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S Liljequist

Publications and source records attributed to S Liljequist.

At least 37 records · Page 2Linked to original sources
PubMed1996

N-Methyl-D-aspartate-induced enhancement of activator protein-1 DNA binding activity is blocked by ethanol in cerebellar granule cells.

The effects of ethanol on N-methyl-D-aspartate (NMDA) and non-NMDA receptor agonist-stimulated activator protein-1 (AP-1) DNA binding activity in primary cultures of rat cerebellar granule cells were investigated. The application of intoxicating concentrations of ethanol produced a concentration-dependent inhibition of NMDA-enhanced AP-1 binding with a significant reduction obtained at 50 mM ethanol. The inhibitory actions of ethanol on alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-stimulated AP-1 binding were considerably weaker as compared to the effects seen following administration of NMDA. The AMPA-induced enhancement of AP-1 DNA binding activity was demonstrated both in the absence and presence of cyclothiazide, a drug, which is known to block the desensitization of AMPA receptors. Our data suggest that moderate concentrations of ethanol modulate glutamate-induced alterations of gene expression in brain neurons.

Animals↗
PubMed1996

A mu-receptor opioid agonist induces AP-1 and NF-kappa B transcription factor activity in primary cultures of rat cortical neurons.

Activator protein 1 (AP-1) and nuclear factor kappa B (NF-kappa B) represent mammalian transcription factors which bind to distinct enhancer motifs. The specific mu-receptor opioid agonist, Tyr, D-Ala2, Gly, N-Me-Phe4, Gly-ol5 (DAMGO), was found to increase AP-1 and NF-kappa B activity in primary cultures of neurons from rat cerebral cortex. Acute (2 h, 4 h) and long-term (72 h) treatment with DAMGO time-dependently increased the DNA-binding activity of both AP-1 and NF-kappa B and the stimulation could be abolished or inhibited by concurrent incubation with naloxone. However, acute naloxone-precipitated withdrawal did not significantly change AP-1 or NF-kappa B activity. These results indicate a mu-opioid receptor-related co-induction of AP-1 and NF-kappa B transcription factors in cultured cortical neurons.

Analgesics↗
PubMed1996

Developmental changes in glutamate receptor-activated translocation of protein kinase C in cerebellar granule neurons.

Developmental changes in glutamate receptor agonist-produced enhancement of 4-beta-[3H]phorbol-12,13-dibutyrate binding ([3H]-PDBu binding), indicative of an intracellular translocation of protein kinase C (PKC), were investigated in cerebellar granule cells. Our observations demonstrate that the magnitude of glutamate-, NMDA-, and kainate-produced enhancement of PKC translocation was dramatically decreased between 2 and 12 DIV, whereas there was only a minor reduction in the corresponding response caused by the non-NMDA receptor agonist, AMPA. The maximally enhanced stimulation of PKC translocation caused by glutamate and NMDA was significantly reduced already at 4 DIV, whereas a significant reduction of the kainate-induced enhancement of [3H]PDBu binding was not observed until 8 DIV. Glutamate- and NMDA-induced responses were effectively blocked by the specific NMDA receptor antagonists MK-801 (1 microM) and APV (100 microM) as well as by the addition of Mg2+ into assay media. In contrast, the non-NMDA receptor antagonist, CNQX (10 microM), effectively blocked the kainate-induced enhancement of [3H]PDBu binding, but had no effect on the NMDA- and glutamate-induced stimulation of PKC translocation. The metabotropic glutamate receptor agonist, ACPD (up to 250 microM), had no effect on the translocation of PKC. Taken together, our data support the working hypothesis that the rapidly occurring changes in the glutamate receptor agonist-produced translocation of PKC are most likely due to a differential maturation of glutamate ionotropic receptor subtypes and/or to development-dependent alterations in mechanisms responsible for the coupling between the glutamate receptor subtypes and the activation of PKC translocation in cerebellar granule neurons.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1996

Is upregulation of benzodiazepine receptors a compensatory reaction to reduced GABAergic tone in the brain of stressed mice?

