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O A Andreassen

Publications and source records attributed to O A Andreassen.

At least 19 recordsLinked to original sources

Early-childhood temperament trajectories map onto transdiagnostic psychiatric risk.

Early-childhood temperament is associated with later mental health. Temperament continues to develop throughout the first years of life, and a single assessment cannot capture its trajectory. Whether departures from an individual's developmental trajectory carry psychiatric risk remains unknown. Using data from more than 50,000 children in the Norwegian Mother, Father and Child Cohort Study, we modeled longitudinal temperament at 1.5, 3, and 5 years of age with the FEMA-Long mixed-effects framework. We then quantified each child's departures from their predicted trajectories. Multivariate analysis revealed two transdiagnostic dimensions linking trajectory departures to psychiatric diagnoses across childhood and adolescence. Higher scores on the first dimension were associated with an increased hazard of subsequent ADHD diagnosis (hazard ratio = 1.54), and higher scores on the second with an increased hazard of Asperger syndrome (hazard ratio = 1.64). To examine the genetic basis of these associations, we performed longitudinal GWAS of temperament and conjunctional FDR analysis to detect loci shared with the associated diagnoses. The effects of these loci changed across early childhood, with some strengthening and others attenuating with age. These findings show that departures from predicted temperament trajectories reflect transdiagnostic psychiatric risk with a shared genetic basis. Longitudinal, trajectory-based monitoring could help identify children at elevated psychiatric risk.

Journal Article↗

Oral dyskinesias and histopathological alterations in substantia nigra after long-term haloperidol treatment of old rats.

The pathophysiologic basis of tardive dyskinesia remains unclear, but several lines of evidence suggest that persistent neuronal changes in the basal ganglia produced by oxidative stress or glutamate toxicity may play a role, especially in the elderly. In the present study we examined whether histopathological alterations in substantia nigra are related to oral dyskinesia in a rodent model of tardive dyskinesia. Haloperidol decanoate (38 mg/kg/4 weeks) was administered to young (8 weeks) and old (38 weeks) rats for a total period of 28 weeks, and the development of vacuous chewing movements (VCM) was observed. Rats with high and low levels of VCM and saline-treated controls were analyzed for histopathological alterations. Reduced nerve cell number and atrophic neurons were prominent features in the substantia nigra of old rats with high levels of VCM. Some alterations were also present in the substantia nigra of the old rats with low levels of VCM and young rats with high VCM levels, but these were significantly less affected than the high VCM rats. These results show that the development of haloperidol-induced oral dyskinesias in old rats is associated with histopathological alterations in the substantia nigra. This suggests that nigral degeneration induced by neuroleptics may contribute to the development of persistent VCM in rats and possibly irreversible tardive dyskinesia in humans.

Aging↗

Lipoic acid improves survival in transgenic mouse models of Huntington's disease.

There is substantial evidence implicating excitotoxicity and oxidative damage in the pathogenesis of Huntington's disease (HD). We therefore examined whether the antioxidants 2-sulpho-tert-phenyibutyinitrone (S-PBN) and alpha-lipoic acid could exert neuroprotective effects in transgenic mouse models of HD. S-PBN showed no effects on either weight loss or survival in the R6/2 transgenic HD mice. alpha-Lipoic acid produced significant increases in survival in both R6/2 and N171-82Q transgenic mouse models of HD. These findings suggest that alpha-lipoic acid might have beneficial effects in HD patients.

Animals↗

Dichloroacetate exerts therapeutic effects in transgenic mouse models of Huntington's disease.

Dichloroacetate (DCA) stimulates pyruvate dehydrogenase complex (PDHC) activity and lowers cerebral lactate concentrations. In the R6/2 and N171-82Q transgenic mouse models of Huntington's disease (HD), DCA significantly increased survival, improved motor function, delayed loss of body weight, attenuated the development of striatal neuron atrophy, and prevented diabetes. The percentage of PDHC in the active form was significantly reduced in R6/2 mice at 12 weeks of age, and DCA ameliorated the deficit. These results provide further evidence for a role of energy dysfunction in HD pathogenesis and suggest that DCA may exert therapeutic benefits in HD.

Animals↗

Mice with a partial deficiency of manganese superoxide dismutase show increased vulnerability to the mitochondrial toxins malonate, 3-nitropropionic acid, and MPTP.

