Biomedical subjects

L Terenius

Publications and source records attributed to L Terenius.

At least 73 records · Page 4Linked to original sources

PubMed1997

Opioid effects on 45Ca2+ uptake and glutamate release in rat cerebral cortex in primary culture.

Primary cultures of rat cortex, conveniently prepared from newborn animals, were used to study opioid effects on 45Ca2+ uptake and glutamate release. 45Ca2+ uptake, induced by treatment with glutamate or NMDA, was largely blocked by the NMDA antagonist MK-801. K+ depolarization-induced 45Ca2+ uptake was also reduced by MK-801, indicating that the effect was mediated by glutamate release. Direct analysis verified that glutamate, and aspartate, were indeed released. Opioid peptides of the prodynorphin system were also released and these, or other peptides, were functionally active, because naloxone treatment increased glutamate release, as well as the 45Ca2+ uptake induced by depolarization. Opioid agonists, selective for mu-, kappa-, and delta-receptors, inhibited the 45Ca2+ uptake induced by K+ depolarization. The combination of low concentrations of MK-801 and opioid agonists resulted in additive inhibition of K(+)-induced 45Ca2+ uptake. The results indicate that this system may be useful as an in vitro CNS model for studying modulation by opioids of glutamate release and Ca2+ uptake under acute, and perhaps also chronic, opiate treatment.

Analgesics, Opioid↗

PubMed1997

Nociceptin/orphanin FQ microinjected into hippocampus impairs spatial learning in rats.

The newly discovered peptide nociceptin/orphanin FQ has been found to increase reactivity to pain and to influence locomotor activity after intracerebroventricular administration. This study investigated the possible role of hippocampal nociceptin/orphanin FQ in spatial learning and in spontaneous locomotion. Male rats were trained in the Morris water task after microinjection of 10 nmol nociceptin/orphanin FQ or artificial cerebrospinal fluid (as control) into the CA3 region of the dorsal hippocampus. Nociceptin/orphanin FQ was found to severely impair spatial learning without interfering with swimming performance. Intrahippocampal injection of nociceptin/ orphanin FQ markedly decreased exploratory locomotor activity including vertical movements (rearing). The data suggest that nociceptin/orphanin FQ is a potent modulator of synaptic plasticity within the hippocampus.

Animals↗

PubMed1997

Tyrosine hydroxylase and dopamine D4 receptor allelic distribution in Scandinavian chronic alcoholics.

Associations of polymorphic genetic markers at the tyrosine hydroxylase (TH) and dopamine D4 receptor (DRD4) loci were examined in Scandinavian chronic alcoholics (n = 72) and control subjects (n = 67). Patients were divided into subgroups with regard to the presence of parental alcoholism and age of onset. Neither the TH nor the DRD4 allele distributions were significantly different when alcoholic samples were compared with control subjects. However, a tendency to high prevalence for 1 of the 5 TH alleles assayed (TH-K3) was observed in a subsample of 44 alcoholics characterized by late onset when compared with control subjects (27.3% vs. 10.6%, p = 0.041). Results suggest that no major influence on alcoholism is exerted through genes associated with the DRD4 or TH allelic markers examined.

Adult↗

PubMed1997

Prodynorphin allelic distribution in Scandinavian chronic alcoholics.

Two regions of the human prodynorphin gene, the exon 4-region coding for the opioid peptides and the putative promotor/exon 1-region were analyzed for possible presence of polymorphisms. No polymorphism was detected in the exon 4-region, whereas a GC/AT base-pair exchange was observed 301 base pairs upstream of the exon 1/intron A boundary. This polymorphic marker was examined in Scandinavian chronic alcoholics (n = 70) and control subjects (n = 55). Prodynorphin allelic distributions were not significantly different in alcoholic patients and control subjects. The results suggest that no major influence on alcoholism is exerted through genes associated with this prodynorphin allelic marker.

Adult↗

PubMed1996

Chronic ethanol enhances NMDA-induced AP-1 activity in cultured rat cerebellar granule cells.