Effects of various forms of stress on the GABAA receptor-chloride ionophore complex in the brain of NMRI mice were investigated. Male albino mice were subjected to stress by placing them on small platforms (SP; 3.5 cm diameter) surrounded by water for 24 h. This experimental model contains several stress factors like rapid eye movement (REM) sleep deprivation, isolation, immobilization, falling into water and soaking. As additional stress control groups we used animals subjected to isolation, large platform (9.0 cm diameter) and repeated swimming stress. SP stress induced an increase in the number of cortical benzodiazepine (BDZ) receptors and a reduction in the GABA-stimulated 36Cl-uptake by brain microsacs, whereas none of these changes could be observed in animals exposed to isolation, swimming or large platform stresses. Furthermore, the amount of GABA-induced stimulation of [3H]flunitrazepam binding was reduced in cortical brain membranes of SP-stressed animals, an effect due to fact that these animals displayed an increase in the basal [3H]flunitrazepam binding, whereas the absolute level of maximally enhanced BDZ binding in the presence of GABA did not differ from those found in controls. Neither basal [3H]muscimol binding or thiopentone sodium-induced stimulation of [3H]flunitrazepam binding were changed in any group of stressed mice. It is proposed that the observed upregulation in the number (Bmax) of cortical BDZ receptors in SP-stressed mice may represent a compensatory response to a stress-induced attenuation of GABAergic neurotransmission.

Animals↗
PubMed1996

Glycine does not reverse the inhibitory actions of ethanol on NMDA receptor functions in cerebellar granule cells.

The effects of ethanol and/or glycine on NMDA-induced enhancement of cytoplasmic free Ca2+ concentrations ([Ca2+]i), 45Ca2+ influx, 4-b-[3H]phorbol-12,13-dibutyrate ([3H]PDBu) binding, and neuronal necrosis in cultured rat cortical and cerebellar granule neurons were examined. Using microfluorimetric techniques in combination with rapid perfusion of single brain neurons, we found that glycine (10 microM) was a necessary co-agonist for NMDA-induced depolarization in cerebellar granule cells. In contrast, depolarization with NMDA in cortical cells was observed even without the addition of exogenous glycine as well as in the absence or presence of 1 mM MgCl2. Ethanol (50 mM) inhibited the effects of NMDA in some, but not all, neurons indicative of the existence of ethanol-sensitive and ethanol-insensitive cortical and cerebellar granule neurons. In studies performed in monolayers of cortical and cerebellar granule cells, we observed that the presence of glycine (10 microM) was a necessary prerequisite to unmask inhibitory actions of ethanol on 45Ca2+ influx induced by NMDA. In another set of experiments, we noted that NMDA-induced stimulation of [3H]PDBu binding to monolayers of intact cerebellar granule cells was inhibited by ethanol (50 mM). Finally, we report that ethanol caused a concentration-dependent inhibition of NMDA-induced necrotic cell death, assessed by measuring the ability of cerebellar granule cells to transform 3-[4, 5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) into formazan. In none of the four assays used to demonstrate the inhibitory effects of ethanol on NMDA receptor activity, the ethanol-induced inhibition was reversed by glycine (up to 100 microM). Thus, in contrast to earlier reports, our data suggest that ethanol and glycine produce their effects by acting at different regulatory sites within the NMDA receptor system in brain neurons.

Animals↗
PubMed1996

Oral administration of glycine and polyamine receptor antagonists blocks ethanol withdrawal seizures.

Cessation of chronic administration of orally administered large amounts of ethanol for 7 days resulted in a markedly increased frequency of audiogenic seizures in Sprague-Dawley rats. Oral administration of the novel glycine receptor antagonist, L-701,324, produced a dose-dependent (2.5 and 5.0 mg/kg; -30 min) inhibition of ethanol withdrawal signs when measured about 12 h after withdrawal of the ethanol treatment. Similarly, using the same experimental paradigm, oral administration of the specific polyamine receptor antagonist, eliprodil, caused a dose-related (2.0 and 5.0 mg/kg; -30 min) inhibition of ethanol withdrawal-induced audiogenic seizure activity. The inhibition of ethanol withdrawal seizures produced by L-701,324 and eliprodil, respectively, was obtained at doses which by themselves did not change the locomotor activity in naive Sprague-Dawley rats. The findings that L-701,324 and eliprodil are potent inhibitors of seizure activity induced by cessation of chronic ethanol administration and the fact that they, in contrast to currently available NMDA receptor antagonists, do not produce psychotomimetic and/or sedative effects, suggest that these drugs may represent a new class of therapeutically useful pharmacological agents for the treatment of ethanol withdrawal seizures. Furthermore, since there is evidence that eliprodil produces its pharmacological actions through a specific inhibition of NMDAR1 and/or NMDAR2B subunits, these data may indicate that certain NMDA receptor subunits may be of particular importance for the mediation of seizure activity following the discontinuation of chronic ethanol exposure.

