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Lars Terenius

Publications and source records attributed to Lars Terenius.

At least 19 recordsLinked to original sources
PubMed2006

Prodynorphin storage and processing in axon terminals and dendrites.

The classical view postulates that neuropeptide precursors in neurons are processed into mature neuropeptides in the somatic trans-Golgi network (TGN) and in secretory vesicles during axonal transport. Here we show that prodynorphin (PDYN), precursor to dynorphin opioid peptides, is predominantly located in axon terminals and dendrites in hippocampal and striatal neurons. The molar content of unprocessed PDYN was much greater than that of dynorphin peptides in axon terminals of PDYN-containing neurons projecting to the CA3 region of the hippocampus and in the striatal projections to the ventral tegmental area. Electron microscopy showed coexistence of PDYN and dynorphins in the same axon terminals with occasional codistribution in individual dense core vesicles. Thus, the precursor protein is apparently stored at presynaptic sites. In comparison with the hippocampus and striatum, PDYN and dynorphins were more equally distributed between neuronal somata and processes in the amygdala and cerebral cortex, suggesting regional differences in the regulation of trafficking and processing of the precursor protein. Potassium-induced depolarization activated PDYN processing and secretion of opioid peptides in neuronal cultures and in a model cell line. Regulation of PDYN storage and processing at synapses by neuronal activity or extracellular stimuli may provide a local mechanism for regulation of synaptic transmission.

Animals↗
PubMed2006

BDNF gene variants and brain morphology in schizophrenia.

The objective was to investigate putative associations between brain-derived neurotrophic factor gene (BDNF) polymorphisms and brain morphology in patients with schizophrenia and healthy control subjects. Four BDNF polymorphisms were genotyped and analyzed versus 39 brain volume measures in 96 patients with schizophrenia or schizoaffective disorder and 104 healthy subjects. In all subjects, quantitative data on segmented gray, white, and cerebrospinal fluid (CSF) tissue class volumes of total brain and major cerebral lobes including ventricular CSF were obtained using magnetic resonance imaging (MRI). In a randomly selected subset of this population (n = 101-122), MR volumes from cerebellar tonsil, hemispheres, and vermis subregions, striatal structures, hippocampus, and corpus callosum were also measured. The BDNF 11757 G/C polymorphism was highly significantly associated with frontal gray matter volume variation in patients alone and in patients and control subjects combined. In patients only, the 270 C/T polymorphism was associated with total caudate volume. Significant associations were demonstrated between the BDNF 11757 G/C and Val66Met polymorphisms and a global haplotype estimate of four BDNF polymorphisms and the posterior superior cerebellar vermis volume in the controls as well as in the combined group, but not in the patients. The 11757 G/C polymorphism was associated with cerebellar hemisphere white and gray matter volumes in the combined group. The BDNF -633 T/A polymorphism was associated with gray matter of the putamen in the controls. Trends for associations between several polymorphisms/haplotype estimates and MRI volumes were found. BDNF gene variation may influence brain morphology. The effects may be different in patients with schizophrenia and healthy subjects.

Adult↗
PubMed2006

Brain-derived neurotrophic factor gene (BDNF) variants and schizophrenia: an association study.

Polymorphisms in the brain-derived neurotrophic factor (BDNF) gene have been suggested to be associated with schizophrenia. In a replication attempt, Swedish patients with schizophrenia (n=187) and control subjects (n=275) were assessed for four BDNF gene polymorphisms. There were no significantly different allele, genotype or haplotype frequencies between cases or controls. Neither were there any differences when schizophrenic patients were sub-divided with regard to a number of different clinical variables, although a small group of psychotic patients with prominent affective features displayed higher frequencies of the less common alleles of the Val66Met and 11757 G/C polymorphisms compared to controls. The present Swedish results do not verify previous associations between putative functional BDNF gene polymorphisms and schizophrenia. However, when combined with previous studies meta-analyses indicated that the BDNF 270 T-allele and the Val66Met homozygous state were associated with the disorder. Thus, the BDNF gene may confer susceptibility to schizophrenia. Additional studies are warranted to shed further light on this possibility.

