RÉSUMÉ
The central nucleus of the amygdala is a CRF-containing limbic brain site which mediates both fear-like and avoidance behaviors; moreover it has been hypothesized that atypical stress responses may contribute to compulsive drug use. Therefore, we studied in rat amygdala the level of CRF mRNA by in situ hybrydization, and the level of the peptide using immunocytochemistry after acute and chronic administration of morphine and cocaine and after their withdrawal. Acute injection of morphine (20 mg/kg i.p.) increased CRF mRNA level, but did not change significantly CRF immunoreactivity in the central nucleus of the amygdala. Chronic morphine administration significantly increased the level of CRF mRNA 3, 24 and 48 h after the last dose. Both, acute and chronic cocaine administration increased CRF mRNA, but the peptide level was decreased only after acute cocaine administration. However, in the late withdrawal (48 h after the last dose of cocaine) both mRNA and the peptide levels tended to decrease. The above data suggest that amygdalar CRF system activity is potently activated after administration of morphine and cocaine, and that activation of this system observed at the time of withdrawal from morphine may be responsible for aversion and anxiety related to these states; therefore a CRF1 receptor may be a target for prospective pharmacotherapies of the withdrawal from abused drugs.
Sujet(s)
Amygdale (système limbique)/métabolisme , Analgésiques morphiniques/pharmacologie , Cocaïne/pharmacologie , Corticolibérine/biosynthèse , Morphine/pharmacologie , Amygdale (système limbique)/effets des médicaments et des substances chimiques , Analgésiques morphiniques/administration et posologie , Analgésiques morphiniques/effets indésirables , Animaux , Immunohistochimie , Hybridation in situ , Injections péritoneales , Mâle , Morphine/administration et posologie , Morphine/effets indésirables , ARN messager/biosynthèse , Rats , Rat Wistar , Syndrome de sevrage/métabolisme , Syndrome de sevrage/psychologieRÉSUMÉ
OBJECTIVE: To determine the role of oxidative stress in mediating HIV dementia and to identify novel therapeutic compounds that may block this oxidative stress. METHODS: Brain tissue from patients with HIV encephalitis and macaques with simian immune deficiency virus encephalitis was immunostained for lipid peroxidation. Oxidized proteins in CSF of patients with various stages of HIV dementia were quantitated and we determined whether CSF from these patients could alter mitochondrial function. Several novel compounds with antioxidant effects were screened to determine their relative efficacy in protecting against CSF-induced neurotoxicity. RESULTS: Evidence for oxidative stress was present both in brain and in CSF. The presence of oxidized proteins in the CSF and CSF-induced progressive decrease in mitochondrial activity correlated with the severity of cognitive impairment, but only the group of patients with moderate to severe dementia reached statistical significance. L-deprenyl, didox, imidate, diosgenin, and ebselen blocked the CSF-induced toxicity. No effect of trimidox, ruthenium red, or Quercetin was seen. CONCLUSIONS: Increased oxidative stress is present in brain and CSF of HIV-infected patients. There is also an accumulation of toxic substances in the CSF that are capable of inducing oxidative stress. The authors have identified several novel compounds that are capable of blocking the CSF-induced toxicity, the therapeutic potential of which is worthy of further exploration.
Sujet(s)
Démence associée au SIDA/physiopathologie , Antioxydants/pharmacologie , Stress oxydatif/effets des médicaments et des substances chimiques , Démence associée au SIDA/anatomopathologie , Aldéhydes/analyse , Aldéhydes/métabolisme , Animaux , Apoptose/effets des médicaments et des substances chimiques , Encéphale/cytologie , Encéphale/métabolisme , Encéphale/anatomopathologie , Cellules cultivées , Liquide cérébrospinal/composition chimique , Liquide cérébrospinal/métabolisme , Protéines du liquide céphalorachidien/composition chimique , Protéines du liquide céphalorachidien/métabolisme , Protéines du liquide céphalorachidien/pharmacologie , Cytochromes de type c/métabolisme , Colorants fluorescents , Humains , Cétones/analyse , Métabolisme lipidique , Macaca , Potentiels de membrane/effets des médicaments et des substances chimiques , Mitochondries/effets des médicaments et des substances chimiques , Neurones/cytologie , Neurones/effets des médicaments et des substances chimiques , Neurones/métabolisme , Oxydoréduction/effets des médicaments et des substances chimiques , Virus de l'immunodéficience simienneRÉSUMÉ
Our earlier findings concerning the 6-OHDA lesion suggested dopaminergic regulation of neuropeptide Y (NPY) and corticotropin releasing factor (CRF) synthesis and expression in amygdala neurons. On the other hand, some other studies indicated that not only dopamine, but also other monoamines may modulate peptidergic neurons. Therefore the present study examined the effect of pharmacological deprivation of monoaminergic influences on NPY and CRF neurons in rat brain amygdala by means of in situ hybridization and immunohistochemical methods. It was found that NPY mRNA expression in the amygdala decreased after 24h blockade of dopaminergic D1 and D2 receptors, by haloperidol or SCH23390. At the same time the NPY-peptide expression measured immunohistochemically was not significantly changed. A prolonged, 14-day, blockade of dopaminergic receptors by haloperidol induced an opposite effect, an increase in NPY mRNA expression. Impairment of the serotonergic transmission by blockade of 5-HT synthesis using p-chlorophenylalanine, as well as attenuation of the noradrenergic transmission by NA depletion from terminals by DSP4, did not significantly change NPY mRNA expression or the mean number of NPY-immunoreactive neurons in the amygdala. Only a decrease in the staining intensity observed as a decreased number of darkly stained neurons was found after both compounds. Neither the dopamine receptor blockade nor the impairment of serotonergic or noradrenergic transmission changed CRF mRNA or the peptide expression in the amygdala. The obtained results indicate that in rat brain amygdala, of all the monoamines, dopamine seems to be the most important modulator of NPY biosynthesis and expression. The effect of blockade of dopaminergic receptors is biphasic: first it induces a decrease and then - after prolonged treatment an increase in NPY mRNA. Serotonergic and noradrenergic systems in the amygdala seem to be connected with regulation of NPY release rather than the biosynthesis.
