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Patrizia Romualdi - One of the best experts on this subject based on the ideXlab platform.
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different alcohol exposures induce selective alterations on the expression of dynorphin and nociceptin systems related genes in rat brain
Addiction Biology, 2013Co-Authors: Sanzio Candeletti, Claudio Daddario, Francesca Felicia Caputi, Roberto Rimondini, Ottavio Gandolfi, Elia Del Borrello, Patrizia RomualdiAbstract:Molecular mechanisms of adaptive transformations caused by alcohol exposure on opioid dynorphin and nociceptin systems have been investigated in the rat brain. Alcohol was intragastrically administered to rats to resemble human drinking with several hours of exposure: water or alcohol (20% in water) at a dose of 1.5 g/kg three times daily for 1 or 5 days. The development of tolerance and dependence were recorded daily. Brains were dissected 30 minutes (1- and 5-day groups) or 1, 3 or 7 days after the last administration for the three other 5-day groups (groups under withdrawal). Specific alterations in opioid genes expression were ascertained. In the amygdala, an up-regulation of Prodynorphin and pronociceptin was observed in the 1-day group; moreover, pronociceptin and the kappa opioid receptor mRNAs in the 5-day group and both peptide precursors in the 1-day withdrawal group were also up-regulated. In the prefrontal cortex, an increase in prodynorhin expression in the 1-day group was detected. These data indicate a relevant role of the dynorphinergic system in the negative hedonic states associated with multiple alcohol exposure. The pattern of alterations observed for the nociceptin system appears to be consistent with its role of functional antagonism towards the actions of ethanol associated with other opioid peptides. Our findings could help to the understanding of how alcohol differentially affects the opioid systems in the brain and also suggest the dynorphin and nociceptin systems as possible targets for the treatment and/or prevention of alcohol dependence.
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ethanol and acetaldehyde exposure induces specific epigenetic modifications in the Prodynorphin gene promoter in a human neuroblastoma cell line
The FASEB Journal, 2011Co-Authors: Sanzio Candeletti, Patrizia Romualdi, Lars Terenius, Claudio Daddario, Sofia Johansson, Sven Ove Ogren, Tomas J EkstromAbstract:Ethanol alters neural activity through interaction with multiple neurotransmitters and neuromodulators. The endogenous opioid system seems to play a key role, since the opioid receptor antagonist naltrexone (ReVia®) attenuates craving for alcohol. We recently reported that ethanol and acetaldehyde, the first product of ethanol metabolism, affect transcription of opioid system genes in human SH-SY5Y neuroblastoma cells. In the current study, potential epigenetic mechanisms were investigated to clarify these effects on Prodynorphin gene expression. DNA methylation was analyzed by bisulfite pyrosequencing, and chromatin immunoprecipitation was used to assess putative specific histone modifications at the Prodynorphin gene promoter. The results demonstrated a temporal relationship between selective chromatin modifications induced by ethanol and acetaldehyde and changes in Prodynorphin gene expression quantitated by real-time qPCR. DNA methylation was not altered in any of the experimental conditions used. The epigenetic changes may precede gene transcription, and histone modifications might keep the Prodynorphin gene in a poised state for later reactivation. A link has been observed between gene expression alterations and selective epigenetic modulation in the Prodynorphin promoter region, demonstrating a specificity of the changes induced by ethanol and acetaldehyde. The latter may be mediating ethanol effects at the genomic level.
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Alterations in Prodynorphin gene expression and dynorphin levels in different brain regions after chronic administration of 14-methoxymetopon and oxycodone-6-oxime.
Brain research bulletin, 2006Co-Authors: Kornél Király, Pál Riba, Claudio D'addario, M. Di Benedetto, Daniela Landuzzi, Sanzio Candeletti, Patrizia Romualdi, Susanna FürstAbstract:Previous studies showed that opioid drugs-oxycodone-6-oxime and 14-methoxy-5-methyl-dihydromorphinone (14-methoxymetopon)-produced less respiratory depressive effect and slower rate of tolerance and dependence, respectively. It was also reported that morphine decreased the Prodynorphin gene expression in the rat hippocampus, striatum and hypothalamus. In this study, we determined the Prodynorphin gene expression and dynorphin levels in selected brain regions of opioid tolerant rats. We found that in the striatum morphine decreased, while oxycodone-6-oxime increased and 14-methoxymetopon did not alter the Prodynorphin gene expression. In the nucleus accumbens, morphine and oxycodone-6-oxime did not change, while 14-methoxymetopon increased the Prodynorphin gene expression. In the hippocampus both oxycodone-6-oxime and 14-methoxymetopon enhanced, whereas morphine did not alter the Prodynorphin gene expression. In the rat striatum only oxycodone-6-oxime increased dynorphin levels significantly in accordance with the Prodynorphin mRNA changes. In the hippocampus both opioid agonists increased the dynorphin levels significantly similarly to the augmented Prodynorphin gene expression. In ventral tegmental area only 14-methoxymetopon increased dynorphin levels significantly. In nucleus accumbens and the temporal-parietal cortex the changes in the Prodynorphin gene expression and the dynorphin levels did not correlate. Since the endogenous Prodynorphin system may play a modulatory role in the development of opioid tolerance, the elevated supraspinal dynorphin levels appear to be partly responsible for the reduced degree of tolerance induced by the investigated opioids.