Adult↗
PubMed2006

Reduced ethanol response in the alcohol-preferring RHA rats and neuropeptide mRNAs in relevant structures.

Roman rat strains, genetically selected for high (RHA) or low (RLA) active avoidance acquisition in the two-way shuttle box, differ in dopaminergic activity. These two strains appear to be a valid laboratory model of divergent sensation/novelty and substance-seeking profiles. RHA rats show higher ethanol intake and preference than do RLA rats, and it was suggested that RHA rats are more tolerant than RLA to the effects of alcohol. In the hole-board test, we found that the non-alcohol-preferring RLA rats showed enhanced responsiveness to the stimulatory effects of intraperitoneal administration of 0.25 g/kg ethanol when compared with RHA rats. In situ hybridization analysis showed higher levels of preprodynorphin in the accumbens shell and higher levels of preproenkephalin in the cingulate cortex in RHA rats. RLA rats showed higher levels of enkephalin gene transcripts in restricted areas of the dorsal striatum. Finally, differences in cholecystokinin gene transcript, suggestive of a different arrangement of certain interneurons, were found in different cortical areas. The differences in peptide gene expression found between the two strains might reflect the differences in alcohol preference and sensitivity. RHA rats may have more predictive value than other rodent alcoholism models, as high initial tolerance to ethanol is a risk factor for alcoholism in humans.

Alcohol Drinking↗
PubMed2005

Opioid-induced regulation of gene expression in PC12 cells stably transfected with mu-opioid receptor.

It has been postulated that opiates induce addictive behaviour via changes in gene expression. PC12 cells were stably transfected with the recombinant human mu-opioid receptor (MOR) to study opioid-induced gene expression. Expression was verified by binding assay, immunocytochemistry, and immunblotting experiments. Forskolin-induced cAMP formation was inhibited by [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin (DAMGO 1 microM), a specific MOR agonist. This effect was completely antagonized by naloxone. By using cDNA arrays, including approximately 1,200 well-defined genes normally expressed in neural tissue, we monitored semi-quantitative changes in gene expression after 3 h short-term exposure to DAMGO. Incubation with DAMGO increased mRNA levels for 13 genes and down-regulated 13 other genes. Annexin V, RGS4 and CREB genes showed pronounced increase in expression after stimulation with DAMGO. Quantitative RT-PCR confirmed that DAMGO increased mRNA levels of Annexin V, an apoptosis-induced gene. We suggest that the PC12 cell transfected with the recombinant human MOR is a useful tool for identification of opioid-induced genes that may provide information on opiate effects of relevance for dependence.

Analgesics, Opioid↗
PubMed2005

Big dynorphin, a prodynorphin-derived peptide produces NMDA receptor-mediated effects on memory, anxiolytic-like and locomotor behavior in mice.

Effects of big dynorphin (Big Dyn), a prodynorphin-derived peptide consisting of dynorphin A (Dyn A) and dynorphin B (Dyn B) on memory function, anxiety, and locomotor activity were studied in mice and compared to those of Dyn A and Dyn B. All peptides administered i.c.v. increased step-through latency in the passive avoidance test with the maximum effective doses of 2.5, 0.005, and 0.7 nmol/animal, respectively. Effects of Big Dyn were inhibited by MK 801 (0.1 mg/kg), an NMDA ion-channel blocker whereas those of dynorphins A and B were blocked by the kappa-opioid antagonist nor-binaltorphimine (6 mg/kg). Big Dyn (2.5 nmol) enhanced locomotor activity in the open field test and induced anxiolytic-like behavior both effects blocked by MK 801. No changes in locomotor activity and no signs of anxiolytic-like behavior were produced by dynorphins A and B. Big Dyn (2.5 nmol) increased time spent in the open branches of the elevated plus maze apparatus with no changes in general locomotion. Whereas dynorphins A and B (i.c.v., 0.05 and 7 nmol/animal, respectively) produced analgesia in the hot-plate test Big Dyn did not. Thus, Big Dyn differs from its fragments dynorphins A and B in its unique pattern of memory enhancing, locomotor- and anxiolytic-like effects that are sensitive to the NMDA receptor blockade. The findings suggest that Big Dyn has its own function in the brain different from those of the prodynorphin-derived peptides acting through kappa-opioid receptors.

