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| 5. |
- Starck, Göran, et al.
(författare)
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A 1H magnetic resonance spectroscopy study in adults with obsessive compulsive disorder: relationship between metabolite concentrations and symptom severity.
- 2008
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Ingår i: Journal of neural transmission (Vienna, Austria : 1996). - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 115:7, s. 1051-62
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Tidskriftsartikel (refereegranskat)abstract
- 1H magnetic resonance spectroscopy (1H MRS) studies exploring brain metabolites, especially glutamine + glutamate (Glx), in obsessive compulsive disorder (OCD) are of vital interest for trying to understand more about the pathophysiology of OCD. Therefore, we conducted the present 1H MRS study with the aims of (1) comparing MRS metabolites in a group of adult patients with OCD and a group of healthy controls, and (2) examining the relationship between MRS metabolite concentrations and symptom severity in the patient group. Three brain regions were studied, the right caudate nucleus, the anterior gyrus cinguli and the occipital cortex bilaterally. Since multivariate analysis is a highly useful tool for extraction of 1H MRS data, we applied principal component analysis (PCA) and partial least square projection to latent structures (PLS) to the MRS data. PLS disclosed a strong relationship between several of the metabolites and OCD symptom severity, as measured with Yale-Brown obsessive-compulsive scale (YBOCS): the YBOCS score was found to be positively correlated to caudate creatine, Glx, glutamate, and choline compounds as well as occipital cortex myoinositol, and negatively correlated to occipital cortex Glx. The negative correlation between occipital cortex Glx and YBOCS was the most impressive. PCA did not reveal any tendency for a separation between the patients with OCD and controls with respect to MRS metabolites. The results are discussed in relation to corticostriatothalamocortical feedback and previous observations of poor visuospatial ability in OCD.
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| 6. |
- Burstein, ES, et al.
(författare)
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II. In vitro evidence that (-)-OSU6162 and (+)-OSU6162 produce their behavioral effects through 5-HT2A serotonin and D2 dopamine receptors
- 2011
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Ingår i: JOURNAL OF NEURAL TRANSMISSION. - 0300-9564. ; 118:11, s. 1523-1533
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Tidskriftsartikel (refereegranskat)abstract
- Abstract: (-)-OSU6162 has promise for treating Parkinson's disease, Huntington's disease and schizophrenia. Behavioral tests evaluating the locomotor effects of (-) and (+)-OSU6162 on 'low activity' animals (reserpinized mice and habituated rats) and 'high activity' animals (drug naive mice and non-habituated rats) revealed that both enantiomers of OSU6162 had dual effects on behavior, stimulating locomotor activity in 'low activity' animals and inhibiting locomotor activity in 'high activity' animals. To elucidate a plausible mechanism of action for their behavioral effects, we evaluated the intrinsic actions of (-)- and (+)-OSU6162, and a collection of other antipsychotic and antiparkinsonian agents at 5-HT2A and D2 receptors in functional assays with various degrees of receptor reserve, including cellular proliferation, phosphatidyl inositol hydrolysis, GTP gamma S and beta-arrestin recruitment assays. We also tested for possible allosteric actions of (-)-OSU6162 at D2 receptors. Both enantiomers of OSU6162 were medium intrinsic activity partial agonists at 5-HT2A receptors and low intrinsic activity partial agonists at D2 receptors. (+)-OSU6162 had higher efficacy at 5-HT2A receptors, which correlated with its greater stimulatory activity in vivo, but (-)-OSU6162 had higher potency at D2 receptors, which correlated with its greater inhibitory activity in vivo. (-)-OSU6162 did not display any convincing allosteric properties. Both (+)- and (-)-OSU6162 were significantly less active at 27 other monoaminergic receptors and reuptake transporters tested suggesting that D2 and 5-HT2A receptors play crucial roles in mediating their behavioral effects. Compounds with balanced effects on these two receptor systems may offer promise for treating neuropsychiatric diseases.
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| 7. |
- Carlsson, Arvid, 1923, et al.
(författare)
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A dopaminergic deficit hypothesis of schizophrenia: the path to discovery.
- 2006
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Ingår i: Dialogues in clinical neuroscience. - 1294-8322. ; 8:1, s. 137-42
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Tidskriftsartikel (refereegranskat)abstract
- In contrast to the conventional view of dopamine involvement in schizophrenia, which posits hyperactive dopaminergic transmission, we propose that for unknown developmental and/or biochemical reasons, a primary defect occurs in efficient, tight dopaminergic synaptic transmission, triggering feedback activation and receptor upregulation, and resulting in the well-characterized increase in dopaminergic tone. This hypothesis is driven by suggestive evidence for subpopulations of dopamine D2 receptors delivering contrasting forms of dopaminergic transmission: synaptic receptors, responsible for basic dopaminergic function and subject to effective feedback control, and poorly controlled extrasynaptic receptors partly responsible for the positive symptoms of psychosis. Since the primary defect is dopamine deficiency, we term this theory the dopaminergic deficit hypothesis of schizophrenia. It is currently informing clinical studies with novel partial dopamine antagonists (dopamine stabilizers) such as ACR16, which preferentially target extrasynaptic receptors while leaving synaptic transmission and basic dopamine function intact.
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| 8. |
- Carlsson, Arvid, 1923, et al.
(författare)
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Adaptive properties and heterogeneity of dopamine D(2) receptors - pharmacological implications.