Sujet(s)
Amygdale (système limbique)/physiologie , Corticolibérine/génétique , Antagonistes de la dopamine/pharmacologie , Halopéridol/pharmacologie , Neuropeptide Y/génétique , Amygdale (système limbique)/composition chimique , Animaux , Benzazépines/pharmacologie , Corticolibérine/analyse , Fenclonine/pharmacologie , Expression des gènes/effets des médicaments et des substances chimiques , Expression des gènes/physiologie , Immunohistochimie , Hybridation in situ , Mâle , Neuropeptide Y/analyse , ARN messager/analyse , Rats , Rat Wistar , Antisérotonines/pharmacologieRÉSUMÉ
BACKGROUND: Human immunodeficiency virus (HIV) infection continues to increase at alarming rates in drug abusers, especially in women. Drugs of abuse can cause long-lasting damage to the brain and HIV infection frequently leads to a dementing illness. To determine how these drugs interact with HIV to cause CNS damage, we used an in vitro human neuronal culture characterized for the presence of dopaminergic receptors, transporters and estrogen receptors. We determined the combined effects of dopaminergic drugs, methamphetamine, or cocaine with neurotoxic HIV proteins, gp120 and Tat. RESULTS: Acute exposure to these substances resulted in synergistic neurotoxic responses as measured by changes in mitochondrial membrane potential and neuronal cell death. Neurotoxicity occurred in a sub-population of neurons. Importantly, the presence of 17beta-estradiol prevented these synergistic neurotoxicities and the neuroprotective effects were partly mediated by estrogen receptors. CONCLUSION: Our observations suggest that methamphetamine and cocaine may affect the course of HIV dementia, and additionally suggest that estrogens modify the HIV-drug interactions.
Sujet(s)
Cocaïne/toxicité , Oestradiol/pharmacologie , Protéines du gène tat/toxicité , Protéine d'enveloppe gp120 du VIH/toxicité , Glycoprotéines membranaires , Métamfétamine/toxicité , Protéines de tissu nerveux , Neurones/effets des médicaments et des substances chimiques , Cellules cultivées , Dopamine/métabolisme , Transporteurs de la dopamine , Relation dose-effet des médicaments , Synergie des médicaments , Antagonistes des oestrogènes/pharmacologie , Protéines du gène tat/antagonistes et inhibiteurs , Protéine d'enveloppe gp120 du VIH/effets des médicaments et des substances chimiques , Humains , Substances illicites/toxicité , Sérums immuns/pharmacologie , Protéines de transport membranaire/métabolisme , Neurones/cytologie , Neurones/métabolisme , Neuroprotecteurs/pharmacologie , Récepteurs dopaminergiques/métabolisme , Récepteurs des oestrogènes/biosynthèse , Récepteurs des oestrogènes/génétiqueRÉSUMÉ
Recent studies demonstrate that activation of proinflammatory cytokines following injury intensifies the process of nociception. The present investigation assessed the influence of pre-injury pentoxifiline (PTFL, a non-specific cytokine inhibitor) on the development of post-injury nociception in animals and patients. It was established that intrathecal or intraperitoneal PTFL, elevated the nociceptive threshold for mechanical stimuli in the formalin test in rats. Pre-injury PTFL also inhibited pain-related behaviour. These findings correlate with a lower TNFalpha level in the serum of animals receiving pre-injury PTFL. In clinical investigations PTFL was administered intravenously before elective cholecystectomy. Patients who received preoperative PTFL had lower opioid requirements in the early postoperative period than control. At the same time, serum levels of TNFalpha and IL6 were lower in the PTFL group. Our results confirm the hypothesis as to the possibility of modulating of nociception through preemptive administration of a cytokine inhibitor.