There is substantial evidence implicating mitochondrial dysfunction and free radical generation as major mechanisms of neuronal death in neurodegenerative diseases. The major free radical scavenging enzyme in mitochondria is manganese superoxide dismutase (SOD2). In the present study we investigated the susceptibility of mice with a partial deficiency of SOD2 to the neurotoxins 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP), 3-nitropropionic acid (3-NP), and malonate, which are commonly used animal models of Parkinson's and Huntington's disease. Heterozygous SOD2 knockout (SOD2(+/-)) mice showed no evidence of neuropathological or behavioral abnormalities at 2-4 months of age. Compared to littermate wild-type mice, mice with partial SOD2 deficiency showed increased vulnerability to dopamine depletion after systemic MPTP treatment and significantly larger striatal lesions produced by both 3-NP and malonate. SOD2(+/-) mice also showed an increased production of "hydroxyl" radicals after malonate injection measured with the salicylate hydroxyl radical trapping method. These results provide further evidence that reactive oxygen species play an important role in the neurotoxicity of MPTP, malonate, and 3-NP. These findings show that a subclinical deficiency in a free radical scavenging enzyme may act in concert with environmental toxins to produce selective neurodegeneration.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

Transgenic ALS mice show increased vulnerability to the mitochondrial toxins MPTP and 3-nitropropionic acid.

The pathogenesis of neurodegenerative diseases may involve a genetic predisposition acting in concert with environmental toxins. To test this hypothesis we examined whether transgenic mice with the G93A mutation in Cu,Zn superoxide dismutase show increased vulnerability to either 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 3-nitropropionic acid (3-NP). Compared to littermate controls G93A transgenic mice showed a greater loss of striatal dopamine, DOPAC, and HVA at 50, 70, and 120 days of age following administration of MPTP; however, cell loss in the substantia nigra was not greater. The G93A transgenic mice showed significantly increased vulnerability to striatal lesions produced by 3-NP compared with littermate controls at 120 days of age. The finding that G93A mice show increased vulnerability to mitochondrial toxins further implicates mitochondrial dysfunction in the pathogenesis of neuronal death in these mice. The findings support the hypothesis that a genetic defect can increase susceptibility to environmental toxins and that this may play a role in the pathogenesis of neurodegenerative diseases.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

Effects of an inhibitor of poly(ADP-ribose) polymerase, desmethylselegiline, trientine, and lipoic acid in transgenic ALS mice.

The development of transgenic mouse models of amyotrophic lateral sclerosis (ALS) allows the testing of neuroprotective agents. We evaluated the effects of five agents in transgenic mice with the G93A Cu,Zn superoxide dismutase mutation. A novel inhibitor of poly(ADP-ribose) polymerase showed no effects on survival. Desmethylselegiline and CGP3466 are agents that exert antiapoptotic effects in vitro by preventing nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase. They had no significant effects on survival in the G93A mice. Trientine, a copper chelator, produced a modest significant increase in survival. Similarly administration of lipoic acid in the diet produced a significant improvement in survival. These results therefore provide evidence for potential therapeutic effects of copper chelators and lipoic acid in the treatment of ALS.

Amphetamines↗

Creatine increase survival and delays motor symptoms in a transgenic animal model of Huntington's disease.

There is substantial evidence for bioenergetic defects in Huntington's disease (HD). Creatine administration increases brain phosphocreatine levels and it stabilizes the mitochondrial permeability transition. We examined the effects of creatine administration in a transgenic mouse model of HD produced by 82 polyglutamine repeats in a 171 amino acid N-terminal fragment of huntingtin (N171-82Q). Dietary supplementation of 2% creatine significantly improved survival, slowed the development of motor symptoms, and delayed the onset of weight loss. Creatine lessened brain atrophy and the formation of intranuclear inclusions, attenuated reductions in striatal N-acetylaspartate as assessed by NMR spectroscopy, and delayed the development of hyperglycemia. These results are similar to those observed using dietary creatine supplementation in the R6/2 transgenic mouse model of HD and provide further evidence that creatine may exert therapeutic effects in HD.

Animals↗

Oral dyskinesias and morphological changes in rat striatum during long-term haloperidol administration.

RATIONALE: Neuroleptic-induced oral dyskinesias in rats, a putative analogue to human tardive dyskinesia, may be due to increased glutamate release within the striatum. This may lead to excitotoxic degeneration and, as a consequence, persistent motor side effects. OBJECTIVES: To investigate whether alterations in glutamatergic synapses within the striatum are associated with the development of neuroleptic-induced oral dyskinesia. METHODS: Haloperidol was administered for 20 weeks, and rats with high and low levels of vacuous chewing movements (VCM) were analyzed for morphological changes with electron microscopy at three time points. RESULTS: At week 8, the high VCM rats had a larger nerve terminal area and lower density of nerve terminal glutamate immunoreactivity than the other groups. After 18 weeks of treatment, the nerve terminal area was increased relative to controls in both the high and low VCM groups. After discontinuation of treatment, there were no significant morphological differences between the groups, but the level of VCM was still significantly increased in the high VCM group. CONCLUSIONS: These results show that striatal glutamatergic transmission is affected during haloperidol treatment and the nerve terminal area and the density of nerve terminal glutamate immunoreactivity are important in determining the VCM response to haloperidol treatment. This indicates that increased glutamatergic synaptic activity in the striatum contributes to the development of human tardive dyskinesia.