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Effects of prolonged treatment with the opiate tramadol on Prodynorphin gene expression in rat CNS.
Journal of molecular neuroscience : MN, 2006Co-Authors: Sanzio Candeletti, Giuseppe Lopetuso, Rosalia Cannarsa, Chiara Cavina, Patrizia RomualdiAbstract:A low abuse liability is reported for tramadol, an analgesic drug centrally acting through either opioid or nonopioid mechanisms. In this paper, we evaluated the effects of the repeated administration (7 d) of different doses of tramadol (10, 20, and 80 mg/kg, intraperitoneally) on the opioid precursor Prodynorphin biosynthesis, in comparison with morphine (10 mg/kg, intraperitoneally), in the rat central nervous system (CNS). Northern analysis showed that morphine and tramadol produced different effects. While morphine caused a down-regulation of Prodynorphin mRNA levels in all investigated areas (hypothalamus, hippocampus, and striatum), tramadol did not cause any significant change in the striatum, and did not decrease Prodynorphin biosynthesis in the hypothalamus and in the hippocampus, at nontoxic doses (10 and 20 mg/kg). The highest dose of tramadol (80 mg/kg) decreased Prodynorphin mRNA levels in the hypothalamus and the hippocampus but not in the striatum. These data give some information on tramadol effects at molecular level in the CNS. They indicate that the alterations of Prodynorphin gene expression caused by tramadol and morphine show a different pattern that may be related to the different abuse potential of the two analgesic drugs.
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Role of serotonin on cocaine-mediated effects on Prodynorphin gene expression in the rat brain
Journal of molecular neuroscience : MN, 2004Co-Authors: Manuela Di Benedetto, Claudio D'addario, Sanzio Candeletti, Sari Izenwasser, Stephanie L. Collins, Patrizia RomualdiAbstract:The effect of the selective serotonin uptake inhibitor fluoxetine was examined on Prodynorphin gene expression. Fluoxetine or vehicle was infused continuously for 7 d via osmotic minipumps into male rats. Northern blot analysis showed significant increases in Prodynorphin gene expression in the hypothalamus (171% of controls) and significant decreases in the caudate putamen and nucleus accumbens (62% and 70% of controls, respectively). There were no significant changes in the hippocampus. Thus, chronic inhibition of serotonin uptake can regulate Prodynorphin gene expression in the hypothalamus, caudate putamen, and nucleus accumbens. Fluoxetine effects were also evaluated in rats treated with p-chloroamphetamine (PCA), a neurotoxin that depletes serotonin. Because we previously reported that continuous infusion of cocaine for 7 d (which inhibits dopamine, serotonin, and norepinephrine uptake), or GBR 12909 (a selective dopamine uptake inhibitor), produced significant decreases in the hypothalamus and cocaine also produced a significant increase in Prodynorphin gene expression in caudate putamen, regulation of Prodynorphin gene expression by fluoxetine is suggested to be different from that by cocaine. Because neither a selective dopamine uptake inhibitor nor a selective serotonin uptake inhibitor produced the same effect as cocaine in the caudate putamen, this effect is likely regulated by the inhibition of norepinephrine uptake, by a combination of effects on two or three neurotransmitter transporters, or by a mechanism unrelated to transporter inhibition.
Carlo Ventura - One of the best experts on this subject based on the ideXlab platform.
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opioid peptide gene expression primes cardiogenesis in embryonal pluripotent stem cells
Circulation Research, 2000Co-Authors: Carlo Ventura, Margherita MaioliAbstract:Abstract —Zinc finger–containing transcription factor GATA-4 and homeodomain Nkx-2.5 govern crucial developmental fates and have been found to promote cardiogenesis in embryonic cells exposed to the differentiating agent DMSO. Nevertheless, intracellular activators of these transcription factors are largely unknown. In this study, pluripotent P19 cells expressed the Prodynorphin gene, an opioid gene encoding for the dynorphin family of opioid peptides. P19 cells were also able to synthesize and secrete dynorphin B, a biologically active end product of the Prodynorphin gene. DMSO-primed GATA-4 and Nkx-2.5 gene expression was preceded by a marked increase in Prodynorphin gene expression and dynorphin B synthesis and secretion. The DMSO effect occurred at the transcriptional level. In the absence of DMSO, dynorphin B triggered GATA-4 and Nkx-2.5 gene expression and led to the appearance of both α-myosin heavy chain and myosin light chain-2V transcripts, two markers of cardiac differentiation. Moreover, dynorphin B–exposed cells were positively stained in the presence of MF 20, a mouse monoclonal antibody raised against the α-myosin heavy chain. Opioid receptor antagonism and inhibition of opioid gene expression by a Prodynorphin antisense phosphorothioate oligonucleotide blocked DMSO-induced cardiogenesis, suggesting an autocrine role of an opioid gene in developmental decisions.