- 2008
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Ingår i: Brain research reviews. - : Elsevier BV. - 0165-0173. ; 58:2, s. 374-8
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Tidskriftsartikel (refereegranskat)abstract
- In this review, we focus on the marked adaptability of dopamine D(2) receptors to varying agonist levels and we discuss the extent to which this phenomenon can account for the heterogeneity of these receptors in regard to function and pharmacological responsiveness. We emphasize the significance of a distinction between synaptic and extrasynaptic receptors in this context. For example, the application of this dichotomy appears to shed new light on the various subgroups of antipsychotic drugs and the mechanisms underlying their different profiles.
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| 9. |
- Carlsson, Arvid, 1923, et al.
(författare)
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Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence
- 2001
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Ingår i: Annu Rev Pharmacol Toxicol. - 0362-1642. ; 41, s. 237-60
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Forskningsöversikt (refereegranskat)abstract
- In spite of its proven heuristic value, the dopamine hypothesis of schizophrenia is now yielding to a multifactorial view, in which the other monoamines as well as glutamate and GABA are included, with a focus on neurotransmitter interactions in complex neurocircuits. The primary lesion(s) in schizophrenia does not necessarily involve any of these neurotransmitters directly but could deal with a more general defect, such as a faulty connectivity of developmental origin. Nevertheless, a precise identification of neurotransmitter aberrations in schizophrenia will probably provide clues for a better understanding of the disease and for the development of new treatment and prevention strategies.
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| 11. |
- Carlsson, Maria L., 1959, et al.
(författare)
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Schizophrenia: from dopamine to glutamate and back.
- 2004
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Ingår i: Current medicinal chemistry. - 0929-8673. ; 11:3, s. 267-77
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Tidskriftsartikel (refereegranskat)abstract
- The first part of the present review describes the exciting journey of dopamine stabilizers, starting in the early eighties with the development of the partial dopamine agonist (-)-3-PPP of phenylpiperidine structure, via various compounds with aminotetraline structure with preferential autoreceptor antagonist properties, and then back again to phenylpiperidine compounds carrying substituents on the aromatic ring that transformed them from partial dopamine agonists to partial dopamine receptor antagonists, such as OSU6162. OSU6162 was brought to the clinic and has in preliminary trials showed antidyskinetic and antipsychotic efficacy. The second part of this review describes results from a hypoglutamatergia mouse model for cognitive symptoms of schizophrenia, where we have tested traditional neuroleptics, new generation antipsychotics with marked 5-HT2 vs dopamine D2 receptor blockade as well as a dopamine stabilizer belonging to the partial dopamine receptor antagonist category.
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| 12. |
- Carlsson, Maria L., 1959, et al.
(författare)
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The 5-HT2A receptor antagonist M100907 is more effective in counteracting NMDA antagonist- than dopamine agonist-induced hyperactivity in mice
- 1999
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Ingår i: J Neural Transm. - 0300-9564. ; 106:2, s. 123-9
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of the present study was to compare the effectiveness of the selective 5-HT2A antagonist M100907 in different psychosis models. The classical neuroleptic haloperidol was used as reference compound. Two hyperdopaminergia and two hypoglutamatergia mouse models were used. Hyperdopaminergia was produced by the DA releaser d-amphetamine or the DA uptake inhibitor GBR 12909. Hypoglutamatergia was produced by the un-competitive NMDA receptor antagonist MK-801 or the competitive NMDA receptor antagonist D-CPPene. M100907 was found to counteract the locomotor stimulant effects of the NMDA receptor antagonists MK-801 and D-CPPene, but spontaneous locomotion, d-amphetamine- and GBR-12909-induced hyperactivity were not significantly affected. Haloperidol, on the other hand, antagonized both NMDA antagonist- and DA agonist-induced hyperactivity, as well as spontaneous locomotion in the highest dose used. Based on the present and previous results we draw the conclusion that 5-HT2A receptor antagonists are particularly effective against behavioural anomalies resulting from hypoglutamatergia of various origins. The clinical implications of our results and conclusions would be that a 5-HT2A receptor antagonist, due to i a the low side effect liability, could be the preferable treatment strategy in various disorders associated with hypoglutamatergia; such conditions might include schizophrenia, childhood autism and dementia disorders.
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| 13. |
- Haghighi, S., et al.
(författare)
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Open-label study with the monoamine stabilizer (-)-OSU6162 in myalgic encephalomyelitis/chronic fatigue syndrome
- 2021
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Ingår i: Brain and Behavior. - : Wiley. - 2162-3279. ; 11:4
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Tidskriftsartikel (refereegranskat)abstract
- Objectives The purpose of the present study was to investigate the safety and tolerability of the monoaminergic stabilizer (-)-OSU6162 in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In addition, a potential therapeutic effect of (-)-OSU6162 in ME/CFS was evaluated by means of observer-rated scales and self-assessment rating scales. Materials and Methods In the current study using an open-label single-arm design ME/CFS patient received treatment with (-)-OSU6162 during 12 weeks. The patients received the following doses of (-)-OSU6162: 15 mg b.i.d. during the first 4-week period, up to 30 mg b.i.d. during the second 4-week period and up to 45 mg b.i.d. during the third 4-week period, with follow-up visits after 16 and 20 weeks. Results Out of 33 included patients, 28 completed the 12 weeks treatment period. (-)-OSU6162 was well tolerated; only one patient discontinued due to an adverse event. Vital signs and physical examinations showed no abnormal changes. Blood analyses showed an increase in serum prolactin. Therapeutically, improvements were seen on the Clinical Global Impression of Change scale, the FibroFatigue scale, the Mental Fatigue Scale, the Fatigue Severity Scale, Beck Depression Inventory, and the Short Form 36 Health Survey Questionnaire. Conclusions (-)-OSU6162 is well tolerated in ME/CFS patients and shows promise as a novel treatment to mitigate fatigue and improve mood and health-related quality of life in ME/CFS. Obviously, the present results need to be confirmed in future placebo-controlled double-blind trials.