Animals↗

Increases in cortical glutamate concentrations in transgenic amyotrophic lateral sclerosis mice are attenuated by creatine supplementation.

Several lines of evidence implicate excitotoxic mechanisms in the pathogenesis of amyotrophic lateral sclerosis (ALS). Transgenic mice with a superoxide dismutase mutation (G93A) have been utilized as an animal model of familial ALS (FALS). We examined the cortical concentrations of glutamate using in vivo microdialysis and in vivo nuclear magnetic resonance (NMR) spectroscopy, and the effect of long-term creatine supplementation. NMDA-stimulated and Ltrans-pyrrolidine-2,4-dicarboxylate (LTPD)-induced increases in glutamate were significantly higher in G93A mice compared with littermate wild-type mice at 115 days of age. At this age, the tissue concentrations of glutamate were also significantly increased as measured with NMR spectroscopy. Creatine significantly increased longevity and motor performance of the G93A mice, and significantly attenuated the increases in glutamate measured with spectroscopy at 75 days of age, but had no effect at 115 days of age. These results are consistent with impaired glutamate transport in G93A transgenic mice. The beneficial effect of creatine may be partially mediated by improved function of the glutamate transporter, which has a high demand for energy and is susceptible to oxidative stress.

ATP-Binding Cassette Transporters↗

Increased oxidative damage to DNA in a transgenic mouse model of Huntington's disease.

Mitochondrial dysfunction and oxidative damage may play a role in the pathogenesis of Huntington's disease (HD). We examined concentrations of 8-hydroxy-2-deoxyguanosine (OH(8)dG), a well-established marker of oxidative damage to DNA, in a transgenic mouse model of HD (R6/2). Increased concentrations of OH(8)dG were found in the urine, plasma and striatal microdialysates of the HD mice. Increased concentrations were also observed in isolated brain DNA at 12 and 14 weeks of age. Immunocytochemistry showed increased OH(8)dG staining in late stages of the illness. These results suggest that oxidative damage may play a role in the pathogenesis of neuronal degeneration in the R6/2 transgenic mouse model of HD.

8-Hydroxy-2'-Deoxyguanosine↗

N-acetyl-L-cysteine improves survival and preserves motor performance in an animal model of familial amyotrophic lateral sclerosis.

Increasing evidence implicates oxidative damage as a major mechanism in the pathogenesis of amyotrophic lateral sclerosis (ALS). We examined the effect of preventative treatment with N-acetyl-L-cysteine (NAC), an agent that reduces free radical damage, in transgenic mice with a superoxide dismutase (SODI) mutation (G93A), used as an animal model of familial ALS. NAC was administered at 1% concentration in the drinking water from 4-5 weeks of age. The treatment caused a significantly prolonged survival and delayed onset of motor impairment in G93A mice treated with NAC compared to control mice. These results provide further evidence for the involvement of free radical damage in the G93A mice, and support the possibility that NAC, an over-the-counter antioxidant, could be explored in clinical trials for ALS.

Acetylcysteine↗

Neuroprotective effects of creatine in a transgenic mouse model of Huntington's disease.

Huntington's disease (HD) is a progressive neurodegenerative illness for which there is no effective therapy. We examined whether creatine, which may exert neuroprotective effects by increasing phosphocreatine levels or by stabilizing the mitochondrial permeability transition, has beneficial effects in a transgenic mouse model of HD (line 6/2). Dietary creatine supplementation significantly improved survival, slowed the development of brain atrophy, and delayed atrophy of striatal neurons and the formation of huntingtin-positive aggregates in R6/2 mice. Body weight and motor performance on the rotarod test were significantly improved in creatine-supplemented R6/2 mice, whereas the onset of diabetes was markedly delayed. Nuclear magnetic resonance spectroscopy showed that creatine supplementation significantly increased brain creatine concentrations and delayed decreases in N-acetylaspartate concentrations. These results support a role of metabolic dysfunction in a transgenic mouse model of HD and suggest a novel therapeutic strategy to slow the pathological process.

Animals↗

Inhibition of neuronal nitric oxide synthase protects against MPTP toxicity.

Previous work showed that several relatively specific inhibitors of neuronal nitric oxide synthase (nNOS) produce protection against MPTP induced dopaminergic toxicity. We examined whether a highly specific novel inhibitor of nNOS, ARRI 7338, could also protect against MPTP toxicity. ARR17338 produced dose-dependent significant protection against MPTP induced depletion of dopamine and protected against MPTP induced depletions of tyrosine hydroxylase immunostained neurons in the substantia nigra. These results provide further evidence that inhibitors of nNOS may be useful for the treatment of Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

No changes in dopamine D(1) receptor mRNA expressing neurons in the dorsal striatum of rats with oral movements induced by long-term haloperidol administration.