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Opioid Peptide Gene Expression in the Primary Hereditary Cardiomyopathy of the Syrian Hamster II. ROLE OF INTRACELLULAR CALCIUM LOADING
Journal of Biological Chemistry, 1997Co-Authors: Carlo Ventura, Gianfranco Pintus, Bruna TadoliniAbstract:Abstract We have previously shown that Prodynorphin gene expression was markedly increased in adult myocytes of BIO 14.6 cardiomyopathic hamsters and that nuclear protein kinase C (PKC) may be involved in the induction of this opioid gene. Here we report that the cytosolic Ca2+ concentration was significantly increased in resting and in KCl-depolarized cardiomyopathic myocytes compared with normal cells. In normal and in cardiomyopathic cells, KCl significantly increased Prodynorphin mRNA levels and Prodynorphin gene transcription. These effects were abolished by the Ca2+ channel blocker verapamil. In control myocytes, the KCl-induced increase in Prodynorphin mRNA expression was in part attenuated by chelerythrine or calphostin C, two selective PKC inhibitors. In these cells, KCl induced the translocation of PKC-α into the nucleus, increasing nuclear PKC activity. In resting cardiomyopathic myocytes, the increase in Prodynorphin mRNA levels and gene transcription were significantly attenuated by the intracellular Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetraacetoxy-methylester being completely abolished when the chelating agent was administered in the presence of PKC inhibitors. KCl and the PKC activator 1,2-dioctanoyl-sn-glycerol additively stimulated Prodynorphin gene expression both in normal and in cardiomyopathic cells. Therefore, we conclude that PKC activation and intracellular Ca2+ overload may represent the two major signaling mechanisms involved in the induction of the Prodynorphin gene in cardiomyopathic cells.
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opioid peptide gene expression in the primary hereditary cardiomyopathy of the syrian hamster i regulation of Prodynorphin gene expression by nuclear protein kinase c
Journal of Biological Chemistry, 1997Co-Authors: Carlo Ventura, Gianfranco Pintus, Maria Giovanna Fiori, Federico Bennardini, G G Pinna, Leonardo GaspaAbstract:Prodynorphin gene expression was investigated in adult ventricular myocytes isolated from normal (F1B) or cardiomyopathic (BIO 14.6) hamsters. Prodynorphin mRNA levels were higher in cardiomyopathic than in control myocytes and were stimulated by treatment of control cells with the protein kinase C (PKC) activator 1, 2-dioctanoyl-sn-glycerol. Both chelerythrine and calphostin C, two PKC inhibitors, abolished the stimulatory effect of the diglyceride and significantly reduced Prodynorphin gene expression in cardiomyopathic myocytes. Nuclear run-off experiments indicated that the Prodynorphin gene was regulated at the transcriptional level and that treatment of nuclei isolated from control cells with 1, 2-dioctanoyl-sn-glycerol increased Prodynorphin gene transcription, whereas chelerythrine or calphostin C abolished this transcriptional effect. Direct exposure of nuclei isolated from cardiomyopathic myocytes to these inhibitors markedly down-regulated the rate of gene transcription. The expression of PKC-alpha, -delta, and -epsilon, as well as PKC activity, were increased in nuclei of cardiomyopathic myocytes compared with nuclei from control cells. The levels of both intracellular and secreted dynorphin B, a biologically active product of the gene, were higher in cardiomyopathic than in control cells and were stimulated or inhibited by cell treatment with 1,2-dioctanoyl-sn-glycerol or PKC inhibitors, respectively.
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Prodynorphin mRNA expression in adult cultured rat ventricular cardiac myocytes.
Biochimica et biophysica acta, 1993Co-Authors: Marco Canossa, Carlo Ventura, Isabella Vaona, Lucia Carboni, Carlo Guarnieri, Santi SpampinatoAbstract:Prodynorphin mRNA was synthesized both in rat atrial and ventricular tissue, as well as in adult cultured rat ventricular cardiac myocytes. In the cultured cells, the content of Prodynorphin mRNA did not differ from that detected in the original ventricle, indicating that the myocardial cell is an important source for Prodynorphin mRNA in the rat ventricular tissue. This study demonstrated the presence of immunoreactive dynorphin B-like material in the cultured cardiomyocytes. Gel permeation chromatography analysis of this material revealed the presence of forms with an apparently higher molecular weight than authentic dynorphin B.
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Prodynorphin mRNA is synthesized in adult cultured rat ventricular cardiomyocytes.
Cardioscience, 1993Co-Authors: Carlo Ventura, Marco Canossa, Isabella Vaona, Lucia Carboni, Santi Spampinato, Claudio Marcello Caldarera, Carlo GuarnieriAbstract:In the myocardial cell, stimulation of the K opioid receptor is involved in the modulation of cytosolic calcium and pH homeostasis, as well as in the regulation of myofilament responsiveness to calcium. In the present study, we found that Prodynorphin mRNA, which encodes for the synthesis of a common precursor of opioid peptides interacting with K sites, is synthesized both in atrial and ventricular tissue of the rat heart. In adult cultured rat ventricular cardiomyocytes, the level of Prodynorphin mRNA did not differ from that detected in the original ventricular tissue. This finding indicates that the myocardial cell is a source for Prodynorphin gene expression and has the potential for an intrinsic synthesis of dynorphin-related peptides.