Amino Acid Sequence↗
PubMed2005

Differential effects of N-peptidyl-O-acyl hydroxylamines on dynorphin-induced antinociception in the mouse capsaicin test.

In the capsaicin test, intrathecal (i.t.) dynorphins are antinociceptive. Cysteine protease inhibitors such as p-hydroxymercuribenzoate (PHMB) given i.t. augment and prolong their activity. The effect of two novel cysteine protease inhibitors, N-peptidyl-O-acyl hydroxylamines, on the antinociception induced by i.t. administered dynorphin A or dynorphin B has been investigated. When administered i.t. 5 min before the injection of capsaicin (800 ng) into the plantar surface of the hindpaw, dynorphin A (62.5-1000 pmol) or dynorphin B (0.5-4 nmol) produced a dose-dependent and significant antinociceptive effect. The effect of dynorphin A (1 nmol) and dynorphin B (4 nmol) disappeared completely within 180 and 60 min, respectively. PHMB (2 nmol) and Boc-Tyr-Gly-NHO-Bz (BYG-Bz) (2 nmol) co-administered with dynorphin A or dynorphin B significantly prolonged antinociception induced by both. On the other hand, Z-Phe-Phe-NHO-Bz (ZFF-Bz) (1 and 2 nmol) only prolonged antinociception induced by dynorphin A. The results suggest that Z-Phe-Phe-NHO-Bz is an inhibitor of cysteine proteases preferring cleavage of dynorphin A, with less specificity towards dynorphin B in the mouse spinal cord.

Analgesics↗
PubMed2005

Prodynorphin transcripts and proteins differentially expressed and regulated in the adult human brain.

Transcription from multiple promoters along with alternative mRNA splicing constitutes the basis for cell-specific gene expression and mRNA and protein diversity. The prodynorphin gene (PDYN) gives rise to prodynorphin (PDYN), precursor to dynorphin opioid peptides that regulate diverse physiological functions and are implicated in various neuropsychiatric disorders. Here, we characterized PDYN transcripts and proteins in the adult human brain and studied PDYN processing and intracellular localization in model cell lines. Seven PDYN mRNAs were identified in the human brain; two of the transcripts, FL1 and FL2, encode the full-length PDYN. The dominant, FL1 transcript shows high expression in limbic-related structures such as the nucleus accumbens and amygdala. The second, FL2 transcript is only expressed in few brain structures such as the claustrum and hypothalamus. FL-PDYN was identified for the first time in the brain as the dominant PDYN protein product. Three novel PDYNs expressed from spliced or truncated PDYN transcripts either lack a central segment but are still processed into dynorphins, or are translated into N-terminally truncated proteins. One truncated PDYN is located in the cell nucleus, suggesting a novel nonopioid function for this protein. The complexity of PDYN expression and diversity of its protein products may be relevant for diverse levels of plasticity in adaptive responses for the dynorphin system.

Adult↗
PubMed2005

Support for limited brain availability of tyrosine in patients with schizophrenia.

Several mechanisms have been suggested to account for altered dopaminergic neurotransmission in schizophrenia. The brain is the only organ for which amino-acid transport is limited and competition for transport over the blood-brain barrier (BBB) occurs at physiological plasma concentrations. One line of research suggests that patients with schizophrenia have altered brain levels of the essential amino acid tyrosine, the precursor for the synthesis of dopamine. The most common hypothesis is that less tyrosine is available because of competition with elevated levels of other amino acids. By consequence, the synthesis of dopamine in the brain will decrease. In contrast, another line of evidence suggests a change in the affinity for one of the transport proteins. A limitation of this research has been that the systems for amino-acid transport across the BBB have not been fully characterized at a molecular or functional level. The L system is the major system for transport of tyrosine across cell membranes including the BBB. The A system is also involved in this transport. Earlier in-vitro studies using fibroblasts have demonstrated a normal L system in schizophrenia but nevertheless reduced tyrosine transport. The combination of molecular research, fibroblast techniques, and brain imaging provides a new basis for clinical research on the role of amino-acid membrane transport in schizophrenia.