Neuroleptic-induced vacuous chewing movements (VCM) in rats, a putative analogue to tardive dyskinesia in man, may involve degeneration within striatum as well as changes in neurotransmitter and receptor expression. In this study, we measured the expression of dopamine D(1) receptor mRNA by dorsal striatal neurons in rats with high and low level of VCM after treatment with haloperidol for 38 weeks. Both the average integrated density of the in situ hybridization signal and number of cells obtained by the stereological cell counting remained within control level, irrespective of the level of haloperidol-induced oral dyskinesia.

Animals↗

Reduced number of striatal neurons expressing preprosomatostatin mRNA in rats with oral dyskinesias after long-term haloperidol administration.

Neuroleptic-induced oral dyskinesia in rats, a putative analogue to human tardive dyskinesia, may be due to degeneration within the striatum. Using unbiased stereological methods, a decreased number of striatal neurons expressing preprosomatostatin mRNA was observed only in rats that developed pronounced oral dyskinesias after 30 weeks of haloperidol administration. The amount of preprosomatostatin mRNA in each striatal neuron, measured in terms of optical densities of individual neurons, was not affected by haloperidol. A tendency toward a reduction in the number of NADPH-diaphorase positive neurons was observed in rats receiving haloperidol. These results indicate that the mechanism by which neuroleptics induce oral dyskinesias in rats, and perhaps tardive dyskinesia in humans, involves a functional disruption and possibly damage of a subpopulation of interneurons in the striatum.

Animals↗

Mice deficient in cellular glutathione peroxidase show increased vulnerability to malonate, 3-nitropropionic acid, and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine.

Glutathione peroxidase (GSHPx) is a critical intracellular enzyme involved in detoxification of hydrogen peroxide (H(2)O(2)) to water. In the present study we examined the susceptibility of mice with a disruption of the glutathione peroxidase gene to the neurotoxic effects of malonate, 3-nitropropionic acid (3-NP), and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP). Glutathione peroxidase knock-out mice showed no evidence of neuropathological or behavioral abnormalities at 2-3 months of age. Intrastriatal injections of malonate resulted in a significant twofold increase in lesion volume in homozygote GSHPx knock-out mice as compared to both heterozygote GSHPx knock-out and wild-type control mice. Malonate-induced increases in conversion of salicylate to 2,3- and 2, 5-dihydroxybenzoic acid, an index of hydroxyl radical generation, were greater in homozygote GSHPx knock-out mice as compared with both heterozygote GSHPx knock-out and wild-type control mice. Administration of MPTP resulted in significantly greater depletions of dopamine, 3,4-dihydroxybenzoic acid, and homovanillic acid in GSHPx knock-out mice than those seen in wild-type control mice. Striatal 3-nitrotyrosine (3-NT) concentrations after MPTP were significantly increased in GSHPx knock-out mice as compared with wild-type control mice. Systemic 3-NP administration resulted in significantly greater striatal damage and increases in 3-NT in GSHPx knock-out mice as compared to wild-type control mice. The present results indicate that a knock-out of GSHPx may be adequately compensated under nonstressed conditions, but that after administration of mitochondrial toxins GSHPx plays an important role in detoxifying increases in oxygen radicals.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

Neurotoxicity associated with neuroleptic-induced oral dyskinesias in rats. Implications for tardive dyskinesia?

Tardive dyskinesia is a serious motor side effect of long-term treatment with neuroleptics, with an unknown pathophysiologic basis. Brain damage and aging are prominent risk-factors, and together with the persistent character of the disorder, it is likely that long-lasting neuronal changes are involved in the pathogenesis. It has been hypothesized that striatal neurodegeneration caused by excitotoxic mechanisms and oxidative stress may play an important role in the development of the disorder, and the scope of the present work is to review the evidence supporting this hypothesis. The rat model of tardive dyskinesia has been used extensively in the field, and the usefulness of this model will be discussed. Neuroleptics are able to induce oxidative stress in vitro and increase striatal glutamatergic activity in rats, which may lead to toxic effects in the striatum. Drugs that block excitotoxicity inhibit the development of persistent oral dyskinesia in the rat model, and impaired energy metabolism leads to increased frequency of oral dyskinesia. There are also signs of altered striatal histology in rats with high frequency of oral dyskinesia. Furthermore, markers of increased oxidative stress and glutamatergic neurotransmission have been found in the cerebrospinal fluid of patients with tardive dyskinesia. In conclusion, several lines of evidence implicate neurotoxic events in the development of neuroleptic induced tardive dyskinesia.

Animals↗