Sujet(s)
Hyperalgésie/prévention et contrôle , Douleur postopératoire/prévention et contrôle , Douleur/traitement médicamenteux , Pentoxifylline/usage thérapeutique , Inhibiteurs de la phosphodiestérase/usage thérapeutique , Adulte , Animaux , Cholécystectomie , Formaldéhyde/administration et posologie , Humains , Hyperalgésie/sang , Injections péritoneales , Injections veineuses , Injections rachidiennes , Interleukine-6/sang , Mâle , Péthidine/administration et posologie , Adulte d'âge moyen , Morphine/administration et posologie , Douleur/sang , Mesure de la douleur , Seuil nociceptif/effets des médicaments et des substances chimiques , Douleur postopératoire/sang , Rats , Rat Wistar , Facteur de nécrose tumorale alpha/métabolismeRÉSUMÉ
The expression of mRNA coding for prepro-thyrotropin releasing hormone (preproTRH) was estimated in the rat brain in two animal models of limbic seizures, evoked by systemic administration of pilocarpine (400 mg/kg ip) or kainate (12 mg/kg ip). As shown by an in situ hybridization study, after 24h both pilocarpine- and kainate-induced seizures profoundly increased the preproTRH mRNA level in the dentate gyrus. After 72h, the preproTRH mRNA level was back to control values. Kainate-treated rats showed an elevated level of TRH in the hippocampus, septum, frontal and occipital cortex after 24 and 72h, whereas in the striatum and amygdala the TRH level was raised after 72h only. In the hypothalamus, TRH levels was lowered after 3 and 24h, and returned to the control after 72h. Pilocarpine-induced seizures also elevated the TRH level after 72h in the majority of the above structures, except for the hypothalamus and amygdala where no changes were found at any time point. A radioreceptor assay showed that kainate decreased the Bmax value of TRH receptors in the striatum and hippocampus after 3 and 24h, respectively, and had no effect on the Kd values. In contrast, pilocarpine-induced seizures lowered the Bmax of TRH receptors in the striatum, hippocampus and piriform cortex after 72h only, and decreased Kd values in the striatum, amygdala and frontal cortex. These data showed that pilocarpine- and kainate-induced seizures enhanced likewise preproTRH mRNA in the dentate gyrus; on the other hand, they differed with respect to time- and structure-related changes in TRH tissue levels and TRH receptors. These differences may have functional significance in TRH-dependent control mechanism of the seizure activity in these two models of limbic epilepsy.
Sujet(s)
Encéphale/métabolisme , Régulation de l'expression des gènes/physiologie , Acide kaïnique/pharmacologie , Pilocarpine/pharmacologie , Récepteur TRH/génétique , Crises épileptiques/métabolisme , Hormone de libération de la thyréostimuline/génétique , Transcription génétique/physiologie , Amygdale (système limbique)/métabolisme , Animaux , Séquence nucléotidique , Encéphale/effets des médicaments et des substances chimiques , Corps strié/métabolisme , Gyrus denté/métabolisme , Lobe frontal/métabolisme , Régulation de l'expression des gènes/effets des médicaments et des substances chimiques , Hypothalamus/métabolisme , Mâle , Données de séquences moléculaires , Lobe occipital/métabolisme , Spécificité d'organe , Précurseurs de protéines/génétique , ARN messager/génétique , Dosage par compétition , Rats , Rat Wistar , Récepteur TRH/biosynthèse , Crises épileptiques/induit chimiquement , Hormone de libération de la thyréostimuline/biosynthèse , Facteurs temps , Transcription génétique/effets des médicaments et des substances chimiquesRÉSUMÉ
The aim of this study was to evaluate the effect of acute, subchronic (14 days) and chronic (28 days) intraperitoneal (i.p.) administration of clozapine (10 or 25 mg/kg) on neuropeptide Y (NPY) system activity in the nucleus accumbens of the rat. NPY-like immunoreactivity (NPY-LI) decreased 24 h after subchronic clozapine while NPY mRNA after both acute and subchronic clozapine treatment. NPY-LI levels were also reduced 8 days after cessation of chronic lower-dose treatment. Subchronic (14 days) administration of the 5-HT2A antagonist ketanserin (1 mg/kg i.p.) or the dopamine D2/D3 antagonist (+/-) sulpiride (100 mg/kg i.p.) reduced NPY-LI levels, whereas the dopamine D1-like antagonist SCH 23390 (0.5 mg/kg i.p.), dopamine D4 antagonist L-745,870 (1 mg/kg per os), and alpha1-adrenergic antagonist prazosin (0.2 mg/kg i.p.) had no effect. There were no significant differences between the ketanserin-induced decrease in NPY-LI levels and the effects of the following two-drug combinations: ketanserin and SCH 23390, ketanserin and L-745,870, and ketanserin and prazosin. The study has shown that clozapine reduces NPY system activity in the rat nucleus accumbens. It seems that the action of clozapine is partly mediated by blockade of 5-HT2A and D2/D3 dopaminergic receptors.
