Fluoxetine-induced conditioned place preference: a preliminary study.
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Animals↗
Biomedical subjects
L Pani
Publications and source records attributed to L Pani.
Circulating levels of anticonvulsant metabolites of progesterone in women with partial epilepsy in the intercritical phase.
The 3alpha-hydroxy metabolites of progesterone (P), 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone, A-PREG) and 3alpha-hydroxy-5beta-pregnan-20-one (pregnanolone, PREG), have been found to be among the most potent ligands of gamma-aminobutyric (GABA)-A receptors; in experimental animals, they have been found to have anxiolytic, hypnotic and anticonvulsant effects. Similar to those of the benzodiazepines and barbiturates that interact with GABA-A receptors. The present study was undertaken to determine plasma A-PREG and PREG concentrations in the luteal phase in women with partial epilepsy, in order to determine if an impaired metabolism of P occurs in this convulsive disorder. We measured plasma P, A-PREG and PREG levels in 15 women with partial epilepsy in the intercritical phase, and in 15 age-matched healthy women, during the luteal phase of the ovarian cycle (22nd-24th day). The mean plasma +/- S.E. A-PREG levels (three blood samples) were 0.7 +/- 0.6 ng/ml in the epileptic women and 0.5 +/- 0.2 ng/ml in controls, with no significant difference between the two groups (p = NS); the PREG levels were also similar (1.4 +/- 1 ng/ml and 1 +/- 1.1 ng/ml, respectively: p = NS). A significant correlation was found between P levels and both A-PREG and PREG levels (r = 0.72, p < 0.001 and r = 0.79, p < 0.001, respectively). There were no significant differences between the two groups in terms of serum adrenocorticotropic hormone, cortisol, dihydroepiandrosterone-sulfate, follicle stimulating hormone, prolactin, luteinizing hormone or estradiol levels.
Adolescent↗
Correlation between increased AP-1NGF binding activity and induction of nerve growth factor transcription by multiple signal transduction pathways in C6-2B glioma cells.
Transcription mechanisms regulating nerve growth factor (NGF) gene expression in the CNS are yet to be thoroughly understood. We have used C6-2B rat glioma cells to characterize the signal transduction pathways that contribute to transcriptional and posttranscriptional regulation of NGF mRNA. Because the NGF promoter contains an AP-1 consensus sequence, we have investigated whether increases in AP-1 binding activity correlate with enhanced NGF mRNA expression. Gel mobility shift assays using an oligonucleotide homologous to the AP-1 responsive element of the rat NGF gene (AP-1NGF) revealed that 12-O-tetradecanoyl phorbol-13-acetate (TPA) and, to a lesser extent, isoproterenol (ISO) and thapsigargin, a microsomal Ca(2+)-ATPase inhibitor, stimulated binding to AP-1NGF within 2 h. All of these stimuli increased NGF mRNA levels within 3 h. Cycloheximide pretreatment blocked the TPA and ISO-mediated binding to AP-1NGF suggesting that de novo synthesis of c-Fos/c-Jun may be required for the transcriptional regulation of NGF gene. Nuclear run-on assays and NGF mRNA decay studies revealed that TPA increases NGF transcription whereas ISO affects both transcription and mRNA stabilization. We propose that (i) different signal transduction mechanisms regulate the expression of the NGF gene in cells derived from the CNS, and (ii) both mRNA transcription and stability account for the cAMP-mediated increase in NGF mRNA levels.
Animals↗
Chronic imipramine, L-sulpiride and mianserin decrease corticotropin releasing factor levels in the rat brain.
Among clinically effective antidepressant drugs, the action mechanism of mianserin has recently been related to variations in corticotropin releasing factor (CRF) levels in the rat locus coeruleus. We describe a specific effect on CRF levels after chronic treatment with different antidepressants: mianserin (10 mg/kg), imipramine (20 mg/kg), both for 21 days, or L-sulpiride (1 mg/kg) for 15 days. While all antidepressants used greatly decreased CRF concentrations in the hypothalamus, only mianserin decreased CRF concentrations by 40% in extrahypothalamic sites. Acute treatments failed to modify CRF levels. Chronic treatment with mianserin did not affect CRF density either in the hypothalamus or the extrahypothalamic areas. This new finding may add another facet to the therapeutic action of certain antidepressants and in particular to the atypical profile of mianserin.
Animals↗
Sleep deprivation in the rat: an animal model of mania.
