Biomedical subjects

W Lasoń

Publications and source records attributed to W Lasoń.

At least 19 recordsLinked to original sources

PubMed2006

Inhibitory effect of antipsychotic drugs on the Con A- and LPS-induced proliferative activity of mouse splenocytes: a possible mechanism of action.

Antipsychotic drugs are widely used to alleviate a number of psychic disorders and have been found to modulate some immune parameters, but the molecular mechanism of their action on the proliferative activity has been poorly recognized. In the present study, we investigated effects of various antipsychotics on the proliferative activity of lymphocytes stimulated by concanavalin A (Con A) and lipopolysaccharide (LPS). Chlorpromazine (3 x 10(-6)-10(-4) M) showed the most potent effect in inhibiting 3H-thymidine incorporation into C57BL/6 mouse spleen cells stimulated by Con A and LPS. Treatment of the cells with thioridazine (10(-5)-10(-4) M), promazine (10(-5)-10(-4) M), haloperidol (10(-5)-10(-4) M), risperidone (10(-5)-10(-4) M), raclopride (3 x 10(-5) - 10(-4) M), remoxipride (3 x 10(-5)-10(-4) M) and clozapine ( 3 x 10(-5)-10(-4) M), but not with sulpiride (10(-7)-10(-4) M), suppressed proliferative activity of splenocytes after Con A stimulation. On the other hand, LPS-induced proliferation of splenocytes was inhibited by clozapine, promazine, thioridazine and haloperidol, but not by risperidone, remoxipride, sulpiride and raclopride. In the next part of the study, the influence of some kinase modulators on chlorpromazine- and clozapine-evoked inhibition of the proliferative activity of splenocytes was determined. Wortmannin, a selective phosphatidylinositol 3-kinase (PI3-K) inhibitor, blocked chlorpromazine and clozapine inhibitory effect on the mitogen-stimulated splenocyte proliferation. The involvement of PI 3-K /protein kinase B (PKB, Akt) pathway was confirmed by the results of the Western blot study, which showed that both drugs increased the level of active phospho-Ser-473 Akt, without changing the total Akt level, and decreased the level of active, nonphosphorylated glycogen synthase kinase-3 (GSK-3beta). Additionally, we have found that chlorpromazine action was also attenuated by a selective p-38-MAPK inhibitor, while clozapine effect was suppressed by a protein kinase C (PKC) activator. The obtained results indicated that atypical antipsychotic drugs markedly inhibited the proliferative activity of splenocytes only after ConA stimulation. Inhibition of the proliferative capability of splenocytes by chlorpromazine and clozapine resulted mainly from the activation of PI3-K/Akt pathway.

Androstadienes↗

PubMed2005

Effect of combined treatment with imipramine and metyrapone on the immobility time, the activity of hypothalamo-pituitary-adrenocortical axis and immunological parameters in the forced swimming test in the rat.

Major depression is frequently associated with the hyperactivity of the hypothalamic-pituitary-adrenocortical axis, and glucocorticoid synthesis inhibitors have been shown to exert antidepressant action. The aim of the present study was to examine the effect of joint administration of metyrapone (50 mg/kg) and imipramine (5 and/or 10 mg/kg) on immobility time, plasma corticosterone concentration, the weight of spleens and thymuses and the proliferative activity of splenocytes in rats subjected to the forced swimming test--an animal model of depression. Metyrapone alone (50 mg/kg) reduced the immobility time of rats in the forced swimming test and decreased plasma corticosterone level, but did not change immunological parameters. Joint administration of metyrapone and imipramine (5 and 10 mg/kg) produced a more pronounced antidepressant-like effect than either of the drugs given alone. The forced swimming procedure significantly increased the proliferative activity of splenocytes, that parameter being reduced only by co-administration of metyrapone and imipramine. Joint administration of metyrapone and imipramine inhibited to a similar extend the corticosterone level as did treatment with metyrapone alone (about twofold); however, the plasma corticosterone level in animals treated with metyrapone and the higher dose of imipramine did not differ from the concentration of this steroid in control, not-stressed rats. The obtained results indicate that metyrapone potentiates the antidepressant-like activity of imipramine and exerts a beneficial effect on the stress-induced increase in plasma corticosterone concentration and the proliferative activity of splenocytes. These finding suggest that a combination of metyrapone and an antidepressant drug may be useful for the treatment drug-resistant depression and/or depression associated with a high cortisol level.