Sujet(s)
Neuroleptiques/pharmacologie , Clozapine/pharmacologie , Neuropeptide Y/métabolisme , Noyau accumbens/effets des médicaments et des substances chimiques , Antagonistes alpha-adrénergiques/pharmacologie , Animaux , Neuroleptiques/administration et posologie , Clozapine/administration et posologie , Antagonistes de la dopamine/pharmacologie , Hybridation in situ , Mâle , Neuropeptide Y/génétique , Neuropeptide Y/immunologie , Noyau accumbens/immunologie , Noyau accumbens/métabolisme , ARN messager/métabolisme , Rats , Rat Wistar , Récepteur de la sérotonine de type 5-HT2A , Récepteurs alpha-1 adrénergiques/métabolisme , Récepteurs dopaminergiques/métabolisme , Récepteurs sérotoninergiques/métabolisme , Antisérotonines/pharmacologieRÉSUMÉ
The present study was carried out to evaluate the effect of morphine, cocaine and ethanol on the density of opioid receptors in the nucleus accumbens and striatum of rat brain. The animals were injected i.p. with morphine in a single dose 20 mg/kg, or twice daily for 10 days in increasing doses of 20-100 mg/kg. Cocaine was administered in a dose of 60 mg/kg/day following the "binge" paradigm, every hour for 3 h, one day (single treatment) or five days (chronic treatment). Ethanol was administered in drinking water at increasing concentrations of 1-6% v/v, for one month. As shown by receptor autoradiography, single morphine and cocaine administration did not influence the binding density of the selective ligand of delta2 receptors [3H]Ile5,6deltorphin b, but single administration of cocaine decreased binding density of a highly selective antagonist of delta receptors, [3H]H-Tyr-Tic psi[CH2-NH]Phe-Phe-OH. Repeated morphine administration decreased the receptor density after both ligands of the delta receptor in the nucleus accumbens after 3, 24 and 48 h, and in the striatum after 24 and 48 h. The density of [3H]Ile5,6deltorphin b binding remained unchanged in both structures following repeated cocaine administration. After repeated cocaine administration either no changes (3 h) or a decrease in the binding of [3H]H-Tyr-Tic psi[CH2-NH]Phe-Phe-OH in the nucleus accumbens and striatum were observed after 24 and 48 h. Ethanol did not influence the binding density of [3H]H-Tyr-Tic psi[CH2-NH]Phe-Phe-OH and [3H]Ile5,6deltorphin b in the nucleus accumbens and striatum at any time-point studied. In the nucleus accumbens and striatum, no changes were found in the binding density of [3H]Tyr-D-Ala-Gly-MePhe-Gly-ol following single or repeated morphine administration. At 3 h after single or repeated "binge" cocaine administration, the binding of [3H]Tyr-D-Ala-Gly-MePhe-Gly-ol was not changed in either structure, but after 24 h the density of mu opioid receptors was decreased in both structures. Ethanol given to rats in drinking water decreased the binding of [3H]Tyr-D-Ala-Gly-MePhe-Gly-ol at the time of exposure to ethanol, yet in the nucleus accumbens only. Ethanol withdrawal decreased the density of the mu receptor in both structures after 24, 48 and 96 h. The above data indicate that repeated administration of morphine evokes a long-lasting down-regulation of the density of delta1 and delta2 opioid receptors, whereas cocaine affects in a similar way only the delta1 subtype in the nucleus accumbens, and to a lesser extent in the striatum. A long-term intake of ethanol solution down-regulates mu opioid receptors in both structures, but has no effect on any type of delta receptors. Thus changes in the particular opioid receptor depend on the type of drug used. Furthermore, the most profound changes are observed after late withdrawal, which may play some role in maintaining the state of dependence.
Sujet(s)
Dépresseurs du système nerveux central/pharmacologie , Cocaïne/administration et posologie , Corps strié/métabolisme , Éthanol/administration et posologie , Morphine/administration et posologie , Stupéfiants/pharmacologie , Noyau accumbens/métabolisme , Récepteurs aux opioïdes/métabolisme , Animaux , Cocaïne/pharmacologie , Corps strié/effets des médicaments et des substances chimiques , Calendrier d'administration des médicaments , Éthanol/pharmacologie , Mâle , Morphine/pharmacologie , Noyau accumbens/effets des médicaments et des substances chimiques , Rats , Rat Wistar , Récepteur delta/métabolisme , Récepteur mu/métabolismeRÉSUMÉ
It has been postulated that changes in thyrotropin-releasing hormone biosynthesis may be involved in the mechanism of kindling--an animal model of epileptogenesis. To test this hypothesis, a time-course study was carried out to investigate the effects of pentylenetetrazole kindling (40 mg/kg i.p., daily for eight days) on the expression of gene coding for preprothyrotropin-releasing hormone, the thyrotropin-releasing hormone tissue level and thyrotropin-releasing hormone receptor parameters in rat brain. As shown by an in situ hybridization study, a single, convulsant dose of pentylenetetrazole (70 mg/kg i.p.) increased the preprothyrotropin-releasing hormone messenger RNA level in the dentate gyrus of the hippocampal formation and piriform cortex after 3 h and, to a greater extent, after 24 h. Those changes were accompanied with increases in the thyrotropin-releasing hormone level in the striatum, hippocampus, amygdala and piriform cortex. Seven days after single pentylenetetrazole administration, the thyrotropin-releasing hormone level was still significantly elevated in the piriform cortex and striatum. Acute pentylenetetrazole decreased the density (Bmax) of thyrotropin-releasing hormone receptors in the striatum after 3 and 24 h, and increased that density in the piriform cortex and amygdala after 24 h and seven days, respectively. The thyrotropin-releasing hormone receptor affinity (Kd) was decreased in the striatum and increased in the amygdala after only 3 h. Kindled rats showed a moderate increase in the preprothyrotropin-releasing hormone messenger RNA content in the dentate gyrus of the hippocampal formation and piriform cortex after 3 and 24 h; however, a significant decrease in those parameters was found after 14 days. After 3 and 24 h, pentylenetetrazole kindling also elevated the thyrotropin-releasing hormone content in the hippocampus, piriform cortex, and striatum (in the latter structure after 24 h only), whereas in the septum the thyrotropin-releasing hormone level was decreased. After seven days, the thyrotropin-releasing hormone level was still elevated in the hippocampus and piriform cortex of kindled rats, but after 14 days it was significantly lowered in the hippocampus. The kindled rats also showed a significant decrease in the density (Bmax) of thyrotropin-releasing hormone receptors in the striatum (after 24 h, seven and 14 days), and an increase in the piriform cortex (after seven days). The thyrotropin-releasing hormone receptor affinity (Kd) value was increased in the hippocampus after seven and 14 days, and in the piriform cortex after seven days. These results indicate that pentylenetetrazole kindling induces long-lasting alterations in the thyrotropin-releasing hormone biosynthesis and thyrotropin-releasing hormone receptor affinity in discrete regions of rat brain. These region-specific changes, in particular down-regulation of the thyrotropin-releasing hormone biosynthesis in the hippocampus, may be involved in chronic neuronal hyperexcitability associated with kindling.
