingerprints were characterised by an increase of partly methylated and not methylated oligomers with decreasing DE. But differences were also seen between these two forms of homogenous de-esterification. Introduction of a certain pattern of methyl ester distribution caused by selective removal of certain methyl ester groups by f-PME is the most reasonable explanation for the detected differences.

Aspergillus niger↗

PubMed2000

Quantification of the amount of galacturonic acid residues in blocksequences in pectin homogalacturonan by enzymatic fingerprinting with exo- and endo-polygalacturonase II from Aspergillus niger.

A method to determine the amount of galacturonic acid in blocksequence (BS) in pectin homogalacturonan (HG) is described. The method is based on a combination of endopolygalacturonase II (endo-PG II) and exopolygalacturonase (exo-PG) digestion followed by quantification of the liberated galacturonic acid monomer. The amount of monomers released is directly related to the amount of non-esterified galacturonic acid units located between two other non-esterified galacturonic acids units on the HG chain. The amount released for exo-PG digestion only corresponds to the BS located at the non-reducing end of the polymer. The difference between total- and exo-BS was calculated to be the amount of endo-BS located either within or on the reducing end of the HG. Three series of model pectins obtained by de-esterification of a high-ester pectin with either plant pectin methyl-esterase (p-PME, P-series), fungal pectin methyl-esterase (f-PME, F-series) and chemical de-esterification using base (B-series) were analysed and compared with a fully de-esterified pectic acid sample obtained from the same raw material. Clear differences for the increase of the amounts of blocksequence could be seen between de-esterification of the P- and F-series samples supporting a blockwise and a homogenous de-esterification mechanism, respectively. f-PME and base treatment showed only minor differences in the increase of galacturonic acid units in BS, despite differences seen in their methyl-esterification pattern. Differences between the amounts of galacturonic acid located in exo- and endo-BS, provided evidence for the need of a certain start side or blocklength for p-PME to de-esterify blockwise.

Aspergillus niger↗

PubMed2000

Involvement of hippocampal neuropeptide Y in mediating the chronic actions of lithium, electroconvulsive stimulation and citalopram.

Neuropeptide Y (NPY) has been considered to be involved in the pathogenesis of affective disorders, and chronic treatment with lithium or electroconvulsive stimuli (ECS) has been shown to increase mRNA and peptide levels of NPY in rat brain tissue. Consequently, parameters reflective of NPYergic neurotransmission were studied in the hippocampus of rats following chronic treatment with lithium, ECS or the selective serotonin re-uptake inhibitor (SSRI), citalopram. Lithium (28 days, diet) and ECS (10 days, once daily) treatments caused a marked increase in levels of preproNPY mRNA in the CA1 area and dentate gyrus (DG). This increase was accompanied by an increase in extracellular levels of NPY in the dorsal hippocampus of freely moving rats as determined by microdialysis, suggesting that lithium and ECS treatments lead to an increased biosynthesis and release of NPY in this area. (125)I-peptide YY (PYY) binding was reduced by 40 and 60% respectively in the DG following the same treatments, showing that the increased release is accompanied by a down-regulation of corresponding binding sites. In contrast, citalopram (10 mg/kg i.p., twice daily for 28 days) caused a 100% increase in (125)I-PYY binding in CA, CA3 and DG while levels of preproNPY mRNA and extracellular NPY in the hippocampus were unaffected. The results indicate that various agents and stimuli exerting antidepressant effects in humans, such as chronic lithium, ECS and citalopram all increase NPYergic neurotransmission in the hippocampus by distinct modes of action. Moreover, NPY (6 microg) given intracerebroventricularly (i.c.v.) induced an antidepressant-like effect in the forced swim test. It is hypothesised that the increase in NPYergic neurotransmission may be associated with the mechanism of action of various antidepressant treatments in the alleviation of depression.

Animals↗

PubMed2000

Electroconvulsive stimuli enhance both neuropeptide Y receptor Y1 and Y2 messenger RNA expression and levels of binding in the rat hippocampus.