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| 14. |
- Haghighi, S., et al.
(författare)
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Open study with (-)-OSU6162 in multiple sclerosis-related fatigue
- 2018
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Ingår i: Acta Neurologica Scandinavica. - : Hindawi Limited. - 0001-6314. ; 138:6, s. 482-489
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Tidskriftsartikel (refereegranskat)abstract
- Objectives The main objective of this study was to investigate the tolerability and safety of the monoaminergic stabilizer (-)-OSU6162 in patients with multiple sclerosis (MS). In addition, a potential therapeutic effect of (-)-OSU6162 with focus on MS-related fatigue was estimated by means of various self-assessment rating scales as well as a clinical investigator-rated scale. Materials and methods In this open-label, single-arm study, 30 MS patients received treatment with the monoaminergic stabilizer (-)-OSU6162 during 12 weeks. The dose of (-)-OSU6162 was 15 mg twice daily during the first 4-week period, up to 30 mg twice daily during the second 4-week period and up to 45 mg twice daily during the third 4-week period, with follow-up visits after 16 and 20 weeks. MS-related fatigue was rated by the clinical investigator or by self-assessments, using mainly established rating scales. Twenty-five patients completed the study. Results (-)-OSU6162 was well tolerated by all patients, and no serious adverse events were observed. Therapeutically, improvements were observed with respect to fatigue and mood, as judged by ratings on the Mental Fatigue Scale (MFS), Short Form-36 (SF-36) scale and Beck Depression Inventory (BDI). Furthermore, the large majority of patients were rated as globally improved in the medical observers' rating scale Clinical Global Impression of Change (CGI-C). Conclusions In view of its good tolerability, (-)-OSU6162 may offer a new treatment option for alleviating mental fatigue, as well as depression, in MS. Larger, randomized double-blind controlled trials are warranted to confirm the present preliminary observations.
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| 15. |
- Johansson, Birgitta, 1957, et al.
(författare)
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Placebo-controlled cross-over study of the monoaminergic stabiliser (-)-OSU6162 in mental fatigue following stroke or traumatic brain injury
- 2012
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Ingår i: Acta Neuropsychiatrica. - : Cambridge University Press (CUP). - 0924-2708 .- 1601-5215. ; 24:5, s. 266-274
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Tidskriftsartikel (refereegranskat)abstract
- Objective Mental fatigue occurring after a stroke or traumatic brain injury (TBI) often results in difficulties returning to work and pursuing social activities. No effective treatment of this condition is available today. In this study, we have tested a novel pharmacological strategy using the monoaminergic stabiliser (-)-OSU6162. Methods (-)-OSU6162 was given orally for 4 weeks in doses increasing from 15 to 45 mg b.i.d. to 12 patients suffering from mental fatigue, following upon stroke (n?=?6) or TBI (n?=?6). (-)-OSU6162 was compared with placebo using a double-blind, randomised cross-over design. Patients included were well rehabilitated physically with no gross impairment in cognitive functions other than those related to the mental fatigue. Results (-)-OSU6162 caused a remarkable improvement in mental stamina, as evaluated by a self-assessment scale on mental fatigue. Statistical significance was reached on the primary endpoint (Mental Fatigue Scale). There was a trend towards improvement in the secondary endpoints processing speed and attention. Principal component analysis showed an overall positive treatment effect in 7 of 12 patients. Beneficial responses were seen already during the first few days of active drug treatment. Increasing dosage caused no further improvement. Adverse reactions consisted of short-lasting mild nausea and attenuated appetite. These side effects disappeared upon dose reduction. Conclusion The monoaminergic stabiliser (-)-OSU6162 offers promise as a candidate for treatment of mental fatigue after a stroke or TBI.
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| 16. |
- Kloberg, A., et al.
(författare)
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Tolerability and efficacy of the monoaminergic stabilizer (-)-OSU6162 (PNU-96391A) in Huntington's disease: A double-blind cross-over study
- 2014
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Ingår i: Acta Neuropsychiatrica. - : Cambridge University Press. - 0924-2708 .- 1601-5215. ; 26:5, s. 298-306
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Tidskriftsartikel (refereegranskat)abstract
- Objective To evaluate the safety (primary objective) and efficacy (secondary objective) of (-)-OSU6162 in Huntington's disease (HD). Methods In a double-blind, cross-over trial, patients with HD were randomly assigned to start treatment on either (-)-OSU6162 or placebo. After 4 weeks, those patients who initially received active drug were switched to placebo for another 4 weeks, and vice versa. During the first week the (-)-OSU6162 dose was 15 mg twice daily, during the second week 30 mg twice daily, and during the last 2 weeks 45 mg twice daily. Motor, cognitive, mental and social functions were rated by the clinical investigator or by self-assessment, using established rating scales. Results Fifteen patients fulfilling inclusion and exclusion criteria completed the study. (-)-OSU6162 was well tolerated by all patients and no adverse effects were observed. (-)-OSU6162 treatment significantly improved the Short Form 36 Vitality score, mainly due to an improvement of the individual item 'worn-out' (VT3). In addition, an improvement of depressive symptoms was found using Beck Depression Inventory. In contrast to a general trend of improvement in several non-motor variables only small and non-significant differences between (-)-OSU6162 and placebo were found regarding motor functions. Conclusions (-)-OSU6162 offers promise for the treatment of HD, as a drug with good tolerability, capable of improving the patients' experienced non-motor functions such as energy and mood and thus alleviating symptoms of great importance for their quality of life. © © Scandinavian College of Neuropsychopharmacology 2014.