Naomi E Rance - One of the best experts on this subject based on the ideXlab platform.
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Changes in Prodynorphin Gene Expression and Neuronal Morphology in the Hypothalamus of Postmenopausal Women
Journal of neuroendocrinology, 2008Co-Authors: A. M. Rometo, Naomi E RanceAbstract:Human menopause is characterised by ovarian failure, gonadotrophin hypersecretion and hypertrophy of neurones expressing neurokinin B (NKB), kisspeptin (KiSS)-1 and oestrogen receptor (ER) alpha gene transcripts within the hypothalamic infundibular (arcuate) nucleus. In the arcuate nucleus of experimental animals, dynorphin, an opioid peptide, is colocalised with NKB, kisspeptin, ER alpha and progesterone receptors. Moreover, ovariectomy decreases the expression of Prodynorphin gene transcripts in the arcuate nucleus of the ewe. Therefore, we hypothesised that the hypertrophied neurones in the infundibular nucleus of postmenopausal women would express Prodynorphin mRNA and that menopause would be accompanied by changes in Prodynorphin gene transcripts. In the present study, in situ hybridisation was performed on hypothalamic sections from premenopausal and postmenopausal women using a radiolabelled cDNA probe targeted to Prodynorphin mRNA. Autoradiography and computer-assisted microscopy were used to map and count labelled neurones, measure neurone size and compare Prodynorphin gene expression between premenopausal and postmenopausal groups. Neurones expressing dynorphin mRNA in the infundibular nucleus of the postmenopausal women were larger and exhibited hypertrophied morphological features. Moreover, there were fewer neurones labelled with the Prodynorphin probe in the infundibular nucleus of the postmenopausal group compared to the premenopausal group. The number of dynorphin mRNA-expressing neurones was also reduced in the medial preoptic/anterior hypothalamic area of postmenopausal women without changes in cell size. No differences in cell number or size of dynorphin mRNA-expressing neurones were observed in any other hypothalamic region. Previous studies using animal models provide strong evidence that the changes in Prodynorphin neuronal size and gene expression in postmenopausal women are secondary to the ovarian failure of menopause. Given the inhibitory effect of dynorphin on the reproductive axis, decreased dynorphin gene expression could play a role in the elevation in luteinising hormone secretion that occurs in postmenopausal women.
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coexpression of dynorphin and neurokinin b immunoreactivity in the rat hypothalamus morphologic evidence of interrelated function within the arcuate nucleus
The Journal of Comparative Neurology, 2006Co-Authors: Michelle C Burke, Penny A Letts, Sally J Krajewski, Naomi E RanceAbstract:Considerable evidence suggests that dynorphin and neurokinin B (NKB) neurons in the hypothalamic arcuate nucleus participate in the sex-steroid regulation of reproduction. In the present study, we used dual-label immunofluorescence to explore the distribution of Prodynorphin and proNKB immunoreactivity in the rat hypothalamus. Additionally, we investigated whether arcuate Prodynorphin-ir (immunoreactive) neurons expressed the neurokinin 3 receptor (NK3R) or nuclear estrogen receptor-alpha (ERalpha). We found that the majority of Prodynorphin-ir neurons in the rat arcuate nucleus expressed proNKB, whereas nearly all (99%) of the proNKB neurons were immunoreactive for Prodynorphin. The arcuate nucleus was the only site in the hypothalamus where neuronal somata coexpressing Prodynorphin and proNKB-immunoreactivity were identified. A dense plexus of double-labeled Prodynorphin/proNKB-ir fibers was found within the arcuate nucleus extending to the median eminence and throughout the periventricular zone of the hypothalamus. Prodynorphin/proNKB fibers were also identified in the paraventricular nucleus, anterior hypothalamic area, medial preoptic area, median preoptic nucleus, anteroventral periventricular nucleus, and bed nucleus of the stria terminalis in a distribution consistent with previously described arcuate nucleus projections. Interestingly, the majority of Prodynorphin-ir neurons in the arcuate nucleus expressed NK3R, and nearly 100% of the Prodynorphin-ir neurons contained nuclear ERalpha. Our results suggest that there is a close functional relationship between dynorphin and NKB peptides within the arcuate nucleus of the rat, which may include an autofeedback loop mediated through NK3R. The diverse hypothalamic projections of fibers expressing both Prodynorphin and proNKB provide evidence that these neurons may participate in a variety of homeostatic and neuroendocrine processes.