We examined the effects of chronic ethanol exposure (50 mM; 3 days) on N-methyl-D-aspartate (NMDA)- and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-induced AP-1 transcription factor DNA binding activity in primary cultures of rat cerebellar granule cells. Chronic ethanol exposure enhanced NMDA-stimulated AP-1 binding activity, with no corresponding change in AMPA-stimulated AP-1 binding. Supershift analysis with specific antibodies against the members of Fos and Jun protein families showed that the NMDA-induced AP-1 protein complex consisted predominantly of c-Fos and Jun D proteins. Chronic ethanol treatment by itself did not change the protein composition of the AP-1 complex.

Animals↗

PubMed1996

Dopamine-related genes and their relationships to monoamine metabolites in CSF.

Monoamine metabolite (MM) levels in lumbar cerebrospinal fluid (CSF) are extensively used as indirect estimates of monoamine turnover in the brain. In this study we investigated genotypes for DNA polymorphisms in the D2 (DRD2), D3 (DRD3), and D4 (DRD4) dopamine receptor and tyrosine hydroxylase (TH) genes and their relationships to CSF MM in healthy volunteers (n = 66). Concentrations of homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA) were corrected for back length, a confounding variable. Corrected MM levels were not related to age, gender, height, weight heredity, season or atmospheric pressure at sampling. Individuals with specific DRD2 and TH allele and genotype configurations significantly differed in HVA and MHPG concentrations. DRD3 homo- and heterozygotic genotypes had significantly different CSF 5-HIAA levels. DRD4 genotypes were not related to MM concentrations. The results suggest that specific DRD2, DRD3, and TH genotypes participate in the regulation of monoamine turnover in the central nervous system. Accordingly monoamine receptors and synthesizing enzyme genotypes appear to be variance factors influencing MM concentrations in CSF. The relationships found in this study support MM concentrations as markers for monoamine transmission in the human brain.

Adult↗

PubMed1996

Inhibition of dynorphin-converting enzymes prolongs the antinociceptive effect of intrathecally administered dynorphin in the mouse formalin test.

The effects of peptidase inhibitors on the antinociceptive induced by intrathecally (i.t.) administered by dynorphin A and dynorphin B in the mouse formalin test were examined. When administered i.t. 5 min before the injection of 0.5% formalin solution into the dorsal surface of a hindpaw, dynorphin A (0.5-2 nmol) and dynorphin B (2-8 nmol) produced a dose-dependent and significant reduction of the paw-licking response. Dynorphin A (2 nmol) and dynorphin B (8 nmol)-induced antinociception disappeared completely within 90 min and 60 min, respectively. p-Hydroxymercuribenzoate, a cysteine proteinase inhibitor, and phosphoramidon, and endopeptidase 24.11 inhibitor simultaneously administered with dynorphin A or dynorphin B. Significantly prolonged antinociception induced by both dynorphins. However, captopril, and angiotensin-converting enzyme inhibitor, bestatin (a general aminopeptidase inhibitor) and a serine proteinase inhibitor phenylmethanesulfonyl fluoride, were active. Dynorphin converting enzyme(s) transform dynorphin-related peptides to [Leu5]enkephalin and [Leu5]enkephalin-Arg6. Neither [Leu5]enkephalin nor [Leu5]enkephalin-Arg6, even at high dose (10 nmol), produced any antinociceptive effect. However, [Leu5[enkephalin-Arg6, but not [Leu5]enkephalin, produced a significant antinociceptive effect when co-administered with phosphoramidon. Therefore, the prolongation of the antinociception induced by both dynorphins in the presence of phosphoramidon, may be due to inhibition of [Leu5]enkephalin-Arg6 degradation. The present results indicate that dynorphin-converting enzyme(s) may be important enzyme(s) responsible for terminating dynorphin-A- and dynorphin-B-induced antinociception at the spinal cord level in mice.

Analgesia↗

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

Arrest of beta-amyloid fibril formation by a pentapeptide ligand.

Polymerization of amyloid beta-peptide (Abeta) into amyloid fibrils is a critical step in the pathogenesis of Alzheimer's disease. Here, we show that peptides incorporating a short Abeta fragment (KLVFF; Abeta16-20) can bind full-length Abeta and prevent its assembly into amyloid fibrils. Through alanine substitution, it was demonstrated that amino acids Lys16, Leu17, and Phe20 are critical for binding to Abeta and inhibition of Abeta fibril formation. A mutant Abeta molecule, in which these residues had been substituted, had a markedly reduced capability of forming amyloid fibrils. The present data suggest that residues Abeta16-20 serve as a binding sequence duringA beta polymerization and fibril formation. Moreover, the present KLVFF peptide may serve as a lead compound for the development of peptide and non-peptide agents aimed at inhibiting Abeta amyloidogenesis in vivo.