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| 17. |
- Lundberg, Stefan, et al.
(författare)
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Nicotine treatment of obsessive-compulsive disorder
- 2004
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Ingår i: PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY. - : Elsevier BV. - 0278-5846. ; 28:7, s. 1195-1199
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Forskningsöversikt (refereegranskat)
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| 18. |
- Nilsson, Marie, 1968, et al.
(författare)
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A behavioural pattern analysis of hypoglutamatergic mice-effects of four different antipsychotic agents
- 2001
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Ingår i: J Neural Transm. - 0300-9564. ; 108:10, s. 1181-96
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Tidskriftsartikel (refereegranskat)abstract
- In a hypoglutamatergic rodent model, we have observed certain behaviours that might have relevance for the cognitive impairments seen in autism and schizophrenia. Thus, hypoglutamatergic mice show defective habituation, impaired attention, a meagre behavioural repertoire and a general behavioural primitivization. The aim of the present study was to characterise and quantify changes in movement pattern in mice rendered hypoglutamatergic by means of MK-801 treatment, using an automated video tracking system. Further, the effects of four different antipsychotic drugs, the classical neuroleptic haloperidol, the atypical antipsychotic clozapine, the DA D2/5-HT2A antagonist risperidone and the selective 5-HT2A-receptor antagonist M100907, were compared with respect to effects on NMDA antagonist-induced movement pattern alterations. We found that each receptor antagonist had a unique effect on the MK-801-induced behavioural primitivization. Haloperidol was unable to affect the monotonous behaviour induced by MK-801, while risperidone, clozapine and M100907 produced movement patterns of high intricacy.
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| 19. |
- Nilsson, Marie, 1968, et al.
(författare)
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A randomised controlled trial of the monoaminergic stabiliser (−)-OSU6162 in treatment of myalgic encephalomyelitis/chronic fatigue syndrome
- 2018
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Ingår i: Acta Neuropsychiatrica. - : Cambridge University Press (CUP). - 0924-2708 .- 1601-5215. ; 30:3, s. 148-57
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Tidskriftsartikel (refereegranskat)abstract
- © Scandinavian College of Neuropsychopharmacology 2017 Objective: The monoaminergic stabiliser (−)-OSU6162 has in previous studies shown promising effects on mental fatigue after stroke and traumatic brain injury. This study investigated the safety and effectiveness of (−)-OSU6162 in patients with myalgic encephalomyelitis/chronic fatigue syndrome. Methods: A total of 62 patients were randomly assigned to placebo or (−)-OSU6162. Primary outcomes were assessment on the mental fatigue scale (MFS) and the clinical global impression of change (CGI-C) scale. Secondary outcomes were results on the FibroFatigue scale (FF), the Beck Depression Inventory (BDI), the pain visual analogue scale and neuropsychological tests. Assessments were performed at baseline, after 1 and 2 weeks of treatment and at follow-up after 6 weeks. Results: MFS and CGI-C showed significant improvements for both treatment groups after treatment but not at follow-up; a similar pattern was seen for FF and BDI. However, significant differences between groups could not be demonstrated. On the other hand, correlation analyses showed a significant correlation between (−)-OSU6162 concentration and change in MFS, FF, and BDI score within the concentration interval 0.1–0.7 µM. Exploratory subgroup analyses showed a larger treatment effect with (−)-OSU6162 in improving MFS and FF symptoms in patients on antidepressant therapy compared to those without antidepressant treatment. Conclusion: (−)-OSU6162 was found to be safe and well tolerated. When analysing the entire material (−)-OSU6162 was not found to differ significantly from placebo in alleviating fatigue in ME patients but was superior to placebo in counteracting fatigue in a subgroup of ME patients who received concomitant pharmacological treatment for depression.
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| 20. |
- Nilsson, Marie, 1968, et al.
(författare)
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Differential effects of the N-methyl-d-aspartate receptor antagonist MK-801 on different stages of object recognition memory in mice.
- 2007
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Ingår i: Neuroscience. - : Elsevier BV. - 0306-4522. ; 149:1, s. 123-30
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to evaluate the effects of systemic administration of the N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 on different stages of non-spatial object recognition memory processing in mice. To this end we used the object recognition test, where the animal is tested for its ability to discriminate between an old, familiar, and a novel object. MK-801 (0.1 or 0.2 mg/kg) or saline was administered 1) 30 min before or 2) directly after the first, introductory, session or 3) 30 min before the recognition session. Memory retention was evaluated 1.5 h after the introductory session. MK-801 appeared to decrease memory retention when given prior to the introductory session, but not when given directly after the introductory session or before the recognition session, where MK-801 instead induced an increased interest for the novel object. These results suggest that activation of NMDA receptors is a requisite for encoding of recognition memory in mice but not for consolidation and retrieval processes. The increased interest for the novel object showing up when MK-801 was given directly after the introductory session or before the recognition session may reflect a facilitation of retention. Alternatively, the phencyclidine-like, psychotogenic properties of MK-801 could result in an amplification of the perceived salience of the novel object, and/or anxiolytic mechanisms could result in neophilic effects.
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| 21. |
- Nilsson, Marie, 1968, et al.