Sujet(s)
Encéphale/métabolisme , Régulation de l'expression des gènes , Embrasement/physiologie , Pentétrazol/toxicité , Précurseurs de protéines/génétique , Récepteur TRH/métabolisme , Hormone de libération de la thyréostimuline/génétique , Amygdale (système limbique)/métabolisme , Animaux , Encéphale/effets des médicaments et des substances chimiques , Corps strié/métabolisme , Hippocampe/métabolisme , Hybridation in situ , Cinétique , Mâle , Spécificité d'organe , Rats , Rat Wistar , Facteurs temps , Transcription génétiqueRÉSUMÉ
The effects of acute, subchronic ( 14 days) or chronic (28 days) intraperitoneal (i.p.) administration of chlorpromazine (2 or 10 mg/kg), haloperidol (0.5 or 2 mg/kg) or sulpiride (50 or 100 mg/kg) on the neuropeptide Y (NPY) system in the rat nucleus accumbens were studied. NPY-like immunoreactivity (NPY-LI) decreased in a dose- and time-dependent manner, and was the lowest after haloperidol. NPY-LI levels increased 8 days after withdrawal of chronic drugs treatment. Acute administration of haloperidol reduced NPY mRNA, while Subchronic treatment did not change it. Subchronic i.p. administration of the dopamine D1-like antagonist SCH 23390 (1 mg/kg) reduced NPY-LI levels but the alpha1-adrenergic antagonist prazosin (0.2 mg/kg) had no effect. The effect of sulpiride coadministered with SCH 23390 was greater than that of SCH 23390 alone, while prazosin coadministered with sulpiride insignificantly reduced the effect of sulpiride. The dopamine D2/D3 agonist quinpirole given as a single injection (3 mg/kg) did not alter NPY-LI content by itself but antagonized the chlorpromazine-induced decrease and attenuated the haloperidol-induced decrease. Our findings indicate that the accumbens NPY system is markedly affected by the antipsychotics studied, and suggest that their effects may be in part mediated by blockade of D2-like (D2, D3) and D1 dopaminergic receptors.
Sujet(s)
Neuroleptiques/pharmacologie , Chlorpromazine/pharmacologie , Antagonistes de la dopamine/pharmacologie , Halopéridol/pharmacologie , Neuropeptide Y/métabolisme , Noyau accumbens/métabolisme , Sulpiride/pharmacologie , Animaux , Antagonistes du récepteur D2 de la dopamine , Immunohistochimie , Hybridation in situ , Mâle , Noyau accumbens/effets des médicaments et des substances chimiques , ARN messager/biosynthèse , Rats , Rat Wistar , Récepteur dopamine D1/antagonistes et inhibiteurs , Syndrome de sevrage/métabolisme , Facteurs tempsRÉSUMÉ
The influence of dopaminergic denervation on neuropeptide Y and corticotropin-releasing factor-containing neurons in the amygdala was investigated in rats by examining the effects of a selective, unilateral 6-hydroxydopamine lesion of mesencephalic dopaminergic neurons in both the substantia nigra and the ventral tegmental area on these peptides and their messenger RNA expression, observed eight to 10 days after the lesion. The studies were conducted by immunocytochemical and in situ hybridization methods. Neuropeptide Y or corticotropin-releasing factor-immunoreactive neurons were counted in sections of the amygdala under a microscope, and the messenger RNA expression was measured as optical density units in autoradiograms. A significant increase in both neuropeptide Y and corticotropin-releasing factor messenger RNA expression was found in the amygdala on the lesioned side in comparison with the contralateral one, as well as with the ipsilateral side of vehicle-injected controls. Immunohistochemical studies showed that the number of neuropeptide Y-immunoreactive neurons increased in the whole amygdala on the lesioned side. At the same time, the number of corticotropin-releasing factor-immunoreactive neurons grouped in the central amygdaloid nucleus declined, and so did the staining intensity. The obtained results indicate that dopaminergic denervation stimulates the synthesis of neuropeptide Y and corticotropin-releasing factor in rat amygdala, but the peptide levels are differently regulated, which points to a diverse release of these peptides.
Sujet(s)
Amygdale (système limbique)/métabolisme , Corticolibérine/métabolisme , Neuropeptide Y/métabolisme , Oxidopamine/pharmacologie , Amygdale (système limbique)/effets des médicaments et des substances chimiques , Animaux , Corticolibérine/génétique , Histocytochimie , Immunohistochimie , Hybridation in situ , Mâle , Neuropeptide Y/génétique , ARN messager/métabolisme , Rats , Rat WistarRÉSUMÉ
Striatal neuropeptide Y-like immunoreactivity (NPY-LI) levels were investigated in naive rats after acute, subchronic (14 days) or chronic (28 days) intraperitoneal (i.p.) treatment with chlorpromazine (2 or 10mg/kg), haloperidol (0.5 or 2 mg/kg), (+/-)sulpiride (50 or 100 mg/kg) or clozapine (10 or 25 mg/kg), and in chronically treated rats after 8-day drug withdrawal. The most pronounced changes in NPY-LI levels were found 24 h after acute chlorpromazine or haloperidol administration (a decrease) and after withdrawal of chlorpromazine, haloperidol or sulpiride (an increase). The effect of clozapine on NPY-LI differed from those of the other antipsychotics: both single doses had no effect, the higher chronic dose increased NPY-LI levels, and its withdrawal resulted in their decrease. No significant alterations were detected in the hybridization signal of NPY mRNA in response to acute or subchronic administration of haloperidol or clozapine. Our results suggest that the effects of antipsychotics are in part mediated by blockade of dopamine D2-like (D2/D3) or serotonin 5HT2A receptors but not dopamine D1, D4 or alpha1-adrenergic receptors. The antipsychotic-induced changes in NPY system activity has been discussed in connection with adaptive alterations in the dopamine system.