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coexpression of dynorphin and neurokinin b immunoreactivity in the rat hypothalamus morphologic evidence of interrelated function within the arcuate nucleus
The Journal of Comparative Neurology, 2006Co-Authors: Michelle C Burke, Penny A Letts, Sally J Krajewski, Naomi E RanceAbstract:Considerable evidence suggests that dynorphin and neurokinin B (NKB) neurons in the hypothalamic arcuate nucleus participate in the sex-steroid regulation of reproduction. In the present study, we used dual-label immunofluorescence to explore the distribution of Prodynorphin and proNKB immunoreactivity in the rat hypothalamus. Additionally, we investigated whether arcuate Prodynorphin-ir (immunoreactive) neurons expressed the neurokinin 3 receptor (NK3R) or nuclear estrogen receptor-α (ERα). We found that the majority of Prodynorphin-ir neurons in the rat arcuate nucleus expressed proNKB, whereas nearly all (99%) of the proNKB neurons were immunoreactive for Prodynorphin. The arcuate nucleus was the only site in the hypothalamus where neuronal somata coexpressing Prodynorphin and proNKB-immunoreactivity were identified. A dense plexus of double-labeled Prodynorphin/proNKB-ir fibers was found within the arcuate nucleus extending to the median eminence and throughout the periventricular zone of the hypothalamus. Prodynorphin/proNKB fibers were also identified in the paraventricular nucleus, anterior hypothalamic area, medial preoptic area, median preoptic nucleus, anteroventral periventricular nucleus, and bed nucleus of the stria terminalis in a distribution consistent with previously described arcuate nucleus projections. Interestingly, the majority of Prodynorphin-ir neurons in the arcuate nucleus expressed NK3R, and nearly 100% of the Prodynorphin-ir neurons contained nuclear ERα. Our results suggest that there is a close functional relationship between dynorphin and NKB peptides within the arcuate nucleus of the rat, which may include an autofeedback loop mediated through NK3R. The diverse hypothalamic projections of fibers expressing both Prodynorphin and proNKB provide evidence that these neurons may participate in a variety of homeostatic and neuroendocrine processes. J. Comp. Neurol. 498:712–726, 2006. © 2006 Wiley-Liss, Inc.
Ryszard Przewlocki - One of the best experts on this subject based on the ideXlab platform.
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Effect of cocaine and amphetamine on biosynthesis of proenkephalin and Prodynorphin in some regions of the rat limbic system.
Polish journal of pharmacology, 2002Co-Authors: J Turchan, Barbara Przewlocka, Marcin Maj, Ryszard PrzewlockiAbstract:A vast body of evidence points to the role of the limbic system in the mechanism of drug dependence. Opioid peptides localized in the limbic system may play a role in central effects of substances of abuse. The goal of the present study was to investigate the influence of acutely and chronically administered drugs of abuse, cocaine and amphetamine on biosynthesis of Prodynorphin and proenkephalin in the rat amygdala, the structure involved in the mechanism of drug addiction. Acute injection of cocaine (20 mg/kg ip every hour for 3 h) or amphetamine (2.5 mg/kg) did not changed or decreased the level of proenkephalin mRNA in the central nucleus of the amygdala. In contrast, the level of Prodynorphin mRNA was significantly increased in this structure after cocaine. Repeated cocaine administration (20 mg/kg ip every hour for 3 h, for 5 days) had no effect on the proenkephalin and Prodynorphin mRNA in the central nucleus of the amygdala. Chronic amphetamine (2.5 mg/kg twice daily for 5 days) administration decreased proenkephalin and increased Prodynorphin mRNA level in the central nucleus of the amygdala (at 24 and 48 h). Moreover, significant increase in Prodynorphin mRNA level was observed in the hippocampal dentate gyrus after acute (cocaine) and chronic (cocaine, amphetamine) administration of the psychostimulants. The observed adaptive changes in the activity of two opioid systems in two structures of the limbic system, central nucleus of amygdala and hippocampus, may contribute to the neurochemical mechanism of drug addiction after psychostimulants. These studies also indicate that the changes in opioid gene expression in the central nucleus of the amygdala are not parallel to those observed in the nucleus accumbens after cocaine and amphetamine, which suggests that peptidergic systems in the structures of extended amygdala might be regulated by different neurochemical mechanisms after psychostymulant administration.
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Effects of repeated psychostimulant administration on the Prodynorphin system activity and kappa opioid receptor density in the rat brain
Neuroscience, 1998Co-Authors: J Turchan, Barbara Przewlocka, W. Lason, Ryszard PrzewlockiAbstract:Abstract The Prodynorphin system is implicated in the neurochemical mechanism of psychostimulants. To elucidate the activity of the endogenous Prodynorphin system upon treatment with psychostimulants, we investigated the effect of single and repeated cocaine and amphetamine on the Prodynorphin messenger RNA level, the Prodynorphin-derived peptide α-neoendorphin tissue level, and its in vitro release in the nucleus accumbens and striatum of rats. The density of κ opioid receptors in those brain regions was also assessed. Rats were injected with cocaine following a “binge” administration pattern, 20 mg/kg i.p. every hour for 3 h, one (single treatment) or five days (chronic treatment). Amphetamine, 2.5 mg/kg i.p. was administered once (single treatment) or twice a day for five days (chronic treatment). As shown by an in situ hybridization study, the Prodynorphin messenger RNA levels in the nucleus accumbens and striatum were raised following single (at 3 h) and chronic (at 3 and 24 h) cocaine administration. The Prodynorphin messenger RNA level in the nucleus accumbens was markedly elevated after single or repeated amphetamine administration. A similar tendency was observed in the striatum. Acute cocaine and amphetamine administration had no effect on the α-neoendorphin tissue level, whereas chronic administration of those drugs elevated the α-neoendorphin level in the nucleus accumbens and striatum at the late time-points studied. Acute and repeated cocaine administration had no effect on α-neoendorphin release in both the nucleus accumbens and striatum at 3 and 48 h after drug injection. In contrast, single and chronic (at 24 and 48 h) amphetamine administration profoundly elevated the release of α-neoendorphin in both these structures. Addition of cocaine or amphetamine to the incubation medium (10 −5 –10 −6 M) decreased the basal release of α-neoendorphin in the nucleus accumbens slices of naive rats, but it did not change the stimulated release (K + 57 mM). On the other hand, in the striatum slices, addition of cocaine to the incubation medium depressed basal and stimulated release of the peptide; no significant changes were observed after addition of amphetamine. Cocaine and amphetamine evoked profound and long-term down-regulation of the κ opioid receptors in both structures. The above data indicate that the amphetamine-induced changes were more abundant than those caused by cocaine; only treatment with amphetamine markedly enhanced the release of Prodynorphin-derived peptide. Furthermore, the psychostimulant-induced enhancement of biosynthetic activity of Prodynorphin neurons was correlated with a marked and persistent decrease in the κ opioid receptor density at a late withdrawal time.