Acoustic Stimulation↗
PubMed1995

Effects of decahydroisoquinoline-3-carboxylic acid monohydrate, a novel AMPA receptor antagonist, on glutamate-induced CA2+ responses and neurotoxicity in rat cortical and cerebellar granule neurons.

In this study, we examined the effects of a novel water-soluble, putative AMPA receptor antagonist, (-)(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]-1,2,3, 4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid monohydrate (LY326325), on glutamate-, N-methyl-D-aspartic acid (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-, and kainic acid (KA)-induced elevations of intracellular Ca2+ concentrations ([Ca2+]i) and 45Ca2+ uptake, as well as glutamate agonist-induced neurotoxicity in primary cultures of intact rat cortical and cerebellar granule neurons. In some experiments, the actions of LY326325 were tested in the presence of cyclothiazide, a compound that is known to block glutamate-induced desensitization of AMPA-preferring subtypes of glutamate receptors, thereby largely potentiating the functional effects of AMPA. LY326325 fully blocked the elevations of [Ca2+]i induced by NMDA and non-NMDA glutamate receptor agonists in both cortical and cerebellar granule neurons. The application of increasing concentrations of cyclothiazide was not able to reverse the LY326325-induced blockade of glutamate receptors in cortical neurons. In contrast, the same cyclothiazide treatment fully reversed the blockade produced by the noncompetitive AMPA/KA receptor antagonist 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2, 3-benzodiazepine HCl (GYKI 52466). In 45Ca2+ uptake studies. LY325325 inhibited the NMDA-, AMPA-, and KA-induced enhancement of 45Ca2+ uptake in a concentration-dependent fashion in both cortical and cerebellar granule cells. In analogy to the results obtained with [Ca2+]i recordings, cyclothiazide failed to counteract the LY326325-induced blockade of KA-stimulated 45Ca2+ uptake in cerebellar granule neurons, whereas the blockade induced by the noncompetitive AMPA/KA receptor blocking agent GYKI 52466 was fully reversed by cyclothiazide. Because a similar, although not identical pattern of actions was seen following the application of the competitive AMPA/KA receptor antagonist 6-nitro-7-sulphamoyl-benzo(f)quinoxaline-2-3-dione (NBQX), it is suggested that the inhibitory actions of LY326325 are similar to those produced by NBQX but clearly differ from those caused by the noncompetitive AMPA/KA receptor antagonist GYKI 52466. Finally, when the neuroprotective actions of LY326325 on glutamate agonist-induced neurotoxicity were examined in cerebellar granule neurons, we found that LY326325 almost completely blocked the neurotoxic actions of NMDA, AMPA, and KA, respectively, whereas it produced only a partial blockade of glutamate-induced neurotoxicity. Taken together, our current results suggest that although LY326325 blocked both nonNMDA and NMDA-induced Ca2+ responses, it still displayed a preferential affinity of nonNMDA receptors as compared to NMDA receptors. However, LY326325 appears to be a less selective AMPA/KA receptor antagonist than NBQX and GYKI52466, respectively.

