Tardive dyskinesia is an insidious and debilitating extrapyramidal side effect of neuroleptic drug treatment. Recent research has suggested that lecithin has been effective in treating tardive dyskinesia. Lecithin's effects were evaluated under double-blind placebo controlled conditions. Treatment conditions included a placebo control group, a lecithin treatment group, and a no-treatment control group. Subjects in the lecithin group received 60 gms/day of lecithin (33 gms of phosphatidylcholine) . Subjects in the placebo group received a similar mixture which contained no lecithin. Subjects received mixtures for 9-11 days. Treatment effectiveness was determined by subjective, objective, and global evaluations. All subjects were evaluated 3 to 4 days prior to treatment and following 9 to 11 days of treatment.

Glutamic Acid Decarboxylase (GAD) is a rate-limiting enzyme responsible for synthesis of the inhibitory neurotransmitter GABA. Dopaminergic denervation in rodents by unilateral injections of 6-OHDA or MPTP causes an increase in Gad67 mRNA in the striatum, which is further exacerbated by administration of L-Dopa (Horvath et al., 2011; Katz et al., 2005 Bacci et al., 2002). Denervation of nigrostriatal neurons is the key pathological hallmark of Parkinson's disease, which results in hypokinetic movement and rigidity. Medium spiny projection neurons of the striatum comprise 95% of the neuronal population and utilize Gad67 (encoded by the Gad1 gene) for the synthesis of basal levels of GABA. The contribution of Gad67 to GABA signaling in medium spiny projection neurons in the striatum has not been thoroughly understood in normal or Parkinsonian states. Mice with a deletion in Gad67 in Gpr88 expressing neurons were generated by crossing mice with a floxed exon 2 of Gad1 with mice expressing Cre recombinase under the control of the Gpr88 promoter. The aim of this study was first, to characterize mice with a deletion in striatal Gad67 by immunohistochmical, electriophysiological and behavioral examination to determine whether Gad67 expression contributes to sensorimotor and learning tasks. And next, to investigate whether a downregulation in striatal Gad67 would decrease dyskinesia and affect the impaired motor symptoms following dopaminergic denervation with a unilateral 6-OHDA lesion and subsequent treatment with L-Dopa. In this study, neuronal Gpr88 expression was indicated by GFP reporter expression, which resulted from Cre-mediated excision of exon 2 of the Gad1 gene. Gpr88 expression was confirmed in the striatum, olfactory tubercle, cortex and brain stem. Furthermore, Gpr88 was confined to striatonigral and striatopallidal MSNs in the striatum. Additionally, Cre-mediated GFP reporter expression indicated that Gpr88 expression occurs throughout various brain regions, including the motor and visual areas of the cortex, amygdala, hippocampus and cerebellum during development. The developmental expression of Gpr88 seems to be a highly regulated process that occurs throughout the brain. In the conditional knockout mouse, deleting striatal Gad67 resulted in an upregualtion of Gad67 in the globus pallidus and downregulation in the substantia nigra. The changes in Gad67 expression indicate the effects of inactivating GABAergic signaling in striatonigral and striatopallidal MSNs in the direct and indirect pathways. Mice with a deletion in striatal Gad67 demonstrated compromised performance in spatial learning in the Morris water maze, suggesting that GABAergic striatal signaling in the direct and indirect pathways accounts for cue-based learning and spatial memory. However, inactivation of GABAergic signaling in striatonigral and striatopallidal MSNs does not account for motor deficits such as bradykinesia, akinesia or hypokinesia in intact mice; instead it perpetuates hyperkinetic motor activity. In the second experiment of this study, dopaminergic denervation by a unilateral 6-OHDA lesion induced bradykinesia and hypokinetic motor behavior, as demonstrated by impaired performance in the rota-rod and pole test. Additionally, L-Dopa administration to 6-OHDA lesioned mice evoked abnormal involuntary movements (AIMs) to the same degree in all dyskinetic mice. A deletion in striatal Gad67 did not decrease symptoms of dyskinesia, nor cause a lessening of motor impairment caused by dopaminergic denervation. Complete inactivation of the indirect pathway is believed to limit the inhibition of unwanted actions and may perpetuate dyskinesia, even when striatonigral MSNs of the direct pathway are inactive.