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Imipramine induces alterations in proenkephalin and Prodynorphin mRNAs level in the nucleus accumbens and striatum in the rat.
Polish journal of pharmacology, 1997Co-Authors: Ryszard Przewlocki, J Turchan, W. Lason, Barbara PrzewlockaAbstract:Endogenous opioids have been implicated in the mechanism of action of antidepressant drugs. In this study, we evaluated effects of single and repeated imipramine administration on proenkephalin and Prodynorphin gene expression in the rat nucleus accumbens and striatum. In situ hybridization study showed that single imipramine injection (10 mg/kg, i.p.) decreased the level of proenkephalin (by ca. 20%) and Prodynorphin (by ca. 25%) mRNA to the same extent in both structures. Repeated imipramine administration (10 mg/kg i.p. twice daily for 10 days) had no effect on proenkephalin mRNA level, whereas the Prodynorphin gene expression was regulated differently. At 3 h after the last dose of imipramine the Prodynorphin mRNA level was decreased (by ca. 25%) in the striatum, but not in the nucleus accumbens, whereas at 24 h an up-regulation (by ca. 27%) of Prodynorphin mRNA level could be observed in the nucleus accumbens only. In the light of involvement of opioids in mood regulation, these adaptive changes may participate in neurochemical mechanisms of antidepressant therapy.
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The effect of single and repeated morphine administration on the Prodynorphin system activity in the nucleus accumbens and striatum of the rat.
Neuroscience, 1996Co-Authors: Barbara Przewlocka, J Turchan, W. Lason, Ryszard PrzewlockiAbstract:Pharmacological data indicate that Prodynorphin peptides and exogenous kappa agonists affect opioid tolerance and dependence. In order to elucidate the activity of the endogenous Prodynorphin system during opiate tolerance and dependence, we investigated the effect of single and repeated morphine administration on the alpha-neoendorphin tissue level, its in vitro release, and the Prodynorphin messenger RNA level in the nucleus accumbens and striatum of the rat. Acute and repeated morphine administration (14 days, increasing doses, 20-100 mg/kg, i.p.) increased the level of alpha-neoendorphin in the nucleus accumbens after 3 h; a similar effect was observed at 24 and 48 h after the last chronic morphine injection. On the other hand, the basal and stimulated (K+, 57 mM) release of alpha-neoendorphin from nucleus accumbens slices were significantly elevated only at 24 h after the last morphine injection. The Prodynorphin messenger RNA hybridization signal in the nucleus accumbens was enhanced at 3 h after acute morphine injection, whereas repeated morphine administration decreased the messenger RNA level at that time point. Upon late chronic morphine withdrawal (at 24 and 48 h), the Prodynorphin messenger RNA level in that tissue was significantly elevated. In the striatum, single morphine administration had no effect on the alpha-neoendorphin tissue level, release of the peptide, and Prodynorphin messenger RNA level. On the other hand, chronic injection of morphine elevated all those parameters. The tissue level of alpha-neoendorphin was elevated at 3 h, and was back to normal at 24 and 48 h after the last drug injection. Both the basal and stimulated alpha-neoendorphin release from striatal slices was significantly increased at all the time points studied. Repeated morphine administration elevated the striatal Prodynorphin messenger RNA level at 24 and 48 h after the drug withdrawal. Addition of morphine to the incubation medium reduced the basal release of alpha-neoendorphin in both the nucleus accumbens and striatal slices in naive animals, whereas the stimulated release was attenuated in the latter tissue only. The present study indicates that withdrawal of chronic morphine leads to enhancement of the Prodynorphin neurons activity in the nucleus accumbens and striatum of the rat. It is suggested that these effects may participate in the mechanism of aversive reactions during withdrawal.
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Repeated ethanol administration decreases Prodynorphin biosynthesis in the rat hippocampus.