Animals↗
PubMed1995

Modulation of AMPA/kainate receptors by cyclothiazide increases cytoplasmic free Ca2+ and 45Ca2+ uptake in brain neurons.

alpha-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-induced Ca2+ responses, and their modulation by cyclothiazide, were investigated in two functional assays of Ca2+ channel activity. AMPA produced a marked increase in cytoplasmic free Ca2+ levels ([Ca2+]i) in single cortical neurons, whereas no such effects of AMPA could be observed in intact cerebellar granule neurons. In monolayer cultures of cortical cells, cyclothiazide caused a pronounced enhancement of AMPA-induced stimulation of 45Ca2+ uptake, whereas similar studies in cerebellar granule neurons revealed only a weak potentiation of AMPA-induced 45Ca2+ uptake. Higher concentrations of cyclothiazide alone produced [Ca2+]i oscillations as well as an increase of basal 45Ca2+ uptake in cortical neurons, whereas no such effects were obtained in cerebellar granule neurons. Our data indicate that AMPA receptors located on cortical and cerebellar granule neurons, respectively, may differ in their permeability to Ca2+ and that this difference is markedly potentiated following the application of cyclothiazide.

Analysis of Variance↗
PubMed1995

Evidence for an anxiogenic action of AMPA receptor antagonists in the plus-maze test.

The effects of the non-NMDA receptor antagonists, the new alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)-selective receptor antagonist, LY326325, and the AMPA/kainate-selective receptor antagonist, NBQX (6-nitro-7-sulfamoylbenzo(f)quinoxaline-2,3-(1H,4H)dione), on plus-maze behavior and locomotor activity were examined. LY326325 induced a dose-dependent decrease in the per cent time spent in open arms as well as in the per cent entries into the open arms. NBQX caused a dose-dependent reduction in the per cent time spent in open arms but had no effect on the per cent entries into the open arms. The behavioral actions of the AMPA receptor antagonists were observed at doses which had no influence on the locomotor activity of the animals. Based upon the current findings it is suggested that AMPA receptor antagonists produce a dose-dependent increase of anxiogenic behavior in the plus-maze test situation.

Animals↗
PubMed1995

Effects of post-ethanol administration of NMDA and non-NMDA receptor antagonists on the development of ethanol tolerance in C57B1 mice.

The effect of post-ethanol administration of NMDA and non-NMDA receptor antagonists on the development of environment-dependent ethanol tolerance was studied in C57B1 mice. Ethanol tolerance was produced by daily injections of ethanol (3.5 g/kg, IP) in the same experimental environment and measured as ethanol-produced "sleep-time" during 5 consecutive days. The non-competitive NMDA receptor antagonist, dizocilpine (MK-801; 0.1 mg/kg, IP), and the competitive NMDA receptor antagonist, CGP 39551 (5 mg/kg, IP), both given 120 min after the administration of ethanol, inhibited the development of tolerance to the hypnotic actions of ethanol. In contrast, the development of ethanol tolerance was not altered by administration of the specific AMPA/KA receptor blocking agents, NBQX (10 mg/kg, IP), and LY326325 (2.5 mg/kg, IP), respectively. Modulation of NMDA receptor activity by drugs like NMDA, d-cycloserine, and milacemide, which are known to enhance learning and memory in rodents, had no significant effect on the development of ethanol tolerance. Our present data confirm and extend previous findings which indicate that NMDA, but not non-NMDA, glutamate receptors may play an important role in the neuroadaptive processes associated with the development of ethanol tolerance.

Animals↗
PubMed1994

Genotypic differences in locomotor stimulation and dopaminergic activity following acute ethanol administration.

The effects of increasing doses of ethanol on locomotor activity and on the metabolism of dopamine (DA) in the limbic forebrain and in the striatum of CBA, C57, and NMRI mice were studied. In NMRI mice, low doses of ethanol produced locomotor stimulation which was followed by inhibition of locomotor activity at higher doses. In C57 and CBA animals, ethanol caused only reduction of locomotor activity. A low dose of ethanol (2.25 g/kg, i.p.) produced a significant enhancement of the release of dopamine (measured as the ratio DOPAC/DA) in limbic brain structures of all animals with no corresponding effect in the striatum. A high dose of ethanol (4.5 g/kg, i.p.) significantly increased the DOPAC/DA ratio both in the limbic forebrain and in the striatum of all animals. The significance of these behavioral and biochemical observations with regard to genetic aspects of the role of DA in the stimulatory/reinforcing properties of ethanol and to previously observed genetic differences in other neurotransmitter systems, especially GABA and glutamate, is discussed.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Genetic aspects on the effects of ethanol and central stimulants on locomotor activity and brain dopamine metabolism in mice.