Repeated electroconvulsive stimulations and other seizure modalities produce an increase in neuropeptide Y synthesis and local release in the rat hippocampus, and perhaps as a consequence, a change in the concentration of neuropeptide Y binding sites in the same region. The aim of the present study was to determine possible changes in the expression of neuropeptide Y receptor subtypes affected by repeated stimulations in the hippocampus. Rats were exposed to 14 daily stimulations, and the brains were removed 24h after the last stimulation. For in vitro receptor autoradiography and in situ hybridisation histochemistry, the brains were frozen, sectioned, and levels of neuropeptide Y binding sites and messenger RNA expressions were determined quantitatively on sections from the same animals. In order to determine the contribution of different neuropeptide Y receptor subtypes, serial sections were incubated with either 125I-labelled peptide YY alone or the same radio-labelled peptide mixed with an excess of a number of displacing compounds with affinity for either neuropeptide Y receptor subtype Y1, Y2, or both. Binding studies revealed that the majority of peptide YY binding sites was represented by Y2, and that electroconvulsive stimulations reduced the binding capacity or the concentration of this receptor. A prominent reduction of Y1-preferring binding sites was determined in the dentate gyrus, and to a lesser extent in the CA1 and CA3 regions. Similarly, the treatment produced a significant reduction of Y2-preferring binding sites in the CA1 and CA3 region, but not in the granular cell layer of the dentate gyrus. Using semi-quantitative in situ hybridization, Y1 receptor messenger RNA level in the granular cell layer of the dentate increased by the stimulations. In the same region, Y2 receptor messenger RNA was expressed in low to undetectable amounts, but after the repeated stimulations, this transcript was found in moderate to high levels. These data suggest that the neuropeptide Yergic system in the dentate gyrus and the pyramidal cell layer are affected by the treatment, and that this includes both Y1 and Y2 receptor subtypes. Because levels of messenger RNA and binding are distinctly regulated, the turnover of both Y1 and Y2 molecules is strongly increased under electroconvulsive stimulations, suggesting that the intrahippocampal neuropeptide Yergic neurotransmission is also increased under the stimulations.

Animals↗

PubMed2000

Increased adenylyl cyclase type 1 mRNA, but not adenylyl cyclase type 2 in the rat hippocampus following antidepressant treatment.

The adenylyl cyclase (AC) system is affected by several types of antidepressant treatments, and increased activity in this system is linked to the therapeutic action of antidepressants. The present study was undertaken to compare the effects of single-dose and long-term treatment with the selective serotonin reuptake inhibitor, citalopram (10 mg/kg, i.p.), on the AC system in the male rat brain of Wistar rats. Furthermore, we compared the effects of long-term citalopram and lithium treatments on the AC system. Long-term citalopram, but not single-dose administration, increased the AC type 1 mRNA in the hippocampus, whereas type 2 mRNA was unaffected. Long-term lithium treatment also increased AC1 in the hippocampus. However, long-term citalopram treatment did not increase AC type 1 protein, basal or forskolin-stimulated AC activity, but GTP increased AC activity in the hippocampus. This may indicate enhanced AC/G protein coupling. Thus, citalopram may increase cAMP signalling by acting on components of the AC system without affecting the protein level of the AC type 1.

Adenylyl Cyclases↗

PubMed1999

D-fenfluramine activates rat oxytocinergic and vasopressinergic neurons through different mechanisms.

Activation of serotonin neurotransmission produces increase of plasma oxytocin, prolactin, vasopressin and ACTH levels. Using dual-immunocytochemistry, the number of oxytocinergic neurons in the hypothalamic magnocellular nuclei co-storing Fos after administration of D-fenfluramine was found to be 15-fold higher compared to vehicle, comprising about 30% of the total number of these neurons. Vasopressinergic neurons were virtually not affected. These results show that serotonergic neurotransmission induces Fos transcription in oxytocinergic neurons that may lead to a release of oxytocin to the general circulation, whereas vasopressinergic neurons are activated through another mechanism.

Animals↗

PubMed1999

Kainic acid seizure suppression by neuropeptide Y is not correlated to immediate early gene mRNA levels in rats.

Kainic acid induces seizures and a rapid induction of immediate early genes and neuronal death. Neuropeptide Y (NPY) is implicated in seizure inhibiting activity. In order to investigate the mechanisms by which NPY inhibits seizure activity, this study was carried out to measure the levels of mRNAs encoding three different immediate early genes, in regions of the hippocampus and relate their induction to the behaviour in the same animals. NPY inhibited both the time spent in seizures, and the number of generalized seizures. However, NPY did not inhibit the induction of c-fos, FosB or junB mRNA in any hippocampal region examined in the same animals, showing lack of correlation between immediate early gene induction and seizure activity.

Animals↗