Blood Monoamine Metabolism in Huntington's Disease

Belendiuk, Krystyna

doi:10.1001/archpsyc.1980.01780160095011

Cited by 44 publications

(15 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, these findings are in contrast to those that have been observed in human post‐mortem HD brains. Specifically, several groups have measured 5‐HT and 5‐HIAA levels in both the blood and brain of HD patients (Belendiuk et al . 1980; Kish et al .…”

Section: Discussionmentioning

confidence: 99%

Inhibition of tryptophan hydroxylase activity and decreased 5‐HT_1A receptor binding in a mouse model of Huntington's disease

Yohrling

Jiang²,

DeJohn

et al. 2002

Journal of Neurochemistry

View full text Add to dashboard Cite

The pathogenic mechanisms of the mutant huntingtin protein that cause Huntington's disease (HD) are unknown. Previous studies have reported significant decreases in the levels of serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the brains of the R6/2 transgenic mouse model of HD. In an attempt to elucidate the cause of these neurochemical perturbations in HD, the protein levels and enzymatic activity of tryptophan hydroxylase (TPH), the ratelimiting enzyme in 5-HT biosynthesis, were determined. Enzyme activity was measured in brainstem homogenates from 4-, 8-, and 12-week-old R6/2 mice and compared with aged-matched wild-type control mice. We observed a 62% decrease in brainstem TPH activity (p ¼ 0.009) in 4-week-old R6/2 mice, well before the onset of behavioral symptoms. In addition, significant decreases in TPH activity were also observed at 8 and 12 weeks of age (61%, p ¼ 0.02 and 86%, p ¼ 0.005, respectively). In the 12-week-old-mice, no change in immunoreactive TPH was observed. In vitro binding showed that TPH does not bind to exon 1 of huntingtin in a polyglutamine-dependent manner. Specifically, glutathione-S-transferase huntingtin exon 1 proteins with 20, 32 or 53 polyglutamines did not interact with radiolabeled tryptophan hydroxylase. Therefore, the inhibition of TPH activity does not appear to result from a direct huntingtin/TPH interaction. Receptor binding analyses for the 5-HT 1A receptor in 12-week-old R6/2 mice revealed significant reductions in 8-OH-[ 3 H]DPAT binding in several hippocampal and cortical regions. These results demonstrate that the serotonergic system in the R6/2 mice is severely disrupted in both presymptomatic and symptomatic mice. The presymptomatic inhibition of TPH activity in the R6/2 mice may help explain the functional consequences of HD and provide insights into new targets for pharmacotherapy.

show abstract

Section: Discussionmentioning

confidence: 99%

Inhibition of tryptophan hydroxylase activity and decreased 5‐HT_1A receptor binding in a mouse model of Huntington's disease

Yohrling

Jiang²,

DeJohn

et al. 2002

Journal of Neurochemistry

View full text Add to dashboard Cite

show abstract

“…Combined with evidence from our laboratory that QUIN injected into the striatum may produce selective neuronal degeneration similar to the pattern observed in Huntington's Disease [30], these data indicate that this disease may be caused by a disorder of tryptophan metabolism. Indeed, isolated case reports have shown rapid clinical deterioration in juvenile Huntington's Disease patients following the repeated ingestion of pharmacological doses of tryptophan [56], and one study has demonstrated correlation of free plasma tryptophan levels with the severity of chorea [57]. The potential excitatory effects of the tryptophan-induced increase in ECF QUIN may be antagonized however by concomitant increases in kynurenic acid (KYNA).…”

Section: Discussionmentioning

confidence: 99%

Neuroactive metabolises of L‐tryptophan, serotonin and quinolinic acid, in striatal extracellular fluid effect of tryptophan loading