The effects of increasing doses of ethanol on locomotor activity and on the metabolism of dopamine (DA) in the limbic forebrain and in the striatum of CBA, C57Bl, and NMRI mice were studied. In NMRI mice, low doses of ethanol produced locomotor stimulation which was followed by inhibition of locomotor activity at higher doses. In C57Bl and CBA animals, ethanol caused only reduction of locomotor activity. A low dose of ethanol (2.25 g/kg, i.p.) produced a significant enhancement in the release of DA (measured as the ratio DOPAC/DA) in limbic brain structures of all animals with no corresponding effect in the striatum. A high dose of ethanol (4.5 g/kg, i.p.) significantly increased the DOPAC/DA ratio both in the limbic forebrain and in the striatum of all animals. The significance of these behavioral and biochemical observations with regard to genetic aspects on the role of DA in the stimulatory/reinforcing properties of ethanol and to previously observed genetic differences in other neurotransmitter systems, especially GABA and glutamate, is discussed.

Amphetamine↗
PubMed1993

Bicuculline-produced regional differences in the modulation of 35S-TBPS binding by GABA, pentobarbital and diazepam in mouse cerebellum and cortex.

The modulation of 35S-t-butylbicyclophosphorothionate (35S-TBPS) binding by in vitro addition of gamma-aminobutyric acid (GABA), diazepam, pentobarbital, etomidate and etazolate was studied in the presence of KCl (100 mM) in the cerebellum and in the cortex of C57Bl mice. In the cortex, all of the depressant drugs caused a biphasic effect (stimulation followed by inhibition) on 35S-TBPS binding, whereas in the cerebellum only inhibition was observed. Saturation analysis revealed that the enhancement of 35S-TBPS binding was due to an increase in the affinity of 35S-TBPS for its binding sites. The introduction of a GABAA receptor antagonist, bicuculline methiodide (10 microM), into assay media altered the effects of the depressants, except for those of diazepam, on 35S-TBPS binding in a complex manner. Our results indicate that bicuculline, in addition to its GABAA receptor blocking properties, also influenced the binding of 35S-TBPS through some other, as yet unknown, mechanism(s). Thus, bicuculline not only produced a rightward shift of the dose-response curves of the central depressant drugs in the cortex, but also increased the maximal stimulation of 35S-TBPS binding. Furthermore, in the cerebellum, the previously observed drug-induced inhibition of 35S-TBPS binding was replaced by stimulation followed by inhibition in the presence of bicuculline. Finally, it was found that the in vitro addition of bicuculline had no effect on the diazepam-induced stimulation of 35S-TBPS binding. It is suggested that the regional differences in the modulation of 35S-TBPS binding in various brain structures may be due to endogenous differences in the molecular composition of GABAA receptors in various brain areas.

Animals↗
PubMed1992

PET analysis of alcohol interaction with the brain disposition of [11C]flumazenil.

Acute alcohol administration to rats has in preliminary studies been reported to drastically increase the binding of the benzodiazepine (BZ) receptor antagonist [3H]flumazenil (Ro 15-1788) to central BZ receptors. In the present study the effect of acute alcohol ingestion on the disposition of [11C]flumazenil in the human brain and plasma was examined by positron emission tomography (PET) in four healthy volunteers. Neocortex, cerebellum and pons (reference region) were delineated using X-ray computerized tomography (CT). Alcohol did not increase either total radioactivity uptake or specific [11C]flumazenil binding in neocortex or cerebellum. However, alcohol had a small but significant effect on [11C]flumazenil in arterial blood. After alcohol the plasma radioactivity peak was higher, more narrow and occurred earlier than in the control experiments. The present experiments contradict the view that alcohol directly affects central BZ receptor binding in man. Thus the dramatic increase of flumazenil binding in rat brain reported previously could not be observed in the human brain.