Sujet(s)
Neuroleptiques/pharmacologie , Corps strié/métabolisme , Neuropeptide Y/génétique , Neuropeptide Y/métabolisme , Antagonistes adrénergiques/pharmacologie , Animaux , Chlorpromazine/pharmacologie , Clozapine/pharmacologie , Corps strié/effets des médicaments et des substances chimiques , Antagonistes de la dopamine/pharmacologie , Halopéridol/pharmacologie , Hybridation in situ , Injections péritoneales , Mâle , Neuropeptide Y/immunologie , ARN messager/métabolisme , Rats , Rat Wistar , Récepteurs alpha-1 adrénergiques/physiologie , Récepteurs dopaminergiques/physiologie , Récepteurs sérotoninergiques/physiologie , Antisérotonines/pharmacologie , Sulpiride/pharmacologieRÉSUMÉ
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 alpha-neoendorphin tissue level, and its in vitro release in the nucleus accumbens and striatum of rats. The density of kappa 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 alpha-neoendorphin tissue level, whereas chronic administration of those drugs elevated the alpha-neoendorphin level in the nucleus accumbens and striatum at the late time-points studied. Acute and repeated cocaine administration had no effect on alpha-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 alpha-neoendorphin in both these structures. Addition of cocaine or amphetamine to the incubation medium (10(-5)-10(-6) M) decreased the basal release of alpha-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 kappa 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 kappa opioid receptor density at a late withdrawal time.
Sujet(s)
Chimie du cerveau/effets des médicaments et des substances chimiques , Stimulants du système nerveux central/pharmacologie , Enképhalines/physiologie , Précurseurs de protéines/physiologie , Récepteur kappa/métabolisme , Amfétamine/pharmacologie , Animaux , Autoradiographie , Cocaïne/pharmacologie , Inhibiteurs de la capture de la dopamine/pharmacologie , Endorphines/biosynthèse , Hybridation in situ , Mâle , Précurseurs de protéines/biosynthèse , ARN messager/biosynthèse , Dosage radioimmunologique , Rats , Rat WistarRÉSUMÉ
It has been hypothesized that changes in the excitatory amino acid receptor biosynthesis may be involved in the mechanism of kindling-an animal model of epileptogenesis. In order to test this hypothesis, we investigated the effects of pentylenetetrazol kindling on the expression of genes coding for NMDAR1 and GluR2 in the rat hippocampal formation. Pentylenetetrazol kindling decreased the hippocampal NMDAR1 mRNA level after 3 and 24 h; lowered the GluR2 flip level and elevated the flop mRNA one in the CA1 field and dentate gyrus after 3 and 24 h, respectively. A receptor autoradiography showed an increase in the [3H]MK-801 binding density in the hippocampus following both acute and repeated pentylenetetrazol administration. We conclude that an early occurrence of downregulation of the glutamate receptor gene expression may be an adaptive response of glutamate receptors to an oversupply of excitatory amino acids during repeated seizures.
Sujet(s)
Régulation de l'expression des gènes/physiologie , Hippocampe/physiologie , Embrasement/physiologie , Pentétrazol/pharmacologie , Récepteur de l'AMPA/biosynthèse , Récepteurs au glutamate/biosynthèse , Récepteurs du N-méthyl-D-aspartate/biosynthèse , Animaux , Autoradiographie , Maléate de dizocilpine/métabolisme , Régulation négative , Régulation de l'expression des gènes/effets des médicaments et des substances chimiques , Hippocampe/effets des médicaments et des substances chimiques , Hippocampe/métabolisme , Cinétique , Mâle , Neurones/effets des médicaments et des substances chimiques , Neurones/métabolisme , Cellules pyramidales/effets des médicaments et des substances chimiques , Cellules pyramidales/métabolisme , ARN messager/biosynthèse , Rats , Rat Wistar , Facteurs temps , TritiumRÉSUMÉ
Involvement of opioid systems in the pathogenesis of absence epilepsy has been postulated. However, the role of the mu opioid receptor has not been fully elucidated as yet. In the present study the role of this receptor in absence epilepsy was investigated autoradiographically and pharmacologically. The density of mu opioid receptors in discrete brain areas was quantified in WAG/Rij rats, which are regarded as a genetic model of primarily generalized absence epilepsy and in three control groups of non-epileptic rats. The autoradiographic study showed an abundance of mu opioid receptors (labelled with [3H]DAMGO) in the structures involved in generation and propagation of spike-wave discharges, such as the thalamus, cortex and striatum. A significant decrease in the mu receptor density was found only in the frontal cortex of epileptic WAG/Rij rats. In the pharmacological study, the effect of mu opioid receptor activation in different brain structures of WAG/Rij rats on the number of complexes of spike-wave discharges was investigated. DAMGO (0.02 and 0.07 microg/0.5 microl) was bilaterally injected into the thalamus, striatum and frontal cortex. DAMGO resulted in a dose-related increase in the number of spike-wave discharges after intracortical and intrastriatal administration by approximately 200-300% and after intrathalamic administration by approximately 500%. The injection of DAMGO into those structures had no significant effect of any kind on the behavior measured, except for passive behavior which was reduced after intrastriatal injection. The high density of mu opioid receptors in the areas involved in the genesis of spike-wave discharges, as well as the highest responsiveness of thalamic mu opioid receptors to the epileptogenic effects of DAMGO, suggest involvement of mu receptors in the genesis of spike-wave discharges.