The model of sleep deprivation in rats by the platform method has been extensively studied in our laboratory as a possible animal model of mania. At the end of the period of sleep deprivation, the rat does not fall asleep as soon as it is returned to its home cage, but shows a period of wakefulness of about 30 min, during which the animal presents a cohort of symptoms that appear to mimic those present in idiopathic mania. In particular, during this period the animal displays insomnia, a high degree of hyperactivity, irritability, aggressiveness, hypersexuality and stereotypy. Haloperidol (0.2 mg/kg) was effective in reducing latency to sleep, while L-sulpiride was much weaker (< 50 mg/kg). The dopamine D1 receptor antagonist SCH 23390 exhibited an extremely high potency and efficacy in reducing sleep latency, a significant effect being observed with 3 micrograms/kg. The administration of the specific D1 receptor agonist SKF 38393 markedly prolonged the period of insomnia with the correlated behavioral syndrome. When lithium was added to the diet and consumed during the sleep deprivation period in adequate amounts to produce serum lithium levels of 0.7-1.0 mEq/l, sleep latency and locomotor activity were significantly reduced. The administration of naloxone (1-10 mg/kg) reduced the latency to sleep in a dose-related manner. By contrast, morphine (1 and 5 mg/kg, i.p.), beta-endorphin and [D-Ala2,D-Leu5]enkephalin (i.c.v., 2 and 1 micrograms, respectively) markedly prolonged the insomnia. The model not only represents a confirmation in the rat that sleep loss often precedes and may trigger a manic episode in man, but suggests that an opioid-dopamine interaction may play a pathogenetic role in mania.
Animals↗
Cytokine regulation of the liver transcription factor hepatocyte nuclear factor-3 beta is mediated by the C/EBP family and interferon regulatory factor 1.
Three distinct hepatocyte nuclear factor-3 (HNF-3) proteins (alpha, beta, and gamma) regulate the transcription of numerous liver-enriched genes. The HNF-3 proteins bind DNA via a homologous winged helix motif common to a number of proteins known to be critical for determination events in embryogenesis. We have demonstrated previously that two binding sites in the -184 HNF-3 beta promoter are recognized by widely distributed factors and that there is also a critical autoregulatory site, we identified a binding site for a cell-specific factor, LF-H3 beta, that may function in restricting HNF-3 beta gene expression to hepatocytes. Our present study demonstrates that members of the C/EBP and proline and acidic amino acid-rich subfamilies of basic region leucine zipper transcription factors bind the LF-H3 beta site, and cotransfection of HepG2 cells shows that these factors are able to activate an HNF-3 beta promoter reporter construct. The LF-H3 beta-C/EBP binding sequence also confers HNF-3 beta promoter stimulation in response to interleukin (IL)-1 and IL-6. Upstream of this HNF-3 beta proximal promoter region, an IFN-stimulated response element core sequence (-231 to -210) was found that mediates transcriptional induction by IFN-gamma but not IFN-alpha. Gel mobility supershift assay demonstrates that an IFN-gamma-induced protein-DNA complex is disrupted by an antibody specific for interferon regulatory factor-1/interferon-stimulated gene factor-2. Consistent with this finding, we observed that IFN-gamma induction requires ongoing protein synthesis. Surprisingly, the effect of the three cytokines (IL-1, IL-6, and IFN-gamma) in combination as assayed by the same model is not synergistic. HNF-3beta joins the C/EBP family on the list of liver-enriched transcription factors, the expression of which is modulated by cytokines.
Base Sequence↗
The long term prophylaxis of affective disorders.
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Adult↗
[Anxious-excited depression: a mixed affective syndrome].
A mixed affective syndrome is described which meets the criteria for major depression but not those of the DSM III-R for a mixed state. The clinical picture is characterized by lack of motor retardation and fluent verbalization; the facial expression is animated and sometimes dramatic. Patients suffer considerably and are often tearful. They complain of inner tension and restlessness, racing thoughts and despair. Emotional lability and momentary irritability are observed. Insomnia occurs initially or with frequent early waking. Suicidal ideation occurs and makes the syndrome of concern in view of its impulsive nature. Antidepressants increase restlessness, insomnia, aggressiveness and the impulsiveness of suicidal ideation. Low-dose neuroleptics, lithium and anticonvulsivants are highly effective. A few sessions of ECT offer rapid improvement.
Anxiety Disorders↗
Pharmacology of neurosteroid biosynthesis. Role of the mitochondrial DBI receptor (MDR) complex.
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Animals↗
Antidepressant-like effect of selective dopamine D1 receptor agonists in the behavioural despair animal model of depression.