(författare)
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Glycine and D-serine decrease MK-801-induced hyperactivity in mice
- 1997
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Ingår i: J Neural Transm. - 0300-9564. ; 104:11-12, s. 1195-205
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Tidskriftsartikel (refereegranskat)abstract
- It is well known that the un-competitive N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine can induce a syndrome in humans that mimics both positive and negative symptoms of schizophrenia. In the light of this observation, it has been hypothesised that schizophrenia might be due to a hypofunction of central glutamate systems. A glycine agonist, by strengthening glutamatergic transmission, has been suggested to be useful as treatment. A crucial issue is the uncertainty regarding the degree of saturation of the glycine site associated with the NMDA receptor. The purpose of this study was to investigate if it is possible to strengthen NMDA receptor-mediated neurotransmission by modulating the associated glycine site. The effects of systemic and intraventricular administration of glycine. D-serine and L-serine on the hyperactivity induced in mice by the uncompetitive NMDA receptor antagonist MK-801 were tested. Systemically administered glycine and D-serine were found to decrease MK-801-induced hyperactivity. Intraventricularly administered D-serine in doses of 50 or 100 micrograms/side was found to decrease MK-801-induced hyperactivity during the second half hour of registration; L-serine given in the same doses did not affect the MK-801-induced hyperactivity during this period. These data may suggest that the NMDA receptor-associated glycine site is not saturated in vivo.
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| 22. |
- Nilsson, Marie, 1968, et al.
(författare)
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The dopaminergic stabiliser ACR16 counteracts the behavioural primitivization induced by the NMDA receptor antagonist MK-801 in mice: implications for cognition
- 2004
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Ingår i: Prog Neuropsychopharmacol Biol Psychiatry. - : Elsevier BV. - 0278-5846. ; 28:4, s. 677-85
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Tidskriftsartikel (refereegranskat)abstract
- The Carlsson research group has developed a series of compounds capable of stabilising the dopamine system without inducing the deleterious hypodopaminergia that encumbers the currently used antipsychotic drugs. In the present study one of these dopaminergic stabilisers, ACR16, was tested in a mouse model for cognitive deficits of schizophrenia and autism. Since we believe that hypoglutamatergia is a key element in both schizophrenia and autism we used mice rendered hypoglutamatergic by treatment with the N-methyl-D-aspartate (NMDA) antagonist MK-801. MK-801 causes both hyperactivity and a behavioural primitivization. ACR16 attenuated the MK-801-induced hyperactivity and, in addition, caused a marked improvement of behavioural quality with a movement pattern approaching that of control animals. Since we believe that the impoverishment of the behavioural repertoire caused by MK-801 may correspond to the cognitive deficits seen in schizophrenia and autism, these results suggest that ACR16 may improve cognitive status in these disorders.
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| 23. |
- Nydén, Agneta, 1945, et al.
(författare)
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Interhemispheric transfer in high-functioning children and adolescents with autism spectrum disorders: a controlled pilot study.
- 2004
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Ingår i: Developmental medicine and child neurology. - 0012-1622. ; 46:7, s. 448-54
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Tidskriftsartikel (refereegranskat)abstract
- Autism is a neurodevelopmental disorder with strong genetic influences. Clinical experience and limited empirical evidence support the view that autism may be associated with aberrant interhemispheric information transfer. This empirical controlled study examined whether, at neuropsychological testing, children with autism showed problems with interhemispheric information transfer. The study included auditory, visual, and motor measures covering information transfer within, as well as across, modalities. Thirty children (24 males, 6 females; mean age 12 years 8 months, SD 2 years 8 months; range 9 years 5 months to 17 years 5 months) without learning disability but with autism spectrum disorders were compared with 30 children from a mainstream school matched for age, sex, and IQ>75. Children with autism spectrum disorder performed significantly worse than the comparison group on most of the tests (p=0.02 for auditory perception and attention, p=0.005 for visual perception, p=0.0001 for motor control, p=0.04 for tactile perception). Results support the notion that aberrant interhemispheric transfer may be involved in the pathogenesis or clinical course of autism. The findings were not accounted for by lower IQ in the group with autism.
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| 24. |
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| 25. |
- Rung, Johan P., 1973, et al.
(författare)
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Effects of (-)-OSU6162 and ACR16 on motor activity in rats, indicating a unique mechanism of dopaminergic stabilization.
- 2008
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Ingår i: Journal of neural transmission. - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 115:6, s. 899-908
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Tidskriftsartikel (refereegranskat)abstract
- Dopaminergic stabilizers can be defined as drugs that stimulate or inhibit dopaminergic signalling depending on the dopaminergic tone. (-)-OSU6162 and ACR16 appear to possess such a profile. They have been proposed to act as partial dopamine receptor agonists or as antagonists with preferential action on dopaminergic autoreceptors. Previous studies have shown either stimulation or inhibition of behaviour in response to (-)-OSU6162 and ACR16, which has been suggested to reflect their dual effects on dopaminergic signalling. The aims of the present work are to (1) examine the relation between behavioural response to these drugs and activity baseline, and (2) test the suggested mechanisms of action by means of close comparisons with the known partial D2-receptor agonists (-)-3-PPP and aripiprazole, and the D2 autoreceptor preferring antagonist amisulpride with respect to effects on behaviour. From the results of these experiments it can be concluded that: (1) The direction of the response to (-)-OSU6162 and ACR16 is dependent on activity baseline, which in turn, under physiological conditions, is determined primarily by test arena size of and degree of habituation to the environment. (2) The effects of (-)-OSU6162 and ACR16 cannot be explained on the basis of either partial dopamine receptor agonism or preferential dopamine autoreceptor antagonism. Nevertheless, the current data suggest at least two different D2-receptor-associated targets which mediate opposite effects on activity. This result fits in with a mechanism proposed from a recent in vitro study, according to which (-)-OSU6162 has a dual action on dopamine D2 receptors, (a) an allosteric effect causing an enhanced response to dopamine, and (b) the previously proposed orthosteric effect antagonizing the action of dopamine.