During

Freese

Heyes³

et al. 1989

FEBS Letters

View full text Add to dashboard Cite

Extracellular fluid levels of the neurotoxin quinolinic acid in the corpus striatum of rats, measured by in vivo microdialysis, were increased in a dose-dependent manner following the intraperitoneal administration of tryptophan. The lowest dose of tryptophan (12.5 mg/kg), equivalent to about 5% of the normal daily intake, increased peak quinolinic acid levels nearly 3-fold. At higher doses of tryptophan (up to 250 mg/kg), concentrations of quinolinic acid increased over 200-fold and exceeded potentially neurotoxic levels (10 PM). In contrast, the increase in extracellular serotonin following even the highest tryptophan dose was small (less than 2-fold). These data indicate that quinolinic acid is present in the extracellular fluid where it may function as a neuromodulator and that it is very responsive to physiological changes in precursor availability.

show abstract

“…“Executive” impairment is an early cognitive manifestation of HD that implicates frontal‐striatal brain circuits, including aspects of attention, conceptual set shifting, and verbal fluency. Reduced levels of serotonin have been found in animal and human HD studies . Treatment trials with selective serotonin reuptake inhibitors (SSRIs) have shown improved symptoms in HD mice, yet only 1 randomized controlled trial (RCT) using an SSRI (fluoxetine) in adults with HD has been conducted .…”

mentioning

confidence: 99%

“…Reduced levels of serotonin have been found in animal and human HD studies. [9][10][11][12][13][14][15] Treatment trials with selective serotonin reuptake inhibitors (SSRIs) have shown improved symptoms in HD mice, 13,16 yet only 1 randomized controlled trial (RCT) using an SSRI (fluoxetine) in adults with HD has been conducted. 17 The current trial is the first RCT in HD with the primary endpoint of improved executive function.…”

mentioning

confidence: 99%

Results of the citalopram to enhance cognition in Huntington disease trial

et al. 2013

View full text Add to dashboard Cite

Objective Evaluate citalopram for executive functioning in HD. Design Randomized, double-blind, placebo-controlled. Patients Thirty-three adults with HD, cognitive complaints and no depression (Hamilton Depression Rating Scale ≤12). Intervention Citalopram 20 mg or placebo [7 visits, 20 weeks], with practice and placebo run-ins. Primary Outcome Change in executive functioning. Results Intent to treat analysis controlling for practice effects comparing visits 1–2 to 5–6 for citalopram vs. placebo. There were no significant benefits on the executive function composite (treatment-placebo mean difference −0.167 95% CI (−0.361 to 0.028), p=.092). Citalopram participants showed improved clinician-rated depression symptoms on the HAM-D (t=−2.02, p=0.05). There were no group differences on motor ratings, self-reported executive functions, psychiatric symptoms or functional status. Conclusion No evidence that short-term treatment with citalopram improved executive functions in HD. Despite excluding patients with active depression, participants on citalopram showed improved mood, raising the possibility of efficacy for subsyndromal depression in HD.

show abstract

Blood Monoamine Metabolism in Huntington's Disease

Cited by 44 publications

References 47 publications

Inhibition of tryptophan hydroxylase activity and decreased 5‐HT_1A receptor binding in a mouse model of Huntington's disease

Inhibition of tryptophan hydroxylase activity and decreased 5‐HT_1A receptor binding in a mouse model of Huntington's disease

Neuroactive metabolises of L‐tryptophan, serotonin and quinolinic acid, in striatal extracellular fluid effect of tryptophan loading

Results of the citalopram to enhance cognition in Huntington disease trial

Contact Info

Product

Resources

About

Blood Monoamine Metabolism in Huntington's Disease

Cited by 44 publications

References 47 publications

Inhibition of tryptophan hydroxylase activity and decreased 5‐HT1A receptor binding in a mouse model of Huntington's disease

Inhibition of tryptophan hydroxylase activity and decreased 5‐HT1A receptor binding in a mouse model of Huntington's disease

Neuroactive metabolises of L‐tryptophan, serotonin and quinolinic acid, in striatal extracellular fluid effect of tryptophan loading

Results of the citalopram to enhance cognition in Huntington disease trial

Contact Info

Product

Resources

About

Inhibition of tryptophan hydroxylase activity and decreased 5‐HT_1A receptor binding in a mouse model of Huntington's disease

Inhibition of tryptophan hydroxylase activity and decreased 5‐HT_1A receptor binding in a mouse model of Huntington's disease