Amino Acid Sequence↗

PubMed1996

Effect of morphine on dynorphin B and GABA release in the basal ganglia of rats.

In vivo microdialysis was used to study the effects of systemic, as well as intracerebral administration of morphine and naloxone on dynorphin B release in neostriatum and substantia nigra of rats. The release of dopamine (DA), gamma-aminobutyric acid (GABA), glutamate (Glu) and aspartate (Asp) was also investigated. Systemic injection of morphine (1 mg/kg s.c.) induced long-lasting increases in extracellular dynorphin B and GABA levels in the substantia nigra, whereas DA, Glu and Asp levels, measured in the same region, were not significantly affected. No effect on striatal neurotransmitter levels was observed following systemic morphine administration. Local perfusion of the substantia nigra with morphine (100 microM) through the microdialysis probe also increased nigral dynorphin B and GABA levels. Perfusion of the neostriatum with morphine (100 microM) significantly increased GABA and dynorphin B levels in the ipsilateral substantia nigra, but no effect was observed locally. Naloxone blocked the effect of systemic morphine administration on nigral dynorphin B and GABA release, already at a dose of 0.2 mg/kg s.c. Naloxone alone, given either systemically (0.2-4 mg/kg s.c.) or intracerebrally (1-100 microM), did not affect dynorphin B or amino acid levels, either in neostriatum or in substantia nigra. However, naloxone produced a concentration-dependent increase in DA levels. The present results indicate that systemic morphine administration stimulates the release of dynorphin B in the substantia nigra, probably by activating the mu-subtype of opioid receptor, since the effect of morphine on nigral dynorphin B and GABA was antagonized by a low dose of naloxone. The increase in extracellular DA levels produced by high concentrations of naloxone, both in neostriatum and substantia nigra, indicates a disinhibitory effect of this drug on DA release, probably via a non-mu subtype of opioid receptors located on nigro-striatal DA neurones.

Animals↗

PubMed1996

Endogenous opioids in frontal cortex of patients with Down syndrome.

The main purpose of this study was to investigate differences regarding endogenous opioids in post-mortem frontal cortex of adult patients with Down syndrome (DS), patients with Alzheimer disease (AD) and neurologically healthy persons, respectively, using specific radioimmunoassays. The results of this study show that there is an increase in the levels of leu-enkephalin and dynorphin A in the frontal cortex of patients with DS as compared to the control group. An almost identical increase was also observed when comparing patients with AD to controls. In conclusion, the results of this study suggest a relationship between elevated tissue levels of leuenkephalin and dynorphin A in cerebral cortex and cognitive impairments in patients with DS and AD.

Aged↗

PubMed1996

Effects of secretogranin II-derived peptides on the release of neurotransmitters monitored in the basal ganglia of the rat with in vivo microdialysis.

In vivo microdialysis was used to study the effect of secretogranin II-derived peptides on dynorphin B (Dyn B), dopamine, gamma-aminobutyric acid (GABA), glutamate and aspartate release in the substantia nigra and neostriatum of halothane-anaesthesized rats. In the substantia nigra, local infusion of secretoneurin (secretogranin II 154-186) (1-50 microM) increased, in a concentration-dependent manner, extracellular aspartate, glutamate, Dyn B, dopamine and GABA levels. The effect was particularly prominent on aspartate and glutamate levels which, following 50 microM of secretoneurin, were increased by > 20 and > 10 fold, respectively. However, the effect of secretoneurin on Dyn B release appeared to be more specific, since a significant increase (> 20 fold) was already observed following 1 microM of secretoneurin. In the neostriatum, Dyn B, glutamate, aspartate and GABA levels were also increased by local secretoneurin infusion, but the effect was less prominent than in the substantia nigra. In the substantia nigra, only Dyn B levels were significantly increased following infusion of 10 microM of the secretoneurin-C terminal (secretoneurin-15C), whereas Dyn B and GABA levels were increased by the same concentration of the secretogranin II C terminus (YM). Only glutamate and aspartate levels were increased by local infusion of 10 microM of secretogranin II 133-151 (LF), a peptide adjacent to secretoneurin in the primary amino acid sequence. In the neostriatum, Dyn B and GABA levels were increased by 10 microM of secretoneurin-15C. Dyn B levels were also increased by 10 microM of YM, and glutamate and aspartate levels were increased by 10 microM of both YM and LF. Thus secretogranin II-derived peptides affect extracellular levels of several putative neurotransmitter systems monitored in the basal ganglia of the rat with in vivo microdialysis. The effect of Dyn B appears to be specific and related to a physiological role of secretoneurin, since (i) it occurs in an area where secretoneurin-immunocytochemistry has been observed, (ii) is exerted at comparatively low concentrations, and (iii) is mimicked by secretoneurin-15C. The increases in excitatory amino acid levels produced by high concentrations of secretoneurin and other secretogranin II-derived peptides reflect, perhaps, a potential neurotoxicity produced by abnormal accumulation of these peptides.