Animals↗

PubMed2005

Effects of estrone on quisqualate-induced toxicity in primary cultures of rat cortical neurons.

Estrogens exert protective effects against neurotoxic changes induced by over-activation of ionotrophic glutamate receptors, whereas little is known about their interaction with changes mediated by metabotropic glutamate receptors. We evaluated effects of estrone on quisqualate (QA)-induced toxicity in neuronal cell cultures on 7 and 12 day in vitro (DIV). Twenty four hour exposure to QA (150 microM and 300 microM) significantly decreased cell survival in 7 day old cultures, but the 12 day old cultures were more resistant to its toxicity. DNQX (10 microM), an AMPA/kainate receptor antagonist, partly attenuated the toxic effects of QA, whereas LY 367 385 (100 microM), a selective mGluR1a antagonist, completely reversed the above effect. QA did not activate, but suppressed spontaneous caspase-3-like activity. Estrone (100 nM and 500 nM) attenuated QA-mediated neurotoxic effects independently of estrogen receptors, as indicated with ICI 182, 780 and without affecting the caspase-3-like activity. At early stage of development in vitro (7 DIV) toxic effects of QA were more profound and mediated mainly by metabotropic glutamate receptors of group I, whereas later (12 DIV) they were mediated mostly by ionotropic AMPA/kainate receptors. The toxic effects of QA were partly accompanied by anti-apoptotic action against spontaneous caspase-3-like activity, possibly due to modulation of neuronal plasticity.

Animals↗

PubMed2004

Neuroprotective effects of (24R)-1,24-dihydroxycholecalciferol in human neuroblastoma SH-SY5Y cell line.

The active form of Vitamin D(3) has been reported to prevent neuronal damage caused by a variety of insults, however, it may also induce undesirable hypercalcemic effects. In the present study, we evaluated effects of (24R)-1,24-dihydroxycholecalciferol (PRI-2191) on hydrogen peroxide- and excitatory amino acid-induced neuronal damage in human neuroblastoma (SH-SY5Y) cell line. Exposure of SH-SY5Y cells to N-methyl-d-aspartate (NMDA; 5mM), kainate (0.2mM) and hydrogen peroxide (0.1-1mM) significantly enhanced lactate dehydrogenase release. Furthermore, the neurotoxic effects of hydrogen peroxide was dependent on c-Jun N-terminal kinase (JNK)- and p38- mitogen-activated protein kinase (MAPK) activity. Both secosteroids at nanomolar concentrations inhibited neuronal damage, but their efficacy varied depending on the toxic agent. PRI-2191 was equipotent as 1alpha,25-dihydroxyVitamin D(3) in protecting SH-SY5Ycells against NMDA toxicity, and had stronger effect against hydrogen peroxide-induced damage, but was less efficient against kainate-induced injury. The obtained results suggest potential usefulness of PRI 2191 in the treatment of neurodegenerative diseases.

Cell Line, Tumor↗

PubMed2004

Effects of estrone on N-methyl-D-aspartic acid- and staurosporine-induced changes in caspase-3-like protease activity and lactate dehydrogenase-release: time- and tissue-dependent effects in neuronal primary cultures.