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| 26. |
- Rung, Johan P., 1973, et al.
(författare)
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Effects of the dopamine stabilizers (S)-(-)-OSU6162 and ACR16 on prolactin secretion in drug-naive and monoamine-depleted rats.
- 2011
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Ingår i: Naunyn-Schmiedeberg's archives of pharmacology. - : Springer Science and Business Media LLC. - 1432-1912 .- 0028-1298.
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Tidskriftsartikel (refereegranskat)abstract
- Dopaminergic stabilizers may be conceptualized as drugs with normalizing effects on dopamine-mediated behaviours and neurochemical events. (S)-(-)-OSU6162 (OSU6162) and ACR16 are two structurally related compounds ascribed such properties, principally because of their stabilizing effects on motor activity in rodents. Reports in the literature indicate possible partial D2 receptor agonist effects using various in vitro systems. This study aimed to measure D2 receptor antagonist and agonist effects of OSU6162 and ACR16 in vivo. To address this, we have studied the effects of both compounds on prolactin secretion in drug-naive and dopamine-depleted rats; dopamine depletion was induced by pretreatment with reserpine plus α-methyl-DL: -p-tyrosine. We find that OSU6162 and ACR16 both stimulate prolactin secretion in drug-naive rats with OSU6162 being considerably more potent and efficacious. Both compounds show a non-significant trend towards reversal of the increased secretion caused by dopamine depletion, whereas the D2 receptor antagonist haloperidol further increased prolactin secretion. Thus, this study suggests that OSU6162 and ACR16 act as D2 receptor antagonists under normal conditions in vivo, possibly with minor agonist effects in a state of dopamine depletion.
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| 27. |
- Rung, Johan P., 1973, et al.
(författare)
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(+)-MK-801 induced social withdrawal in rats; a model for negative symptoms of schizophrenia.
- 2005
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Ingår i: Progress in neuro-psychopharmacology & biological psychiatry. - : Elsevier BV. - 0278-5846. ; 29:5, s. 827-32
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Tidskriftsartikel (refereegranskat)abstract
- Dopaminergic agonists and NMDA-receptor antagonists form the basis for the dopamine and glutamate models of schizophrenia, respectively. In human subjects dopaminergic agonists evoke a psychosis resembling positive symptoms of schizophrenia, while NMDA-receptor antagonists produce both positive and negative symptoms. Consequently, the glutamate model may be considered the most complete of the two models. Alterations in animal behaviour, in response to amphetamine or NMDA-receptor antagonists, are widely used to model schizophrenia. NMDA-receptor antagonist induced social withdrawal in rat is an established model for negative symptoms of schizophrenia. In this study we have set up an automated method, based on video tracking, to assess social behaviour, motor activity and movement pattern in rats. This method was then used to evaluate the effects of amphetamine and the NMDA-receptor antagonist (+)-MK-801, administered as single intraperitoneal injections, on rat behaviour. Amphetamine caused significantly increased motor activity and a tendency towards stimulation of social interactions. (+)-MK-801 also stimulated motor activity, but induced a significant inhibition of social interactions. These results indicate that a single injection of (+)-MK-801 to rats models both positive and negative symptoms of schizophrenia. Amphetamine, in contrast, reflects only the positive symptoms of schizophrenia in this model.
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| 28. |
- Rung, Johan P., 1973, et al.
(författare)
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The dopaminergic stabilizers (-)-OSU6162 and ACR16 reverse (+)-MK-801-induced social withdrawal in rats.
- 2005
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Ingår i: Progress in neuro-psychopharmacology & biological psychiatry. - : Elsevier BV. - 0278-5846. ; 29:5, s. 833-9
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Tidskriftsartikel (refereegranskat)abstract
- Schizophrenia is manifested by positive and negative symptoms, as well as cognitive deficits. Most existing antipsychotic agents have poor effects on the negative symptoms of schizophrenia, thus emphasizing the necessity for developing new antipsychotic treatments. Dopaminergic stabilizers constitute one of the latest novelties in the quest for new antipsychotic drugs. Social withdrawal in rats, in response to treatment with NMDA-receptor antagonists such as (+)-MK-801, may be used to model negative symptoms. In this study we aimed to evaluate the dopaminergic stabilizers (-)-OSU6162 and ACR16, compared to haloperidol and clozapine, in a rat model for schizophrenia, focusing on (+)-MK-801 induced social withdrawal. Social behaviour and motor activity were assessed using a videotracking system, allowing automated analysis of the behaviour. Both (-)-OSU6162 and ACR16 were capable of restoring social behaviour, measured as proximity, to control level. These results indicate that these drugs may be effective in the treatments of negative symptoms.
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| 29. |
- Tolboom, N., et al.