We compared the effect of two selective dopamine D1 receptor agonists, SKF 38393 ((+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol.HCl) and A68930 ((1R,3S)-1-aminomethyl-5,6-dihydroxy-3-phenylisochroman.HCl), and that of imipramine in the behavioural despair model of depression. The dopamine D1 receptor agonists and imipramine showed an anti-immobility effect. Moreover we found that the 'antidepressant' effect of imipramine in the behavioural despair test was antagonized by SCH 23390, a selective dopamine D1 receptor blocker. The results further support the hypothesis that dopamine D1 receptor stimulation plays an important role in the mechanism of action of antidepressants and suggest that dopamine D1 receptor agonists might be considered as potential antidepressant drugs.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Cloning and tissue-specific functional characterization of the promoter of the rat diazepam binding inhibitor, a peptide with multiple biological actions.
Diazepam binding inhibitor (DBI) is a 10-kDa polypeptide that regulates mitochondrial steroidogenesis, glucose-induced insulin secretion, metabolism of acyl-CoA esters, and the action of gamma-aminobutyrate on GABAA receptors. To investigate the regulation of DBI gene expression, three positive clones were isolated from a rat genomic library. One of them contained a DBI genomic DNA fragment encompassing 4 kb of the 5' untranslated region, the first two exons, and part of the second intron of the DBI gene. Two other overlapping clones contained a processed DBI pseudogene. Several transcription initiation sites were detected by RNase protection and primer extension assays. Different tissues exhibited clear differences in the efficiencies of transcription startpoint usage. Transient expression experiments using DNA fragments of different length from the 5' untranslated region of the DBI gene showed that basal promoter activity required 146 bp of the proximal DBI sequence, whereas full activation was achieved with 423 bp of the 5' untranslated region. DNase I protection experiments with liver nuclear proteins demonstrated three protected regions at nt -387 to -333, -295 to -271, and -176 to -139 relative to the ATG initiation codon; in other tissues the pattern of protection was different. In gel shift assays the most proximal region (-176 to -139) was found to bind several general transcription factors as well as cell type-restricted nuclear proteins which may be related to specific regulatory patterns in different tissues. Thus, the DBI gene possesses some features of a housekeeping gene but also includes a variable regulation which appears to change with the function that it subserves in different cell types.
Animals↗
Identification of nine tissue-specific transcription factors of the hepatocyte nuclear factor 3/forkhead DNA-binding-domain family.
Hepatocyte nuclear factor (HNF)-3 alpha, -3 beta, and -3 gamma are liver transcription factors that mediate the coordinate expression of a number of hepatocyte-specific genes. The HNF-3 proteins share DNA-binding-domain homology among themselves and with the Drosophila homeotic protein forkhead (fkh). The HNF-3/fkh DNA-binding domain constitutes an uncharacterized protein motif that recognizes its cognate DNA binding site as a monomer. Additional HNF-3/fkh-related proteins are known to be required for determination events during embryogenesis in Drosophila and Xenopus. In this report, we describe the isolation of nine additional HNF-3/fkh homologue (HFH) clones from rodent tissue cDNAs by using both low-stringency hybridization and a polymerase chain reaction protocol. Many of the HFH genes exhibit a tissue-restricted expression pattern and are transcribed in tissues other than liver, including brain, kidney, lung, and intestine. The HNF-3/fkh motif therefore comprises a large gene family of transcription factors that play a role in tissue-specific gene regulation and development.
Amino Acid Sequence↗
ACTH-induced mitochondrial DBI receptor (MDR) and diazepam binding inhibitor (DBI) expression in adrenals of hypophysectomized rats is not cause-effect related to its immediate steroidogenic action.
Diazepam binding inhibitor (DBI) is a 10-kDa polypeptide that is enriched in steroidogenic cells such as adrenocortical, Leydig, and glial cells. In these cells, DBI and some of its processing products bind to the mitochondrial DBI receptor (MDR), located on the outer mitochondrial membrane, and stimulate pregnenolone formation by facilitating cholesterol access to the inner mitochondrial membrane where the cytochrome P-450 side chain cleavage enzyme is located. To determine whether the ACTH-induced increase in adrenal steroidogenesis occurs via changes in DBI and MDR expression the adrenal content of DBI-like immunoreactivity (DBI-LI), the MDR density, and the expression of mRNAs encoding for DBI and MDR were studied in hypophysectomized rats treated with vehicle or ACTH. After 9 days from the hypophysectomy, the levels of DBI-like immunoreactivity (DBI-LI) and DBI-mRNA declined to approximately 20% of their normal value; in contrast MDR-density and MDR-mRNA levels were reduced by 50-60% and were associated to a similar decrease in the activity of type A monoamine oxidase, a marker for mitochondrial proteins. Prolonged administration of ACTH-R (ACTH in saline containing 16% gelatin, 15 U/kg/day, from day 7 after surgery) to hypophysectomized rats, completely restored DBI and MDR adrenal expression to values similar to those of sham-operated rats. Our results indicate that ACTH, probably acting at the transcriptional level, is required for the normal expression of DBI and MDR in adrenal cortex. Changes in DBI and MDR expression after ACTH administration were not temporally related to the immediate steroidogenesis induced by ACTH, and may reflect its long-term trophic action on adrenocortical cells.