Adult↗
PubMed1991

Effect of the NMDA receptor antagonist, MK-801, on locomotor activity and on the metabolism of dopamine in various brain areas of mice.

Various doses (0.1-0.5 mg/kg i.p.) of the N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801, produced a dose-dependent increase in well-coordinated locomotor activity of NMRI mice. Higher doses (greater than 0.5 mg/kg) produced a typical motor syndrome characterized by head weaving, body rolling, ataxia and salivation. MK-801, 0.2 mg/kg i.p., a dose which produced marked locomotor stimulation, increased the rate of disappearance of dopamine in the striatum and in the limbic forebrain of the animals, whereas the rate of disappearance of noradrenaline remained unchanged in the limbic forebrain and in the hippocampus. MK-801 increased the rate of tyrosine hydroxylation (measured as the accumulation of 3,4-dihydroxyphenylalanine (DOPA) after inhibition of DOPA decarboxylase) in the striatum with no change in DOPA formation in the limbic forebrain. The levels of 3,4-dihydroxyphenylacetic acid (DOPAC) remained unchanged both in the striatum and in the limbic forebrain following the administration of MK-801. It is concluded that MK-801 may facilitate the activation of dopaminergic mechanisms through an indirect (perhaps by reducing glutamatergic activity) rather than a direct effect on dopamine neurons.

Animals↗
PubMed1991

Genetic differences in the effects of competitive and non-competitive NMDA receptor antagonists on locomotor activity in mice.

The effects of non-competitive (MK-801, phencyclidine, and ketamine) and competitive (CGP 39551, CGS 19755, and NPC 12626) N-methyl-D-aspartate (NMDA) receptor antagonists on locomotor activity in inbred CBA and C57, and in outbred NMRI mice were examined. Administration of the non-competitive NMDA antagonists produced a dose-dependent increase in well-coordinated locomotor activity at lower doses, followed by a bizarre behavioral syndrome (head weaving, body rolling, rotations, ataxia) after higher doses. The pharmacological profile of the competitive antagonists CGP 39551, CGS 19755, and NPC 12626 was more complex. CGP 39551 dose-dependently inhibited locomotor activity, whereas CGS 19755 and NPC 12626 displayed a biphasic action, that is low doses inhibited locomotor activity, whereas higher doses produced mild behavioral stimulation. The behavioral effects of NMDA antagonists appear to be genetically determined, since CBA animals were most sensitive to both non-competitive and competitive antagonists, followed by NMRI and C57 animals. The differential effects of NMDA antagonists in various strains of mice suggest that the observed behavioral differences may be due to genetic differences in the NMDA/glutamate receptor channel complex.

Amino Acids↗
PubMed1991

Evidence that genetic differences in habituation and GABAergic mechanisms may be related to sensitivity to ethanol and development of ethanol tolerance in mice.

Habituation to a test environment following daily exposure for 5 days was examined in three genetically different strains of mice. C57 animals showed significant habituation to the new environment already on the second day. The habituation of NMRI mice was significant on the third day, whereas CBA mice showed no habituation at all during the experimental period. There was no difference between the animal strains in learning capacity in a passive avoidance test, but CBA mice displayed a significant increase in latency in their performance. When tested for sensitivity to the convulsant actions of GABAergic antagonists, picrotoxin produced seizures at lower doses in CBA as compared to NMRI and C57 mice, whereas there was no difference between the strains in the seizure activity produced by the specific GABA receptor antagonist bicuculline. When the animals were tested for sensitivity to ethanol in a horizontal wire test, ethanol (2 g/kg, IP) produced muscle relaxation in CBA mice whereas the performance of NMRI and C57 was not affected. A large dose of ethanol (4 g/kg, IP) produced a significantly longer sleeping time in CBA mice as compared to NMRI and C57 animals. Ethanol-produced hypothermia was, however, similar in all animals. Environment-dependent development of tolerance to ethanol following daily injections of ethanol for 4 days was examined. C57 mice showed the most rapid development of tolerance towards ethanol's hypnotic actions, whereas CBA mice showed no tolerance to this effect of ethanol. No difference between the strains to the development of tolerance to ethanol's hypothermic effects was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