Animals↗

PubMed1996

A search for association between schizophrenia and dopamine-related alleles.

Dopamine receptor dysfunction and altered tyrosine hydroxylase activity have both been implicated in the pathophysiology of schizophrenia. Schizophrenic patients and control subjects were examined for allele frequencies in the tyrosine hydroxylase and dopamine D2 and D4 receptor genes. No significant differences of allele or genotype frequencies were found between the two groups after adjustment for multiple comparisons. Neither were any significant relationships observed between allele frequencies and a number of clinical variables within the schizophrenic subsample. When no adjustment was made for multiple testing a few significant tendencies were obtained which warrant further research in extended patient and control materials. The results are compatible with the view that the tyrosine hydroxylase, dopamine receptor D2 and D4 gene polymorphisms examined are not of major importance in the aetiology or pathophysiology of schizophrenia.

Adult↗

PubMed1996

Modulation of neurotransmitter release by cholecystokinin in the neostriatum and substantia nigra of the rat: regional and receptor specificity.

The effect of cholecystokinin peptides on the release of dynorphin B, aspartate, glutamate, dopamine and GABA in the neostriatum and substantia nigra of the rat was investigated using in vivo microdialysis. Sulphated cholecystokinin-8S in the dialysis perfusate (1-100 microM) induced a concentration-dependent increase in extracellular dynorphin B and aspartate levels, both in the neostriatum and substantia nigra. Striatal dopamine levels were only increased by 100 microM of cholecystokinin-8S, while in the substantia nigra they were increased by 10-100 microM of cholecystokinin-8S. Extracellular GABA and glutamate levels were increased following 100 microM of cholecystokinin-8S only. Striatal cholecystokinin-8S administration also produced a significant increase in nigral dynorphin B levels. Local cholecystokinin-4 (100 microM) produced a moderate, but significant, increase of extracellular dynorphin B and aspartate levels in the neostriatum and substantia nigra. No effect was observed on the other neurotransmitters investigated. A 6-hydroxydopamine lesion of the nigrostriatal dopamine pathway did not affect the increases in dynorphin B and aspartate levels produced by local administration of cholecystokinin-8S. Basal extracellular GABA levels were increased significantly in both the neostriatum and substantia nigra ipsilateral to the lesion. Nigral glutamate and aspartate levels were also increased in the lesioned substantia nigra, but in the lesioned neostriatum aspartate levels were decreased. The cholecystokinin-B antagonist L-365,260 (20 mg/kg, s.c.), but not the cholecystokinin-A antagonist L-364,718 (devazepide; 20 mg/kg, s.c.), significantly inhibited the effect of cholecystokinin-8S on striatal dynorphin B and aspartate levels. In the substantia nigra, however, the effect of cholecystokinin-8S on dynorphin B and aspartate levels was inhibited to a similar extent by both L-365,260 and L-364,718. Pretreatment with L-364,718, but not with L-365.260, prevented the increase in nigral dopamine levels produced by nigral cholecystokinin-8S administration. Taken together, these results suggest that cholecystokinin-8S modulates dynorphin B and aspartate release in the neostriatum and substantia nigra of the rat via different receptor mechanisms. In the neostriatum, the effect of cholecystokinin-8S on dynorphin B and aspartate release is mediated via the cholecystokinin-B receptor subtype, while in the substantia nigra, cholecystokinin-8S modulates dynorphin B and aspartate release via both cholecystokinin-A and cholecystokinin-B receptor subtypes. Cholecystokinin-8S modulates dopamine release mainly in the substantia nigra, via the cholecystokinin-A receptor subtype.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1996

On the origin of extracellular glutamate levels monitored in the basal ganglia of the rat by in vivo microdialysis.