(författare)
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The Dopamine Stabilizer (-)-OSU6162 Occupies a Subpopulation of Striatal Dopamine D2/D3 Receptors: An C-11 Raclopride PET Study in Healthy Human Subjects
- 2015
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Ingår i: Neuropsychopharmacology. - : Springer Science and Business Media LLC. - 0893-133X .- 1740-634X. ; 40:2, s. 472-479
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Tidskriftsartikel (refereegranskat)abstract
- (-)-OSU6162 is a dopamine stabilizer that can counteract both hyperdopaminergic and hypodopaminergic states. In this study, D2/D3 receptor occupancy of (-)-OSU6162 in the human brain was investigated using positron emission tomography (PET). Twelve male healthy volunteers underwent [C-11] raclopride PET scanning before and 1 h after a single oral dose of (-)-OSU6162 (15-90 mg). Blood samples for determination of (-)-OSU6162 and prolactin plasma levels were collected at T-max. Parametric images of [ 11 C] raclopride binding potential relative to nondisplaceable tissue (cerebellar grey matter) uptake (BPND) at baseline and after (-)-OSU6162 administration were generated using the simplified reference tissue model. MRI-based regions of interest were defined for the striatum, composed of caudate nucleus and putamen, and projected onto the co-registered parametric [C-11] raclopride BPND image. Furthermore, three striatal subregions, ie, anterior dorsal caudate, anterior dorsal putamen, and ventral striatum, were defined manually and additionally analyzed. Plasma concentrations of (-)-OSU6162, ranging from 0.01 to 0.9 mu M, showed a linear relationship with prolactin levels, reflecting blockade of pituitary D2 receptors. A concentration-dependent increase in striatal D2/D3 receptor occupancy was observed, reaching a value of about 20% at an (-)-OSU6162 plasma level of 0.2 mu M, and which for higher concentrations leveled off to a maximal occupancy of about 40%. Findings were similar in the striatal subregions. The present data corroborate the notion that (-)-OSU6162 binds preferentially to a subpopulation of D2/D3 receptors, possibly predominantly extrasynaptic, and this may form the basis for the dopamine-stabilizing properties of (-)-OSU6162.
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| 30. |
- Carlsson, Maria L., 1959
(författare)
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Autism and glutamate
- 2015
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Ingår i: The Molecular Basis of Autism. - New York, NY : Springer. - 9781493921904 ; , s. 243-256
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Bokkapitel (refereegranskat)abstract
- In recent years there has been a growing interest in the role played by the excitatory neurotransmitter glutamate in autism spectrum disorders. The present chapter describes results from brain imaging and biochemical studies that directly or indirectly strengthen the notion of dysfunctional glutamatergic transmission in autism spectrum disorders. Of particular interest is the increasing number of studies showing white matter, including corpus callosum, abnormalities and deficient cortical "connectivity" in autism. Accumulating biochemical evidence also points to aberrations in glutamatergic signalling in autism. Several studies testing different agents that modulate glutamatergic transmission have been conducted but larger placebo-controlled studies are needed. An alternative possible avenue involves combined dopaminergic and serotonergic stabilization which would mediate indirect modulation of glutamatergic systems. © Springer Science+Business Media New York 2015.
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| 31. |
- Fagevik Olsén, Monika, 1964, et al.
(författare)
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Evaluation of Pressure Generated by Resistors From Different Positive Expiratory Pressure Devices
- 2015
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Ingår i: Respiratory Care. - : Daedalus Enterprises. - 0020-1324 .- 1943-3654. ; 60:10, s. 1418-1423
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Breathing exercises with positive expiratory pressure (PEP) are used to improve pulmonary function and airway clearance. Different PEP devices are available, but there have been no studies that describe the pressure generated by different resistors. The purpose of this study was to compare pressures generated from the proprietary resistor components of 4 commercial flow-dependent PEP valves with all other parameters kept constant. METHODS: Resistors from 4 flow-regulated PEP devices (Pep/Rmt system, Wellspect HealthCare; Pipe P breathing exerciser, Koo Medical Equipment; Mini-PEP, Philips Respironics [including resistors by Rusch]; and 15-mm endo-adapter, VBM Medizintechnik) were tested randomly by a blinded tester at constant flows of 10 and 18 L/min from an external gas system. All resistors were tested 3 times. RESULTS: Resistors with a similar diameter produced statistically significant different pressures at the same flow. The differences were smaller when the flow was 10 L/min compared with 18 L/min. The differences were also smaller when the diameter of the resistor was increased. The pressures produced by the 4 resistors of the same size were all significantly different when measuring 1.5- and 2.0-mm resistors at a flow of 10 L/min and 2.0-mm resistors at a flow of 18 L/min (P < .001). There were no significant differences between any of the resistors when testing sizes of 4.5 and 5.0 mm at either flow. The Mini-PEP and adapter resistors gave the highest pressures. CONCLUSIONS: Pressures generated by the different proprietary resistor components of 4 commercial PEP devices were not comparable, even though the diameter of the resistors is reported to be the same. The pressures generated were significantly different, particularly when using small-diameter resistors at a high flow. Therefore, the resistors may not be interchangeable. This is important information for clinicians, particularly when considering PEP for patients who do not tolerate higher pressures. (C) 2015 Daedalus Enterprises
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| 32. |
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| 33. |
- Nilsson, Marie, 1968, et al.
(författare)
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Differential effects of classical neuroleptics and a newer generation antipsychotics on the MK-801 induced behavioural primitivization in mouse
- 2006
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Ingår i: Prog Neuropsychopharmacol Biol Psychiatry. - : Elsevier BV. - 0278-5846. ; 30:3, s. 521-30
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Tidskriftsartikel (refereegranskat)abstract
- Cognitive dysfunction plays an important role in mental disorders like schizophrenia and may involve inadequate glutamatergic signalling in different regions of the brain, mediated by e.g. glutamatergic N-methyl-D-aspartate (NMDA) receptors. In rodents, NMDA receptor antagonists often increase motor activity; in addition they induce a more primitive and undifferentiated behavioural pattern, which we believe may correspond to some of the cognitive defects seen in schizophrenia. In the present study, the movement pattern of mice treated with the uncompetitive NMDA receptor antagonist MK-801 in conjunction with six antipsychotic agents, some with reported clinical effects on cognition, was characterised and quantified. The classical neuroleptic drugs chlorpromazine and trifluoperazine, the atypical antipsychotic agents ziprasidone and olanzapine, the gamma-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-receptor potentiator CX516 and the serotonin (5-HT)2A-antagonist M100907 were tested. In accordance with previous observations, MK-801 was found to induce a primitive and monotonous behavioural pattern dominated by forward locomotion; spatial movements, the number of switches between the states moving and stationary, and rearing frequency were reduced. All test substances counteracted MK-801-induced hyperactivity, but differed in their ability to improve behavioural quality. Chlorpromazine and trifluoperazine were unable to restore behavioural diversity while ziprasidone, olanzapine, CX516 and M100907 restored it to varying degrees. A striking similarity in movement pattern was seen between the hypoglutamatergic mice treated with the AMPA-receptor agonist CX516, and those receiving the 5HT2A-antagonist M100907.