Animals↗
PubMed2005

Translocation of dynorphin neuropeptides across the plasma membrane. A putative mechanism of signal transmission.

Several peptides, including penetratin and Tat, are known to translocate across the plasma membrane. Dynorphin opioid peptides are similar to cell-penetrating peptides in a high content of basic and hydrophobic amino acid residues. We demonstrate that dynorphin A and big dynorphin, consisting of dynorphins A and B, can penetrate into neurons and non-neuronal cells using confocal fluorescence microscopy/immunolabeling. The peptide distribution was characterized by cytoplasmic labeling with minimal signal in the cell nucleus and on the plasma membrane. Translocated peptides were associated with the endoplasmic reticulum but not with the Golgi apparatus or clathrin-coated endocytotic vesicles. Rapid entry of dynorphin A into the cytoplasm of live cells was revealed by fluorescence correlation spectroscopy. The translocation potential of dynorphin A was comparable with that of transportan-10, a prototypical cell-penetrating peptide. A central big dynorphin fragment, which retains all basic amino acids, and dynorphin B did not enter the cells. The latter two peptides interacted with negatively charged phospholipid vesicles similarly to big dynorphin and dynorphin A, suggesting that interactions of these peptides with phospholipids in the plasma membrane are not impaired. Translocation was not mediated via opioid receptors. The potential of dynorphins to penetrate into cells correlates with their ability to induce non-opioid effects in animals. Translocation across the plasma membrane may represent a previously unknown mechanism by which dynorphins can signal information to the cell interior.

Animals↗
PubMed2005

Pronociceptive role of dynorphins in uninjured animals: N-ethylmaleimide-induced nociceptive behavior mediated through inhibition of dynorphin degradation.

Intrathecal (i.t.) administration into mice of N-ethylmaleimide (NEM), a cysteine protease inhibitor, produced a characteristic behavioral response, the biting and/or licking of the hindpaw and the tail along with slight hindlimb scratching directed toward the flank. The behavior induced by NEM was inhibited by the intraperitoneal injection of morphine. We have recently reported that dynorphin A and, more potently big dynorphin, consisting of dynorphins A and B, produce the same type of nociceptive response whereas dynorphin B does not [Tan-No K, Esashi A, Nakagawasai O, Niijima F, Tadano T, Sakurada C, Sakurada T, Bakalkin G, Terenius L, Kisara K. Intrathecally administered big dynorphin, a prodynorphin-derived peptide, produces nociceptive behavior through an N-methyl-d-aspartate receptor mechanism. Brain Res 2002;952:7-14]. The NEM-induced nociceptive behavior was inhibited by pretreatment with dynorphin A- or dynorphin B-antiserum and each antiserum also reduced the nociceptive effects of i.t.-injected synthetic big dynorphin. The characteristic NEM-evoked response was not observed in prodynorphin knockout mice. Naloxone, an opioid receptor antagonist, had no effects on the NEM-induced behavior. Ifenprodil, arcaine and agmatine, antagonists at the polyamine recognition site on the N-methyl-D-aspartate (NMDA) receptor ion-channel complex, and MK-801, an NMDA ion-channel blocker inhibited the NEM-induced effects. Ro25-6981, an antagonist of the NMDA receptor subtype containing NR2B subunit was not active. NEM completely inhibited degradation of dynorphin A by soluble and particulate fractions of mouse spinal cord. Collectively, the results demonstrate that endogenous prodynorphin-derived peptides are pronociceptive in uninjured animals, and required for the NEM-induced behavior. The NEM effects may be mediated through inhibition of the degradation of endogenous dynorphins, presumably big dynorphin that in turn activates the NMDA receptor ion-channel complex by acting on the polyamine recognition site.

Agmatine↗
PubMed2004

YY1 binding to a subset of p53 DNA-target sites regulates p53-dependent transcription.