Several putative neurotransmitters and metabolites were monitored simultaneously in the extracellular space of neostriatum, substantia nigra, and cortex and in subcutaneous tissue of the rat by in vivo microdialysis. Glutamate (Glu) and aspartate (Asp) were at submicromolar and gamma-aminobutyric acid (GABA) was at nanomolar concentrations in all brain regions. The highest concentration of dopamine (DA) was in the neostriatum. Dynorphin B (Dyn B) was in the picomolar range in all brain regions. Although no GABA, DA, or Dyn B could be detected in subcutaneous tissue, Glu and Asp levels were 5 and approximately 5 and approximately 0.4 microM, respectively. Lactate and pyruvate concentrations were approximately 200 and approximately 10 microM in all regions. The following criteria were applied to ascertain the neuronal origin of substances quantified by microdialysis: sensitivity to (a) K+ depolarization, (b) Na+ channel blockade, (c) removal of extracellular Ca2+, and (d) depletion of presynaptic vesicles by local administration of alpha-latrotoxin. DA, Dyn B, and GABA largely satisfied all these criteria. In contrast, Glu and Asp levels were not greatly affected by K+ depolarization and were increased by perfusing with tetrodotoxin or with Ca2+-free medium, arguing against a neuronal origin. However, Glu and Asp, as well as DA and GABA, levels were decreased under both basal and K+-depolarizing conditions by alpha-latrotoxin. Because the effect of K+ depolarization on Glu and Asp could be masked by reuptake into nerve terminals and glial cells, the reuptake blocker dihydrokainic acid (DHKA) or L-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) was included in the microdialysis perfusion medium. The effect of K+ depolarization on Glu and Asp levels was increased by DHKA, but GABA levels were also affected. In contrast, PDC increased only Glu levels. It is concluded that there is pool of releasable Glu and Asp in the rat brain. However, extracellular levels of amino acids monitored by in vivo microdialysis reflect the balance between neuronal release and reuptake into surrounding nerve terminals and glial elements.

Amino Acids↗

PubMed1996

High-resolution separation of amyloid beta-peptides: structural variants present in Alzheimer's disease amyloid.

In Alzheimer's disease (AD), one of the cardinal neuropathological signs is deposition of amyloid, primarily consisting of the amyloid beta-peptide (Abeta). Structural variants of AD-associated Abeta peptides have been difficult to purify by high-resolution chromatographic techniques. We therefore developed a novel chromatographic protocol, enabling high-resolution reverse-phase liquid chromatography (RPLC) purification of Abeta variants displaying very small structural differences. By using a combination of size-exclusion chromatography and the novel RPLC protocol, Abeta peptides extracted from AD amyloid were purified and subsequently characterized. Structural analysis by microsequencing and electrospray-ionization mass spectrometry revealed that the RPLC system resolved a complex mixture of Abeta variants terminating at either residue 40 or 42. Abeta variants differing by as little as one amino acid residue could be purified rapidly to apparent homogeneity. The resolution of the system was further illustrated by its ability to separate the structural isomers of Abeta1-40. The present chromatography system might provide further insight into the role of N-terminally and posttranslationally modified Abeta variants, because each variant can now be studied individually.

Alzheimer Disease↗

PubMed1995

Characterization of human prodynorphin gene transcripts.

Prodynorphin gene transcripts have been characterized in human tissues with cRNA probes covering parts of the non-coding exon 1 and the main coding exon 4 using Northern blot and RNase protection experiments. A 2.8-kb signal was observed in human brain RNA with both the exon 1 and exon 4 probes. An RNase protection assay with the exon 1 probe, performed to map the 5' end of this transcript, produced protected fragments in the range of 0.11 to 0.15 kb indicating that exon 1 is 1.2 kb shorter than previously proposed. 5'-RACE-PCR and sequencing of amplified cDNA fragments confirmed this assignment. In adrenal gland, testis and the human small cell lung carcinoma cell line, U1690, several prodynorphin-like mRNAs structurally different from the brain prodynorphin mRNA species were observed.

Adrenal Glands↗