Neuroscience letters, 1992Co-Authors: Barbara Przewlocka, W. Lason, Ryszard PrzewlockiAbstract:The effect of single and repeated (19 days) intragastric ethanol administration on Prodynorphin mRNA and alpha-neoendorphin levels in the hippocampus of the rat was studied using in situ hybridization and RIA methods, respectively. Single ethanol administration had no effect on either of these two parameters. Repeated ethanol administration decreased both immunoreactive (ir) alpha-neoendorphin (by ca. 37%) and Prodynorphin mRNA (by ca. 57%) levels. Two days after the last dose of ethanol no changes in the ir-alpha-neoendorphin tissue content were found, whereas the level of Prodynorphin mRNA remained decreased (by ca. 44%). These results suggest that repeated ethanol evokes a long-lasting decrease in the biosynthesis of hippocampal Prodynorphin, this effect that may play some role in the ethanol-induced deficiency of neuronal functions.
Barbara Przewlocka - One of the best experts on this subject based on the ideXlab platform.
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Effect of cocaine and amphetamine on biosynthesis of proenkephalin and Prodynorphin in some regions of the rat limbic system.
Polish journal of pharmacology, 2002Co-Authors: J Turchan, Barbara Przewlocka, Marcin Maj, Ryszard PrzewlockiAbstract:A vast body of evidence points to the role of the limbic system in the mechanism of drug dependence. Opioid peptides localized in the limbic system may play a role in central effects of substances of abuse. The goal of the present study was to investigate the influence of acutely and chronically administered drugs of abuse, cocaine and amphetamine on biosynthesis of Prodynorphin and proenkephalin in the rat amygdala, the structure involved in the mechanism of drug addiction. Acute injection of cocaine (20 mg/kg ip every hour for 3 h) or amphetamine (2.5 mg/kg) did not changed or decreased the level of proenkephalin mRNA in the central nucleus of the amygdala. In contrast, the level of Prodynorphin mRNA was significantly increased in this structure after cocaine. Repeated cocaine administration (20 mg/kg ip every hour for 3 h, for 5 days) had no effect on the proenkephalin and Prodynorphin mRNA in the central nucleus of the amygdala. Chronic amphetamine (2.5 mg/kg twice daily for 5 days) administration decreased proenkephalin and increased Prodynorphin mRNA level in the central nucleus of the amygdala (at 24 and 48 h). Moreover, significant increase in Prodynorphin mRNA level was observed in the hippocampal dentate gyrus after acute (cocaine) and chronic (cocaine, amphetamine) administration of the psychostimulants. The observed adaptive changes in the activity of two opioid systems in two structures of the limbic system, central nucleus of amygdala and hippocampus, may contribute to the neurochemical mechanism of drug addiction after psychostimulants. These studies also indicate that the changes in opioid gene expression in the central nucleus of the amygdala are not parallel to those observed in the nucleus accumbens after cocaine and amphetamine, which suggests that peptidergic systems in the structures of extended amygdala might be regulated by different neurochemical mechanisms after psychostymulant administration.
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Effects of repeated psychostimulant administration on the Prodynorphin system activity and kappa opioid receptor density in the rat brain
Neuroscience, 1998Co-Authors: J Turchan, Barbara Przewlocka, W. Lason, Ryszard PrzewlockiAbstract:Abstract The Prodynorphin system is implicated in the neurochemical mechanism of psychostimulants. To elucidate the activity of the endogenous Prodynorphin system upon treatment with psychostimulants, we investigated the effect of single and repeated cocaine and amphetamine on the Prodynorphin messenger RNA level, the Prodynorphin-derived peptide α-neoendorphin tissue level, and its in vitro release in the nucleus accumbens and striatum of rats. The density of κ opioid receptors in those brain regions was also assessed. Rats were injected with cocaine following a “binge” administration pattern, 20 mg/kg i.p. every hour for 3 h, one (single treatment) or five days (chronic treatment). Amphetamine, 2.5 mg/kg i.p. was administered once (single treatment) or twice a day for five days (chronic treatment). As shown by an in situ hybridization study, the Prodynorphin messenger RNA levels in the nucleus accumbens and striatum were raised following single (at 3 h) and chronic (at 3 and 24 h) cocaine administration. The Prodynorphin messenger RNA level in the nucleus accumbens was markedly elevated after single or repeated amphetamine administration. A similar tendency was observed in the striatum. Acute cocaine and amphetamine administration had no effect on the α-neoendorphin tissue level, whereas chronic administration of those drugs elevated the α-neoendorphin level in the nucleus accumbens and striatum at the late time-points studied. Acute and repeated cocaine administration had no effect on α-neoendorphin release in both the nucleus accumbens and striatum at 3 and 48 h after drug injection. In contrast, single and chronic (at 24 and 48 h) amphetamine administration profoundly elevated the release of α-neoendorphin in both these structures. Addition of cocaine or amphetamine to the incubation medium (10 −5 –10 −6 M) decreased the basal release of α-neoendorphin in the nucleus accumbens slices of naive rats, but it did not change the stimulated release (K + 57 mM). On the other hand, in the striatum slices, addition of cocaine to the incubation medium depressed basal and stimulated release of the peptide; no significant changes were observed after addition of amphetamine. Cocaine and amphetamine evoked profound and long-term down-regulation of the κ opioid receptors in both structures. The above data indicate that the amphetamine-induced changes were more abundant than those caused by cocaine; only treatment with amphetamine markedly enhanced the release of Prodynorphin-derived peptide. Furthermore, the psychostimulant-induced enhancement of biosynthetic activity of Prodynorphin neurons was correlated with a marked and persistent decrease in the κ opioid receptor density at a late withdrawal time.