A growing body of evidence indicates that estrogens affect apoptotic processes in neuronal cells. However, their effects seem to depend on type of neuronal tissue, stage of development and apoptosis inducing factors. In the present study we compared effects of estrone (100 and 500 nM) on N-methyl-D-aspartic acid (NMDA) (1 mM)- and staurosporine (1 microM)-induced caspase-3-like activity and lactate dehydrogenase (LDH)-release in primary cultures of rat hippocampal and neocortical neurons. Fluorometric and colorimetric determination of enzyme activity was performed 6 h, 14 h, and 24 h after exposure to apoptotic agents. In the hippocampal cell cultures on 7 days in vitro (DIV), a time-dependent NMDA-induced activation of caspase-3-like proteases was accompanied by increased LDH-release. In neocortical cell cultures on 7 DIV NMDA did not affect caspase activity and decreased LDH-release. In neocortical cell cultures on 12 DIV NMDA inhibited spontaneous caspase activity, but was toxic to neurons after 24 h exposure suggesting that these cells underwent necrotic rather than apoptotic death. Estrone has attenuated both pro- and anti-apoptotic NMDA-induced changes in rat primary neuronal cultures acting independently of estrogen receptors, as detected with ICI 182, 780. In hippocampal neurons estrone antagonized not only the NMDA-induced caspase-3-like activity, but also NMDA-mediated LDH-release. However, in neocortical neurons estrone either attenuated NMDA-induced inhibition of caspase-3-like activity (12 DIV) or partly blocked NMDA-mediated decrease in LDH-release (7 DIV). In contrast to NMDA, staurosporine elevated caspase-3-like activity and LDH-release in a time-dependent manner in all used culture systems. Estrone inhibited pro-apoptotic effects of staurosporine in neocortical neurons, but only at later stage of development in vitro, which points to the protective role of estrogens during the brain tissue maturation. Since estrone triggered its effects via non-genomic mechanisms, it suggests that the other estradiol metabolites exhibiting low affinity to hormone receptors may be potent neuroprotective agents, which could retain the favorable and minimize the adverse side effects of estrogens.

Animals↗

PubMed2002

Chlorpromazine inhibits the glucocorticoid receptor-mediated gene transcription in a calcium-dependent manner.

Antipsychotic drugs can modulate transcription factors and also nuclear receptors, but their action on glucocorticoid receptors (GR)-members of the steroid/thyroid hormone receptor family has not been studied so far. In the present study we investigated effects of various antipsychotics on the glucocorticoid-mediated gene transcription in fibroblast cells, stably transfected with a mouse mammary tumor virus promoter (LMCAT cells). Chlorpromazine (3-100 microM) inhibited the corticosterone-induced gene transcription in a concentration- and time-dependent manner. Clozapine showed a similar, but less potent effect, while haloperidol acted only in high concentrations, and other antipsychotic drugs (sulpiride, raclopride, remoxipride) were without any effect. It was also found that a phorbol ester (an activator of protein kinase C (PKC)) and A-23187 (Ca(2+)-ionophore) attenuated the inhibitory effect of chlorpromazine on the GR-induced gene transcription. An antagonist of the L-type Ca(2+) channel, as well as an inhibitor of phospholipase C (PLC) inhibited the corticosterone-induced gene transcription, but had no effect on the chlorpromazine-induced changes. The involvement of a PKC/PLC pathway in the chlorpromazine action was confirmed by Western blot analysis which showed that the drug in question decreased the PLC-beta(1) protein level, and to a lesser extent that of the PKC-alpha protein in LMCAT cells. The aforementioned data suggest that inhibition of the glucocorticosteroid-induced gene transcription by chlorpromazine and clozapine may be a mechanism by which these drugs block some effects induced by glucocorticoids. The inhibitory effect of chlorpromazine on the corticosterone-induced gene transcription seems to depend on the inhibition of Ca(2+) influx and/or the inhibition of some calcium-dependent enzymes, e.g. phospholipase beta(1).

Animals↗

PubMed2002

Effect of allopregnanolone on d-[3H]-aspartate release and [3H]-glutamate uptake in the hippocampus of kainate-treated mice.