The tumor suppressor protein p53 regulates gene transcription through binding to specific DNA-target sites. We here demonstrate that a subset of these sites is targeted by another DNA-binding factor. Binding specificity, reactivity with specific antibodies, and experiments with purified protein identified the factor as the multifunctional transcription regulator YY1. The YY1 core binding sequence ACAT is present in the center of p53-half-binding sites in the p21 and GADD45 genes regulating growth arrest and DNA repair, respectively, but is absent in those of the Bax gene critical for apoptosis. In transfection experiments YY1 inhibits p53-activated transcription from the p53-binding site that contains the ACAT sequence. YY1 and p53 are colocalized around the nucleoli and in discrete nuclear domains in PC12 cells undergoing apoptosis. YY1 might attenuate p53-dependent transcription from a subset of p53-target genes and this may be relevant for directing cells either to growth arrest or apoptosis upon p53 activation.

Animals↗
PubMed2004

Nociceptive behavior induced by poly-L-lysine and other basic compounds involves the spinal NMDA receptors.

We have previously shown that spermine, a basic polyamine, and big dynorphin, a basic polypeptide, induce nociceptive behavior if injected intrathecally (i.t.) in mice (see [Pain 86 (2000) 55-61] and [Brain Res. 952 (2002) 7-14]). This suggests that other basic molecules might have the same effects. Here, i.t. administration of poly-L-lysine (12 and 36 pg) to mice was found to produce the same characteristic behavioral response, biting and/or licking of the hindpaw and the tail along with slight hindlimb scratching directed toward the flank, which peaked at 0-10 min after injection. The behavior induced by poly-L-lysine (12 pg) was dose-dependently inhibited by intraperitoneal injection of morphine (0.25-4 mg/kg) and also dose-dependently, by i.t. co-administration of D-(-)-2-amino-5-phosphonovaleric acid (D-APV) (1-4 nmol), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5,10-imine hydrogen maleate (MK-801) (0.0156-4 nmol), an NMDA ion-channel blocker, and ifenprodil (2-8 nmol), an antagonist of the polyamine recognition site and the NR2B-containing NMDA receptor subtype. On the other hand, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non-NMDA glutamate receptor antagonist, 7-chlorokynurenic acid, a competitive antagonist of the glycine recognition site on the NMDA receptor ion-channel complex, [D-Phe7, d-His9]-substance P (6-11), a specific antagonist for substance P (NK1) receptors, or MEN-10,376, a tachykinin NK2 receptor antagonist, had no effect. These results confirm the observations obtained with other basic molecules and suggest that the behavior induced by poly-l-lysine is mediated through the activation of the NMDA receptor ion-channel complex acting either on the polyamine recognition site or on the NR2B subunit.

Analysis of Variance↗
PubMed2004

Denaturation of dsDNA by p53: fluorescence correlation spectroscopy study.

p53 activates transcription through interaction with specific DNA sequences in gene promoters. It also regulates DNA replication, recombination, and repair apparently through interactions with DNA intermediates of these reactions. Biochemical activities relevant for these functions of p53 include binding to the ends and internal segments of single-stranded DNA molecules, catalysis of DNA renaturation, and strand exchange. We report a novel activity of p53, its ability to denature double-stranded DNA molecules aggregated by basic peptides. Stable complexes of coiled single-stranded DNA molecules with basic peptides are formed in this reaction. Thus, complementary to the ability to catalyze DNA renaturation, p53 denatures double-stranded DNA when the latter reaction is thermodynamically favorable. This p53 activity, along with its ability to interact physically with DNA helicases, may be relevant for resolving double-stranded DNA intermediates and inhibition of DNA recombination, which is critical for guarding of the genome.

DNA↗
PubMed2004

Nociceptin/orphanin FQ modulates spatial learning via ORL-1 receptors in the dorsal hippocampus of the rat.