Adrenal Glands↗
The restricted promoter activity of the liver transcription factor hepatocyte nuclear factor 3 beta involves a cell-specific factor and positive autoactivation.
The transcription factor hepatocyte nuclear factor 3 (HNF-3) is involved in the coordinate expression of several liver genes. HNF-3 DNA binding activity is composed of three different liver proteins which recognize the same DNA site. The HNF-3 proteins (designated alpha, beta, and gamma) possess homology in the DNA binding domain and in several additional regions. To understand the cell-type-specific expression of HNF-3 beta, we have defined the regulatory sequences that elicit hepatoma-specific expression. Promoter activity requires -134 bp of HNF-3 beta proximal sequences and binds four nuclear proteins, including two ubiquitous factors. One of these promoter sites interacts with a novel cell-specific factor, LF-H3 beta, whose binding activity correlates with the HNF-3 beta tissue expression pattern. Furthermore, there is a binding site for the HNF-3 protein within its own promoter, suggesting that an autoactivation mechanism is involved in the establishment of HNF-3 beta expression. We propose that both the LF-H3 beta and HNF-3 sites play an important role in the cell-type-specific expression of the HNF-3 beta transcription factor.
Base Sequence↗
Hepatocyte nuclear factor 3 beta contains two transcriptional activation domains, one of which is novel and conserved with the Drosophila fork head protein.
The hepatocyte nuclear factor 3 (HNF-3) gene family is composed of three proteins (alpha, beta, and gamma) that are transcription factors involved in the coordinate expression of several liver genes. All three proteins share strong homology in their DNA binding domains (region I) and are able to recognize the same DNA sequence. They also possess two similar stretches of amino acids at the carboxyl terminus (regions II and III) and a fourth segment of homology at the amino terminus (region IV). Furthermore, the HNF-3 proteins demonstrate homology with the Drosophila homeotic gene fork head in regions I, II, and III, suggesting that HNF-3 may be its mammalian homolog. In order to define HNF-3 beta protein domains involved in transcriptional activation, we have used a reporter gene, whose transcription is dependent on HNF-3 binding, for hepatoma cell cotransfection assays with expression vectors that produced different truncated HNF-3 beta proteins. A position-independent activation domain which contained conserved regions II and III was identified at the carboxyl terminus of the HNF-3 beta protein (amino acids 361 to 458). Moreover, site-directed mutations that altered the sequences within regions II and III demonstrated their importance to transactivation. The region II-III domain does not possess amino acid sequences in common with other transcription factors and may define a novel activation motif. HNF-3 beta amino-terminal sequences defined by conserved region IV also contributed to transactivation, but region IV activity required the participation of the region II-III domain. Region IV is abundant in serine amino acids and contains two putative casein kinase I phosphorylation sites, a feature similar to protein motifs described for the transcription factors Pit-1/GHF-1 and HNF-1.
Amino Acid Sequence↗
Inhibition of [3H]dopamine uptake by flunarizine.
The effect of different calcium channel blockers was studied on basal and cocaine-inhibited [3H]dopamine uptake in rat striatal synaptosomes. Isradipine (dihydropyridine calcium antagonist) and diltiazem (L-type calcium antagonist) were devoid of effect on [3H]dopamine uptake, while flunarizine (T-type calcium antagonist) inhibited [3H]dopamine uptake. Flunarizine inhibition was competitive and the inhibitory curve was biphasic with a Hill coefficient of 2.1. The high Hill number suggested a mechanism of positive cooperativity between two sites. Flunarizine inhibition showed a complex interaction with cocaine inhibition. While flunarizine at low concentrations interacts with a distinct site, at higher concentrations it interacts with the same site as cocaine. The relevance of this finding for the potentiation by flunarizine of cocaine-induced dopamine release in vivo is discussed.
Animals↗
The calcium antagonist PN 200-110 inhibits the reinforcing properties of cocaine.
The effect of a dihydropyridine (DHP) calcium antagonist, PN 200-110, on cocaine reinforcing properties was investigated using conditioned place preference paradigm. PN 200-110 in nonsedative doses (0.62-1.25-2.5 mg/kg SC) was able to inhibit cocaine-(10 mg/kg IP) induced place preference with ED50 1.57 (0.88-2.58). The results suggest a possible use of DHPs in the treatment of cocaine-related disorders.
Animals↗