In order to determine whether the status epilepticus leads to alterations in the neurosteroid effect on excitatory amino acid transmission, we studied the influence of allopregnanolone on aspartate release and glutamate uptake in mouse hippocampus at various times after kainate administration. No significant differences in the K+-stimulated D-[3H]-aspartate release from the hippocampi of saline- and kainate-treated mice were observed; however, that parameter tended to fall in tissues collected I h after kainate administration. Allopregnanolone significantly attenuated the K+-stimulated D-[3H]-aspartate release from the hippocampi of control animals, as well at 24 h and 7 days after kainate injection; in contrast it did not affect amino acid release from the hippocampi collected 1 h after kainate administration. Kainate administration had no effect on [3H]-glutamate uptake after 1 and 24 h, but elevated that parameter on day 7. Allopregnanolone (10 and 100 microM) did not affect [3H]-glutamate uptake in control and kainate-treated mice. In conclusion, the present study indicates a loss of the inhibitory effect of allopregnanolone on the potasium-stimulated D-[3H]-aspartate release from mouse hippocampus during the kainate-induced status epilepticus; moreover, it excludes involvement of this neurosteroid in the regulation of hippocampal [3H]-glutamate uptake in both control and kainate-treated mice.

Animals↗

PubMed2001

Protective effects of TRH and its stable analogue, RGH-2202, on kainate-induced seizures and neurotoxicity in rodents.

Thyrotropin-releasing hormone (TRH) has been postulated to be involved in the regulation of seizures and neural degeneration. We examined the effects of TRH and its stable analogue, RGH-2202, on the kainate-induced seizures and excitotoxicity in mice - a model of a drug-resistant temporal lobe epilepsy. We found that TRH (2.0 and 5.0 mg/kg) and RGH-2202 (2.5 and 5 mg/kg) elevated the ED(50) for kainate-induced convulsions and tended to decrease mortality. A histological analysis showed that kainate caused a neuronal loss of CA(1) and CA(3) hippocampal fields. TRH (10, 20 and 50 mg/kg) and RGH-2202 (2.5, 7.5 and 10.0 mg/kg) markedly reduced the excitotoxic effect of kainate. Further studies showed that TRH (1-100 microM) and RGH-2202 (100 microM) significantly attenuated the kainate (150 microM)-induced lactate dehydrogenase release in a primary cortical cell culture from rat embryos. In conclusion, the present study showed that TRH and RGH-2202 attenuated the kainate-induced seizures and inhibited the kainate-evoked neurotoxicity in vivo and in vitro. These results support the hypothesis of a potential utility of TRH and its analogues in the treatment of seizures and some neurodegenerative diseases.

Animals↗

PubMed2001

The ovarian hormones and absence epilepsy: a long-term EEG study and pharmacological effects in a genetic absence epilepsy model.

In the first experiment, the relationship between the phase of the estrous cycle and the number of spontaneously occurring spike-wave discharges was investigated in WAG/Rij rats, a model for generalized absence epilepsy. The electroencephalogram (EEG) was continuously recorded for 96 h in eight rats chronically equipped with cortical EEG electrodes. A circadian pattern emerged for the number of spike-wave discharges: a nadir during the first hours of the light period, and an acrophase during the first hours of the dark period. This daily maximum was increased at proestrus day compared with the other days of the cycle, when the plasma level of progesterone is enhanced specifically at these hours of this day. This suggests that progesterone enhances spike-wave discharges. There was no difference in the first few hours of the light period in the number of spike-wave discharges between proestrus and the three other days, suggesting that estradiol has no effect on spike-wave discharges. In the second study, the effects of the systemic administration of progesterone and 17 beta-estradiol on spike-wave discharges and spontaneous behavior were investigated. It was shown that progesterone (20 and 30 mg/kg) but not estradiol (0.17-1.5 mg/kg) increased the number and total duration of spike-wave discharges. On the other hand, injection of RU 38486 (10 and 30 mg/kg), an antagonist of intracellular progesterone receptors, had no effect on spike-wave discharges and did not block the stimulatory effect of progesterone. The antagonist of 17 beta-estradiol tamoxifen (1 and 3 mg/kg) did not evoke alterations in the number or duration of spike-wave discharges. Our results indicate that progesterone aggravates spike-wave discharges, but is not mediated through intracellular receptors. Since progesterone is rapidly metabolized in the brain to the positive modulator of GABA(A) receptor allopregnanolone, which increases spike-wave discharges in WAG/Rij rats, it is possible that the epileptiformic effects of progesterone are mediated through this metabolite.

Animals↗

PubMed2001

Estrone, but not 17 beta-estradiol, attenuates kainate-induced seizures and toxicity in male mice.