The endogenous peptide nociceptin (orphanin FQ) plays a role in several important physiological functions in the CNS such as pain, anxiety and locomotion. It has previously been found that injection of 10 nmol nociceptin into the CA3 region of the hippocampus markedly impairs spatial learning and memory in the rat. The present study examined the effects of lower doses of nociceptin (3.3, 1, 0.33 and 0.1 nmol/rat) on spatial learning. The 3.3 nmol dose impaired spatial learning over the 5 days of training although the effect was not as strong as with 10 nmol. In contrast, the two lower doses, 1 and 0.33 nmol/rat, improved spatial learning whereas the lowest dose, 0.1 nmol/rat, had no significant effect. Both the impairing and facilitating effect of nociceptin could be blocked by an ORL-1 receptor antagonist, [Phe1Psi(CH(2)-NH)Gly2]NC(1-13)NH2 (10 nmol/rat), indicating that both effects are ORL-1 receptor-mediated. The 3.3 nmol dose of nociceptin did not impair the performance in the visual platform task and did not alter swim speed or motor activity indicating no effects on motivation or motor performance. Taken together, these results show that nociceptin has a biphasic dose-effect curve and provide further evidence for a role of this neuropeptide in cognitive processes in the hippocampus.

Animals↗
PubMed2003

Evidence in locomotion test for the functional heterogeneity of ORL-1 receptors.

1. The ORL1 agonists nociceptin and Ro 64-6198 were compared in their ability to modify spontaneous locomotor activity in male NMRI mice not habituated to the test environment. 2. Higher doses of nociceptin (>5 nmol i.c.v.) reduced whereas lower doses (<1 nmol i.c.v.) stimulated locomotor activity. Both effects were blocked by the putative ORL1 antagonists [NPhe1]nociceptin(1-13)NH2 (10 nmol i.c.v.) and UFP101 (10 nmol, i.c.v.). The effects were also blocked by naloxone benzoylhydrazone (1 mg x kg(-1) s.c.), but not by the nonselective opioid antagonist naloxone (1 mg x kg(-1) s.c.). 3 In contrast to nociceptin, the synthetic ORL1 agonist Ro 64-6198 (0.01-1.0 mg x kg(-1) i.p.) produced monophasic inhibition of locomotor activity, which was insensitive to the treatment with [NPhe1]nociceptin(1-13)NH2 or naloxone benzoylhydrazone. Treatment with UFP101 abolished the locomotor inhibition induced by Ro 64-6198 (1.0 mg x kg(-1)), whereas naloxone (1.0 mg x kg(-1), s.c.) further increased the locomotor-inhibitory effects. 4. Naloxone benzoylhydrazone (0.3; 1.0 and 3.0 mg x kg(-1) s.c.) increased locomotor activity, although the effect was statistically significant only with the highest dose used. 5. Pretreatment with the tyrosine hydroxylase inhibitor H44-68 totally eliminated the motor-stimulatory effects of low doses of nociceptin, probably via dopamine depletion. 6. The results suggest that nociceptin stimulates locomotor activity at low doses if dopamine activity is intact. High doses of nociceptin and all the tested doses of Ro 64-6198 seem to interact with a functionally different subset of ORL1 receptors. In addition, the effects of Ro 64-6198 are modulated by tonic opioid receptor activity.

Animals↗
PubMed2003

Dopamine D2 receptor gene Ser311Cys variant and schizophrenia: association study and meta-analysis.

An association has been reported between a dopamine D(2) receptor gene (DRD2) Ser311Cys variant and schizophrenia. In a replication attempt, Swedish patients with schizophrenia (n = 173) and control subjects (n = 236) were assessed for the DRD2 Ser311Cys variant. Schizophrenic patients displayed higher Cys311 allele frequencies than control subjects (4.0 vs. 0.8%, chi(2) = 9.49, df = 1, P = 0.002; odds ratio (OR) 4.93, 95% confidence interval (95% CI) 1.61-15.12). The association was detected only in men. The results were supported by a meta-analysis of all published case-control studies comprising a total of 9,152 subjects (chi(2) = 11.37, df = 1, P < 0.001; OR 1.43, 95% CI 1.16-1.78). The present results support the involvement of the DRD2 gene in the pathogenesis of schizophrenia.

Adult↗