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Imipramine induces alterations in proenkephalin and Prodynorphin mRNAs level in the nucleus accumbens and striatum in the rat.
Polish journal of pharmacology, 1997Co-Authors: Ryszard Przewlocki, J Turchan, W. Lason, Barbara PrzewlockaAbstract:Endogenous opioids have been implicated in the mechanism of action of antidepressant drugs. In this study, we evaluated effects of single and repeated imipramine administration on proenkephalin and Prodynorphin gene expression in the rat nucleus accumbens and striatum. In situ hybridization study showed that single imipramine injection (10 mg/kg, i.p.) decreased the level of proenkephalin (by ca. 20%) and Prodynorphin (by ca. 25%) mRNA to the same extent in both structures. Repeated imipramine administration (10 mg/kg i.p. twice daily for 10 days) had no effect on proenkephalin mRNA level, whereas the Prodynorphin gene expression was regulated differently. At 3 h after the last dose of imipramine the Prodynorphin mRNA level was decreased (by ca. 25%) in the striatum, but not in the nucleus accumbens, whereas at 24 h an up-regulation (by ca. 27%) of Prodynorphin mRNA level could be observed in the nucleus accumbens only. In the light of involvement of opioids in mood regulation, these adaptive changes may participate in neurochemical mechanisms of antidepressant therapy.
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The effect of single and repeated morphine administration on the Prodynorphin system activity in the nucleus accumbens and striatum of the rat.
Neuroscience, 1996Co-Authors: Barbara Przewlocka, J Turchan, W. Lason, Ryszard PrzewlockiAbstract:Pharmacological data indicate that Prodynorphin peptides and exogenous kappa agonists affect opioid tolerance and dependence. In order to elucidate the activity of the endogenous Prodynorphin system during opiate tolerance and dependence, we investigated the effect of single and repeated morphine administration on the alpha-neoendorphin tissue level, its in vitro release, and the Prodynorphin messenger RNA level in the nucleus accumbens and striatum of the rat. Acute and repeated morphine administration (14 days, increasing doses, 20-100 mg/kg, i.p.) increased the level of alpha-neoendorphin in the nucleus accumbens after 3 h; a similar effect was observed at 24 and 48 h after the last chronic morphine injection. On the other hand, the basal and stimulated (K+, 57 mM) release of alpha-neoendorphin from nucleus accumbens slices were significantly elevated only at 24 h after the last morphine injection. The Prodynorphin messenger RNA hybridization signal in the nucleus accumbens was enhanced at 3 h after acute morphine injection, whereas repeated morphine administration decreased the messenger RNA level at that time point. Upon late chronic morphine withdrawal (at 24 and 48 h), the Prodynorphin messenger RNA level in that tissue was significantly elevated. In the striatum, single morphine administration had no effect on the alpha-neoendorphin tissue level, release of the peptide, and Prodynorphin messenger RNA level. On the other hand, chronic injection of morphine elevated all those parameters. The tissue level of alpha-neoendorphin was elevated at 3 h, and was back to normal at 24 and 48 h after the last drug injection. Both the basal and stimulated alpha-neoendorphin release from striatal slices was significantly increased at all the time points studied. Repeated morphine administration elevated the striatal Prodynorphin messenger RNA level at 24 and 48 h after the drug withdrawal. Addition of morphine to the incubation medium reduced the basal release of alpha-neoendorphin in both the nucleus accumbens and striatal slices in naive animals, whereas the stimulated release was attenuated in the latter tissue only. The present study indicates that withdrawal of chronic morphine leads to enhancement of the Prodynorphin neurons activity in the nucleus accumbens and striatum of the rat. It is suggested that these effects may participate in the mechanism of aversive reactions during withdrawal.
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Nitric oxide synthase inhibitor l-name prevents amphetamine-induced Prodynorphin gene expression in the rat
Progress in neuro-psychopharmacology & biological psychiatry, 1996Co-Authors: Barbara Przewlocka, J Turchan, Halina Machelska, Dominika Labuz, W. LasonAbstract:Abstract 1. 1. The effect of nitric oxide synthase inhibitor on amphetamine-induced behavioral changes and Prodynorphin gene expression in the nucleus accumbens and striatum of the rat has been studied. 2. 2. L-NAME attenuated behavioral Stereotypie activity evoked by amphetamine administration. 3. 3. Acute amphetamine administration (5mg/kg i.p.) increased the Prodynorphin mRNA level in the nucleus accumbens and striatum after 3hr. 4. 4. A nitric oxide synthase inhibitor L-nitro-arginine methyl ester (L-NAME, 10, 50 mg/kg i.p.) had no effect on the level of Prodynorphin mRNA, but prevented dose-dependently the amphetamine-induced increase in Prodynorphin gene expression in both the nucleus accumbens and the striatum. 5. 5. These data indicate that inhibition of the nitric oxide pathway attenuates biochemical and behavioral effects of amphetamine.