Schizophrenia (SCZ) is a severe neuropsychiatric disorder with a genetic component. Most candidate gene association studies have given mixed results. We investigated the GABAA receptor gamma2 subunit gene GABRG2, the dopamine receptor gene DRD3, and the Brain-derived neurotrophic factor gene BDNF that is required for D3 expression by genotyping polymorphisms spanning and surrounding these genes for association with SCZ, as well as suicidal behaviour. We also examined the BDNF, DRD3, as well as the dopamine receptor gene DRD2 and Protein Kinase B gene AKT1 for association with Tardive Dyskinesia (TD), a potentially irreversible motor side effect of long-term antipsychotic medication. Our analysis included single-marker tests, haplotype tests, and gene-gene interactions. We found a haplotype in the 5’ region of GABRG2 to be associated with SCZ in both families and matched case-control samples. We also found two synonymous DRD2 polymorphisms, rs6275 (C939T) and rs6277 (C957T), and their haplotypes, as well as a polymorphism 5’ of DRD3, rs905568, to be associated with TD. Further, we reviewed two putative functional DRD2 polymorphisms, -141C Ins/Del and TaqIA, in TD and found TaqIA 3’ of the gene to be associated with TD in a meta-analysis. Lastly, we found a significant interaction between AKT1 rs3730358 and DRD2 C939T in TD. Though replication studies are required, these results contribute to the future development of genetic tests to assess for the risks of SCZ and TD, leading to better outcome for patients suffering from these debilitating conditions.

Schizophrenia (SCZ) is a severe neuropsychiatric disorder with a genetic component. Most candidate gene association studies have given mixed results. We investigated the GABAA receptor gamma2 subunit gene GABRG2, the dopamine receptor gene DRD3, and the Brain-derived neurotrophic factor gene BDNF that is required for D3 expression by genotyping polymorphisms spanning and surrounding these genes for association with SCZ, as well as suicidal behaviour. We also examined the BDNF, DRD3, as well as the dopamine receptor gene DRD2 and Protein Kinase B gene AKT1 for association with Tardive Dyskinesia (TD), a potentially irreversible motor side effect of long-term antipsychotic medication. Our analysis included single-marker tests, haplotype tests, and gene-gene interactions. We found a haplotype in the 5’ region of GABRG2 to be associated with SCZ in both families and matched case-control samples. We also found two synonymous DRD2 polymorphisms, rs6275 (C939T) and rs6277 (C957T), and their haplotypes, as well as a polymorphism 5’ of DRD3, rs905568, to be associated with TD. Further, we reviewed two putative functional DRD2 polymorphisms, -141C Ins/Del and TaqIA, in TD and found TaqIA 3’ of the gene to be associated with TD in a meta-analysis. Lastly, we found a significant interaction between AKT1 rs3730358 and DRD2 C939T in TD. Though replication studies are required, these results contribute to the future development of genetic tests to assess for the risks of SCZ and TD, leading to better outcome for patients suffering from these debilitating conditions.

Parkinson’s disease is a common neurodegenerative disorder caused by nigrostriatal dopamine loss, with motor deficiencies as the primary outcome. To increase the striatal dopamine content, patients are treated with 3,4-dihydroxyphenyl-l-alanine (l-DOPA). Beneficial relief of the motor symptoms is achieved initially, although the efficacy is lost with time and severe side effects, referred to as l-DOPA-induced dyskinesia, manifest in the majority of patients. Biological mechanisms responsible for the dopaminergic degeneration and the upcoming of dyskinesia are still unclear, and thus knowledge regarding critical factors for maintenance of the nigrostriatal system as well as neurochemical changes upon chronic l-DOPA is urgent. The present work aims at studying the importance of glial cell line-derived neurotrophic factor (GDNF) for nigrostriatal preservation, and the involvement of the dopaminergic, serotonergic, and glutamatergic systems in l-DOPA-induced dyskinesia. Effects from different levels of GDNF expression were evaluated on fetal mouse nigrostriatal tissue in a grafting study. In GDNF gene-deleted grafts, degeneration of the entire nigrostriatal system was evident at 6 months. In grafts with partial GDNF expression, significant loss of dopamine neurons was observed at later time points, although deviant findings in the dopamine integrity such as reduced innervation capacity and presence of intracellular inclusions-like structures were already present at earlier stages. The results emphasize GDNF as a crucial factor for long-term maintenance of the nigrostriatal system. Furthermore, striatal neurochemical alterations upon chronic l-DOPA treatment were studied in hemiparkinsonian rats using in vivo voltametry. The findings demonstrated impaired dopamine as well as glutamate releases in dyskinetic subjects, with no effects from acute l-DOPA administration. Conversely, in l-DOPA naïve dopamine-lesioned animals, dopamine release was increased and glutamate release attenuated upon a l-DOPA challenge. Moreover, l-DOPA-derived dopamine release was demonstrated to originate from serotonergic nerve fibers in the dopamine-lesioned striatum, an event that contributes significantly to dopamine levels also in intact striatum, and thus, is not a consequence from dopamine depletion. Assessment of serotonergic nerve fibers in l-DOPA treated animals and in a grafting study concluded that nerve fiber density was not affected by chronic l-DOPA treatment, nevertheless, dysfunction of this system can be suspected in dyskinetic animals since dopamine release was impaired and regulation of glutamate release by serotonergic 5-HT1A receptor activation was achieved in normal but not in dyskinetic animals. Furthermore, the selective serotonin reuptake inhibitor, fluoxetine, attenuated l-DOPA-induced dyskientic behavior, an effect that was demonstrated to be mediated via 5-HT1A receptors. In conclusion, dysmodulation of multiple transmitter systems is evident in LID.