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| 34. |
- Nilsson, Marie, 1968, et al.
(författare)
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Effect of the monoaminergic stabiliser (-)-OSU6162 on mental fatigue following stroke or traumatic brain injury
- 2020
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Ingår i: Acta Neuropsychiatrica. - : Cambridge University Press (CUP). - 0924-2708 .- 1601-5215. ; 32:6, s. 303-312
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Tidskriftsartikel (refereegranskat)abstract
- Objective:The purpose of the present study was to evaluate the efficacy and safety of (-)-OSU6162 in doses up to 30 mg b.i.d. in patients suffering from mental fatigue following stroke or traumatic brain injury (TBI).Methods:This 4+4 weeks double blind randomised cross-over study included 30 patients afflicted with mental fatigue following a stroke or head trauma occurring at least twelve months earlier. Efficacy was assessed using the Mental Fatigue Scale (MFS), the Self-rating Scale for Affective Syndromes (CPRS), the Frenchay Activity Index (FAI), and a battery of neuropsychological tests. Safety was evaluated by recording spontaneously reported adverse events.Results:There were significant differences on the patients' total FAI scores (p=0.0097), the subscale FAI outdoor scores (p=0.0243), and on the trail making test (TMT-B) (p=0.0325) in favour of (-)-OSU6162 treatment. Principal component analysis showed a clear overall positive treatment effect in 10 of 28 patients; those who responded best to treatment had their greatest improvements on the MFS. Reported adverse events were mild or moderate in severity and did not differ between the (-)-OSU6162 and the placebo period.Conclusion:The most obvious beneficial effects of (-)-OSU6162 was on the patients' activity level, illustrated by the improvement on the FAI scale. Moreover, a subgroup of patients showed substantial improvements on the Mental Fatigue Scale. Based on these observed therapeutic effects, in conjunction with the good tolerability of (-)-OSU6162, this compound may offer promise for treating at least part of the symptomatology in patients suffering from stroke-or TBI-induced mental fatigue. © Scandinavian College of Neuropsychopharmacology 2020.
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| 35. |
- Nilsson, Marie, 1968, et al.
(författare)
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The glycine antagonist (+)-HA-966 injected into the nucleus accumbens stimulates locomotion in mice. (Rapid communication)
- 1997
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Ingår i: J Neural Transm. - 0300-9564. ; 104:4-5, s. 419-25
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Tidskriftsartikel (refereegranskat)abstract
- We have previously observed that NMDA antagonists injected into the ventral striatum cause locomotor stimulation in both normal and monoamine-depleted mice. Since glycine receptor activation is claimed to be a prerequisite for NMDA receptor channel opening, also a glycine site antagonist injected into the ventral striatum should cause behavioural activation. The present study was aimed at investigating whether this is the case. The glycine site antagonist (+)-HA-966, as well as its (-)-enantiomer, were injected bilaterally into the nucleus accumbens of normal, habituated mice. (+)-HA-966, but not (-)-HA-966, was found to stimulate locomotion. The stereoselective response suggests that the underlying mechanism involves the NMDA receptor-coupled glycine site. The present results support the notion that a glycine agonist might be of value in the treatment of schizophrenia, whereas a glycine antagonist should be expected to have psychotogenic effects.
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| 36. |
- Nilsson, Marie, 1968, et al.
(författare)
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The monoaminergic stabilizer (-)-OSU6162 reverses delay-dependent natural forgetting and improves memory impairment induced by scopolamine in mice
- 2013
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Ingår i: Neuropharmacology. - : Elsevier BV. - 0028-3908. ; 75, s. 399-406
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to evaluate the effect of the monoaminergic stabilizer (-)-OSU6162 on spatial recognition memory. Male NMRI mice were tested in the object location model which is based on the animals’ inherent interest to examine changes in their environment: The animals’ propensity to explore relocated objects in relation to unaltered objects, presented in two different sessions (sample and trial), was studied. In a first series of experiments the effect of (-)-OSU6162 on natural forgetting was evaluated. With an inter-session interval (ISI) of 30 min or an hour, untreated mice spent longer time exploring the displaced object, but when the time between sessions was as long as 6 h, the mice did not identify the displaced object. However, using the 6 h ISI design we found that (-)-OSU6162 in doses up to 30 mmol/kg, given directly after the sample session, caused an increased interest for the displaced object. Twenty-four hours after administration, (-)-OSU6162 was still effective in facilitating identification of the displaced object. We also evaluated the effect of (-)-OSU6162 on scopolamine-induced memory deficits in this model e the two agents were given 30 min before the sample session and the ISI was one hour. Under these conditions scopolamine induced a deficit in object location memory and this effect was counteracted by (-)-OSU6162. The data from the present study suggest that (-)-OSU6162 prolongs object location memory in normal mice and reverses scopolamine-induced memory deficits. (-)-OSU6162 might be a valuable drug candidate for memory deficits and other cognitive impairments.
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