Sujet(s)
Encéphale/anatomie et histologie , Encéphale/physiopathologie , Petit mal épileptique/physiopathologie , Récepteur mu/physiologie , Analgésiques morphiniques/administration et posologie , Analgésiques morphiniques/pharmacologie , Animaux , Autoradiographie , Comportement animal/effets des médicaments et des substances chimiques , Électroencéphalographie/effets des médicaments et des substances chimiques , Lobe frontal/effets des médicaments et des substances chimiques , Injections ventriculaires , Mâle , Putamen/effets des médicaments et des substances chimiques , Rats , Lignées consanguines de rats , Récepteur mu/agonistes , Noyaux du thalamus/composition chimique , Noyaux du thalamus/effets des médicaments et des substances chimiquesRÉSUMÉ
Effects of acute and chronic treatment with the noncompetitive NMDA receptor antagonist MK-801 on the NMDAR1 and GluR2 (flip and flop) receptor mRNA levels were estimated in the rat hippocampal formation. An in situ hybridization study showed that a single injection of MK-801 increased the NMDAR1 mRNA level in the CA1 region after 3 and 24 h, and in the CA3 one after 3 h, whereas chronic administration of the drug increased the mRNA level in the dentate gyrus and CA1 at the latter time. The level of the flip version of GluR2 mRNA was decreased in the CA3 region, and dentate gyrus at 3 and 24 h following acute MK-801 administration. Chronic MK-801 administration decreased GluR2 flip mRNA level in the dentate gyrus at 3 and 24 h, and in the CA1 region at 3 h only. On the other hand, chronic, but not acute, MK-801 administration elevated the GluR2 flop mRNA level in the CA1 region and dentate gyrus 24 h after the last drug injection. In summary, the above data indicate that both acute and chronic MK-801 administration affect the NMDAR1 and GluR2 receptor gene expression in the rat hippocampal formation in a time- and region-specific manner. These changes may, in turn, influence the glutamatergic transmission and/or susceptibility to the EAA-mediated excitotoxicity of hippocampal neurons.
Sujet(s)
Maléate de dizocilpine/pharmacologie , Antagonistes des acides aminés excitateurs/pharmacologie , Régulation de l'expression des gènes/effets des médicaments et des substances chimiques , Hippocampe/effets des médicaments et des substances chimiques , Récepteur de l'AMPA/effets des médicaments et des substances chimiques , Récepteurs au glutamate/effets des médicaments et des substances chimiques , Récepteurs du N-méthyl-D-aspartate/effets des médicaments et des substances chimiques , Animaux , ADN complémentaire/métabolisme , Gyrus denté/métabolisme , Maléate de dizocilpine/administration et posologie , Hippocampe/métabolisme , Hybridation in situ , Mâle , ARN messager/métabolisme , Rats , Rat Wistar , Récepteur de l'AMPA/génétique , Récepteurs au glutamate/métabolisme , Récepteurs du N-méthyl-D-aspartate/génétiqueRÉSUMÉ
The effect of alpha 2 adrenoceptor stimulation on neuropeptide Y (NPY) and NPYmRNA expression was studied in the rat cerebral cortex. For receptor stimulation clonidine was used in a dose of 50 micrograms/kg s.c., 3 times at every 8 h; brains were studied 30-40 min after the last dose using radioimmunoassay (RIA), immunocytochemistry and in situ hybridization methods. The RIA of NPY did not show any significant changes in the NPY immunoreactivity (IR) level in the whole cortex, whereas the immunohistochemical analysis demonstrated an increase in the number of NPY-IR neurons in ventral cortical regions, especially in external cortical layers. In situ hybridization histochemistry of NPYmRNA also performed in ventral cortical sections showed that clonidine increased NPY synthesis in some cortical neurons. The obtained results indicate that the alpha 2 adrenoceptor stimulation by clonidine increases the NPY content and synthesis in rat cortical neurons.