Estrogens change the susceptibility to seizures in humans and experimental animals. In this study, the effect of estrone and 17 beta-estradiol on kainate-induced seizures and neurotoxicity was investigated in male mice. Pre-treatment with estrone (250-1000 micrograms/kg) at 24 and 2 hours before kainate (40 mg/kg) administration significantly decreased both the percentage of animals with clonic seizures and their mortality (the latter at a dose of 1000 micrograms/kg only). On the other hand, 17 beta-estradiol (10-500 micrograms/kg) had no effect on seizures, and its dose of 10 micrograms/kg increased mortality. When given alone at a dose of 1 mg/kg, tamoxifen, an antagonist at estrogene receptors, did not affect the kainate-induced seizures, but prevented the anticonvulsant effect of estrone. A histological analysis showed that 73% of mice injected with vehiculum and kainate incurred hippocampal damage. Estrone (2000 micrograms/kg) decreased the percentage of animals with hippocampal neuronal loss down to 43%, and that effect was not antagonized by tamoxifen. Pretreatment of mice with 17 beta-estradiol had no effect on the kainate-induced neuronal loss. Additionally, we found that kainate injected i.p. had a profound effect on the immune system of mice, as reflected by a decrease in the thymus weight and an increased metabolic activity of splenocytes. The anticonvulsive dose of estrone (1000 micrograms/kg) did not change the immunoreactivity of either control or kainate-treated mice. In conclusion, the obtained data indicate that estrone, but not 17 beta-estradiol, attenuates the kainate-induced seizures, mortality and excitotoxicity in male mice. Moreover, it is suggested that the suppressive effect of estrone on clonic seizures involves intracellular receptors, whereas its antineurotoxic activity seems to depend on a non-genomic mechanism.

Animals↗

PubMed2001

Effects of 17-beta estradiol and estriol on NMDA-induced toxicity and apoptosis in primary cultures of rat cortical neurons.

Estrogens possess neuroprotective and antiapoptotic properties, however, the issue of involvement of estrogen receptors (ER)-dependent genomic pathway in these effects still remains controversial. Moreover, the majority of data on antiapoptotic effects of estrogens concern non-neuronal cells. In the present study we compared effects of the potent ER agonist, estradiol-17beta (E2), and its metabolite with a weak affinity for ER, estriol, on the neurotoxicity induced by high (1 and 5 mM) NMDA concentrations and on the apoptosis induced by low (0.1 mM) concentration of NMDA in rat primary cortical neurons. The obtained data showed that 24-hour exposure of cortical neurons to NMDA (0.1-5 mM) resulted in a dose-dependent increase in LDH level. Twenty four-hour pretreatment with estriol (100 nM and 500 nM) reduced the NMDA (1 and 5 mM)-induced toxicity by 16-26%, while estradiol-17beta (500 nM) reduced NMDA (5 mM)- induced toxicity by 14%. Twenty four hour exposure of cortical neurons to NMDA (0.1 mM) resulted in decrease of the level of antiapoptotic protein - Bcl-2 by 60% and increased the number of apoptotic cells by 50% compared to the control. Twenty four hour pretreatment with estradiol-17beta or estriol (100 and 1000 nM) prevented the NMDA-induced apoptotic changes. The specific estrogen receptor antagonist ICI 182,780 (100 nM) had no effect alone and did not antagonize the effects of estrogens on NMDA-induced toxicity as well as on changes in Bcl-2 level. The higher efficacy of estriol, together with the fact that the specific ER receptor antagonist, ICI 182,780, did not inhibit the above-described effects support the hypothesis about a nongenomic mechanism of the anti-NMDA action of estrogens.

Adrenocorticotropic Hormone↗

PubMed2000

Antidepressant drugs inhibit glucocorticoid receptor-mediated gene transcription - a possible mechanism.