Diss. (sammanfattning) Uppsala : Univ., 2003. / Härtill 5 uppsatser.

ABSTRAKT INTRODUKTION: Huvudvärk av spänningstyp (HST) är den vanligaste huvudvärksformen som diagnostiseras och representerar 90 % av fallen som söker sjukvård med huvudvärk och nästan nio av tio kvinnor drabbas av denna typ av huvudvärk någon gång i livet. Skapulär dyskinesi (SD) som beskriver positionsskillnad mellan skulderbladen kan orsakas av olika faktorer och är ett tillstånd som kan vara osymptomatiskt eller symptomatiskt. Den vanligaste orsaken är på grund av svaghet av de viktigaste skulderstabilisatorerna och sambandet mellan HST och SD är att i båda tillstånd ingår träning av styrka och uthållighet av nack- och skulderbladsmuskulatur.   SYFTE: Syftet med arbetet är att undersöka förekomsten av skapulär dyskinesi hos fysisk aktiva kvinnor med huvudvärk av spänningstyp.   METOD: För arbetet rekryterades fysisk aktiva kvinnor med huvudvärk från olika sportföreningar och kvinnor som sökte sig till öppenvården på Aleris Rehab Tullinge. Det användes en enkät som innehöll två delar. Första delen bestod av två frågor från enkäten Neck Disability Index (NDI) som skulle besvaras och andra delen av enkäten fylldes i av undersökaren efter en manuell isometrisk muskeltest av skuldrorna för att diagnostisera SD. Totalt undersöktes 25 kvinnor med huvudvärk. Resultatet sammanställdes i diagram för bättre analys.   RESULTAT: Av 25 fysiska aktiva kvinnor som drabbades av huvudvärk visade 23 kvinnor någon form av SD, vilket motsvarar 92 %. Vilken typ av SD var inte av intresse eftersom syftet var enbart att undersöka förekomsten av SD hos kvinnor med HST.   KONKLUSSION: Fler studier rekommenderas mellan huvudvärk och skapulär dyskinesi eftersom eventuella fynd kan hjälpa fysioterapeuter att ändra eller justera deras träningssätt för att undvika och förebygga HST och SD för bättre prestation av idrottaren. / ABSTRACT INTRODUCTION: Tension type headache (TTH) is the most common type of headache diagnosed and represents 90 % of cases seeking headache healthcare and nearly nine out of ten women suffer from this type of headache sometime in life. Scapular dyskinesia (SD) that describes the position difference between the shoulder blades can be caused by various factors and is a condition that may be symptomatic or symptomatic. The most common reason is the weakness of the main shoulder stabilizers, and the connection between TTH and SD is that in both states it includes training of strength and endurance of the neck and shoulder blades muscles.   OBJECTIVE: The purpose of the work is to investigate the occurrence of scapular dyskinesia in physically active women with tension type headache.   METHOD: For the study, physically active women were recruited with headaches from various sports associations and women who sought outpatient care at Aleris Rehab Tullinge. A survey was used that contained two parts. The first part consisted of two questions from the Neck Disability Index (NDI) questionnaire that were to be answered and the second part of the survey was filled in by the investigator following a manual isometric muscle test of the shoulders to diagnose SD. A total of 25 women with headache were examined. The result was compiled in charts for better analysis.   RESULTS: Of 25 physical active women affected by headache, 23 women showed some form of SD, which represents 92 %. What kind of SD was not of interest because the purpose was to investigate the presence of SD in women with TTH.   CONCLUSION: More studies are recommended between headache and scapular dyskinesia because any findings may help physiotherapists to change or adjust their training methods to avoid and prevent TTH and SD for better athletes performance.

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