Sujet(s)
Agonistes alpha-adrénergiques/pharmacologie , Cortex cérébral/cytologie , Clonidine/pharmacologie , Neuropeptide Y/génétique , Animaux , Anticorps/pharmacologie , Cortex cérébral/composition chimique , Cortex cérébral/métabolisme , Immunohistochimie , Hybridation in situ , Mâle , Neurones/composition chimique , Neurones/effets des médicaments et des substances chimiques , Neurones/métabolisme , Neuropeptide Y/immunologie , Neuropeptide Y/métabolisme , ARN messager/métabolisme , Dosage radioimmunologique , Rats , Rat WistarRÉSUMÉ
The effects of pilocarpine- and kainate-induced seizures on N-methyl-D-aspartate receptor subunit-1 messenger RNA and [3H]dizocilpine maleate binding were studied in the rat hippocampal formation. Pilocarpine- but not kainate-induced seizures decreased N-methyl-D-aspartate receptor subunit-1 messenger RNA level in dentate gyrus at 24 and 72 h after drug injection. Both convulsants decreased the messenger RNA level in CA1 pyramidal cells at 24 and 72 h, the effects of kainate being more profound. Kainate also decreased the N-methyl-D-aspartate receptor subunit-1 messenger RNA level in CA3 region after 24 and 72 h, whereas pilocarpine decreased the messenger RNA level at 72 h only. At 3 h after kainate, but not pilocarpine, an increased binding of [3H]dizocilpine maleate in several apical dendritic fields of pyramidal cells was found. Pilocarpine reduced the [3H]dizocilpine maleate binding in stratum lucidum only at 3 and 24 h after the drug injection. Pilocarpine but not kainate induced prolonged decrease in N-methyl-D-aspartate receptor subunit-1 gene expression in dentate gyrus. However, at the latest time measured, kainate had the stronger effect in decreasing both messenger RNA N-methyl-D-aspartate receptor subunit-1 and [3H]dizocilpine maleate binding in CA1 and CA3 hippocampal pyramidal cells. The latter changes corresponded, however, to neuronal loss and may reflect higher neurotoxic potency of kainate. These data point to some differences in hippocampal N-methyl-D-aspartate receptor regulation in pilocarpine and kainate models of limbic seizures. Moreover, our results suggest that the N-methyl-D-aspartate receptor subunit-1 messenger RNA level is more susceptible to limbic seizures than is [3H]dizocilpine maleate binding in the rat hippocampal formation.
Sujet(s)
Agonistes des acides aminés excitateurs , Expression des gènes , Hippocampe/effets des médicaments et des substances chimiques , Hippocampe/physiopathologie , Acide kaïnique , Pilocarpine , Récepteurs du N-méthyl-D-aspartate/génétique , Crises épileptiques/induit chimiquement , Animaux , Comportement animal , Maléate de dizocilpine/métabolisme , Antagonistes des acides aminés excitateurs/métabolisme , Hippocampe/anatomopathologie , Mâle , ARN messager/métabolisme , Rats , Rat Wistar , Crises épileptiques/métabolisme , Crises épileptiques/anatomopathologieRÉSUMÉ
Effects of single (20 mg/kg i.p.) and repeated morphine administration (increasing doses: from 10 to 50 mg/kg i.p. twice daily for 7 days) on the proenkephalin (PENK), prodynorphin (PDYN) and dopamine D2 receptor (D2) mRNA levels in the nucleus accumbens and striatum of the mouse were investigated. As shown by an in situ hybridization, a single dose of morphine had no significant effect on the PDYN, PENK and D2 mRNA levels in the nucleus accumbens and striatum. Repeated treatment with morphine increased the PDYN mRNA level in both those structures after 2 and 72 h. In contrast to PDYN, the PENK mRNA level was reduced in the nucleus accumbens and remained unchanged in the striatum following repeated morphine administration. Repeated morphine had no effect on the D2 mRNA level in the nucleus accumbens and striatum after 2 h, and decreased it in the nucleus accumbens after 72 h only. The above results indicate that repeated morphine leads to long-lasting upregulation of the PDYN gene expression in the mouse nucleus accumbens and striatum; on the other hand, the PENK and D2 mRNA gene expressions are either inhibited or remain unchanged, significant changes being observed in the nucleus accumbens only.
Sujet(s)
Chimie du cerveau/effets des médicaments et des substances chimiques , Enképhalines/génétique , Morphine/pharmacologie , Stupéfiants/pharmacologie , Précurseurs de protéines/génétique , Récepteur D2 de la dopamine/génétique , Animaux , Autoradiographie , Chimie du cerveau/génétique , Corps strié/composition chimique , Corps strié/effets des médicaments et des substances chimiques , Expression des gènes/effets des médicaments et des substances chimiques , Mâle , Souris , Noyau accumbens/composition chimique , Noyau accumbens/effets des médicaments et des substances chimiques , ARN messager/métabolismeRÉSUMÉ
The expression of mRNA coding for AMPA selective glutamate (Glu) R2 receptor and kainate selective GluR5 receptor was studied in the rat hippocampal formation in two animal models of limbic seizures evoked by systemic administration of pilocarpine (400 mg/kg i.p.) or kainate (15 mg/kg i.p.). As shown by an in situ hybridization study, pilocarpine decreased the GluR2 flip mRNA level in CA1 and CA3 areas of the hippocampus after 3h and kainate after 24h, e.g. at the time preceding neuronal degeneration. No changes in the GluR2 flop or GluR5 mRNA level were found in those regions. In the dentate gyrus, resistant to neurodegeneration, pilocarpine and kainate differentially affected the expression of GluR2 and GluR5 mRNAs. After 72h pilocarpine, but not kainate, increased the GluR2 flop mRNA level and decreased the flip one, which suggests attenuation of the GluR2 sensitivity. On the other hand, kainate, elevated the GluR2 flip and GluR5 mRNA level in the dentate gyrus after 72h. All in all the above data suggest that changes in the GluR2 gene expression may play some role in the neuronal damage to vulnerable areas (CA1, CA3). However, differences in the kainate-and pilocarpine-induced changes in the dentate gyrus at the late time points indicate that alterations in the stoichiometry of GluR2 forms of GluR5 gene expression in this brain region are not a common causal factor responsible for delayed neuronal hyperexcitability.