1. Antidepressant drugs are known to inhibit some changes evoked by glucocorticoids, as well as a hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis, often observed in depression. 2. The aim of present study was to investigate effects of various antidepressant drugs on the glucocorticoid-mediated gene transcription in fibroblast cells, stably transfected with an MMTV promoter (LMCAT cells). 3. The present study have shown that antidepressants (imipramine, amitriptyline, desipramine, fluoxetine, tianeptine, mianserin and moclobemide), but not cocaine, inhibit the corticosterone-induced gene transcription in a concentration- and a time-dependent manner. 4. Drugs which are known to augment clinical effects of medication in depressed patients (lithium chloride, amantadine, memantine), do not affect the inhibitory effects of imipramine on the glucocorticoid receptor (GR)-mediated gene transcription. 5. Inhibitors of phospholipase C (PLC), protein kinase C (PKC), Ca(2+)/calmodulin-dependent protein kinase (CaMK) and antagonists of the L-type Ca(2+) channel also inhibit the corticosterone-induced gene transcription. 6. Inhibitors of protein kinase A (PKA) and protein kinase G (PKG) are without effect on the GR-induced gene transcription. 7. Phorbol ester (an activator of PKC) attenuates the inhibitory effect of imipramine on the GR-induced gene transcription. 8. Imipramine decreases binding of corticosterone-receptor complex to DNA. 9. It is concluded that antidepressant drugs inhibit the corticosterone-induced gene transcription, and that the inhibitory effect of imipramine depends partly on the PLC/PKC pathway.

Amantadine↗

PubMed2000

Oestrogen effects on kainate-induced toxicity in primary cultures of rat cortical neurons.

Oestrogens protect neurons against excitatory amino acid-induced toxicity; however data on their interaction with particular subtype of glutamate receptors are sparse. Therefore in the present study we investigated oestrogen effects on kainate neurotoxicity in primary cortical neurons. The data showed that both oestradiol-17 beta and oestrone (100 nM and 200 nM) reduced kainate toxicity by ca. 40%. Since tamoxifen only partly inhibited the above effects, we suggest that both genomic and non-genomic mechanisms are involved in the anti-kainate action of oestrogens.

Animals↗

PubMed2000

[Effects of corticosteroids on seizures and neurotoxicity].

Neurosteroids are precursors or metabolites of steroid hormones, which influence the excitability of central nervous system via nongenomic mechanism. Neurosteroids which are positive allosteric modulators of GABAA receptors, show anticonvulsant effects in a variety of animal models of epilepsy. Furthermore, some neurosteroids can prevent excitatory amino acid- and oxidative stress-induced neuronal damage both in vivo and in vitro. The efficacy and low intrinsic toxicity of neurosteroids, suggest their potential use in therapy of some neurological diseases.

Anti-Inflammatory Agents↗

PubMed1999

Effects of pilocarpine- and kainate-induced seizures on thyrotropin-releasing hormone biosynthesis and receptors in the rat brain.

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.

Amygdala↗

PubMed1999

Effects of pentylenetetrazole-induced kindling on thyrotropin-releasing hormone biosynthesis and receptors in rat brain.

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.

Amygdala↗

PubMed1999

The effect of repeated administration of morphine, cocaine and ethanol on mu and delta opioid receptor density in the nucleus accumbens and striatum of the rat.

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.

Animals↗

PubMed1999

Effects of neurosteroids on spike-wave discharges in the genetic epileptic WAG/Rij rat.

Effects of i.p. administration of the neurosteroids, allopregnanolone and pregnenolone sulfate, were studied in WAG/Rij rats, a genetic model for generalized absence epilepsy. EEG recordings showed that allopregnanolone, a positive modulator of the GABA(A) receptor, in doses ranging from 5 to 20 mg/kg, increased dose-dependently the number- and total duration of spike-wave discharges. Pregnenolone sulfate, a positive modulator of NMDA receptors, also increased those parameters, though only at the highest dose used (100 mg/kg). Significant changes in spike-wave discharges occurred during the first hour post-injection and were not accompanied with behavioral alterations. The obtained data indicate that both these neurosteroids aggravate the spike-wave activity. This finding contrasts with the anti-convulsant effects of some neurosteroids and they point to a different pharmacological profile of epilepsy with convulsive or non-convulsive seizures.

Animals↗