Differential involvement of hippocampal serotonin(1A) receptors and re-uptake sites in non-cognitive behaviors of Alzheimer's disease

Memory, Aging and Cognition Centre, National University Health System, Kent Ridge, Singapore.
Psychopharmacology (Impact Factor: 3.88). 02/2011; 213(2-3):431-9. DOI: 10.1007/s00213-010-1936-2
Source: PubMed


Previous studies have shown extensive serotonergic deficits in the hippocampus of Alzheimer's disease (AD) patients. However, it is unclear whether such deficits play a role in non-cognitive, neuropsychiatric behaviors that occur frequently in AD and cause significant caregiver distress.
In this study, we aimed to correlate serotonergic markers in the AD hippocampus with neuropsychiatric behaviors.
Using postmortem hippocampal homogenates from aged controls as well as a cohort of longitudinally assessed AD patients, measurements of 5-HT(1A) receptors, 5-HT(2A) receptors, and serotonin re-uptake (5-HTT) sites were performed by binding with (3)H-labeled 8-OH-DPAT, ketanserin, and citalopram, respectively.
Alterations of 5-HT(1A) receptors and 5-HTT were found to be differentially involved in neuropsychiatric behaviors, with loss of 5-HT(1A) receptors specifically correlated with depressive symptoms, while 5-HTT sites were preserved or up-regulated in patients with aggressive behaviors.
Our data suggest that neuropsychiatric behaviors in AD share certain neurochemical features with psychiatric disorders like major depression and that serotonergic drugs used in psychiatric disorders may also be efficacious against behavioral symptoms in AD.

1 Follower
8 Reads
  • Source
    • "One of the earliest studies reported an association between major depression in AD at baseline and 5-HT (2A) and 5-HT (2C) receptor polymorphisms , with CC carriers of the 5-HT (2A) C102 allele five times more likely than heterozygotes and 5-HT (2C) Ser allele carriers 12 times more likely than 5-HT (2C) Cys allele carriers to develop depression [29]. Moreover, reduced 5-HT (1A) receptor expression was specifically correlated with depressive symptoms [30]. In contrast, Pritchard and colleagues found no significant association between depression in AD and either the C allele/CC genotype of the T102C variant of 5HT (2A) or the cys23ser variant of 5HT (2C) receptor, although these alleles were associated with psychosis and aberrant motor behavior [31]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neuropsychiatric symptoms (NPS) such as depression, apathy, aggression, and psychosis are now recognized as core features of Alzheimer's disease (AD), and there is a general consensus that greater symptom severity is predictive of faster cognitive decline, loss of independence, and even shorter survival. Whether these symptoms result from the same pathogenic processes responsible for cognitive decline or have unique etiologies independent of AD-associated neurodegeneration is unclear. Many structural and metabolic features of the AD brain are associated with individual neuropsychiatric symptoms or symptom clusters. In addition, many genes have been identified and confirmed that are associated with symptom risk in a few cases. However, there are no single genes strongly predictive of individual neuropsychiatric syndromes, while functional and structural brain changes unique to specific symptoms may reflect variability in progression of the same pathological processes. Unfortunately, treatment success for these psychiatric symptoms may be lower when comorbid with AD, underscoring the importance of future research on their pathobiology and treatment. This review summarizes some of the most salient aspects of NPS pathogenesis.
    BioMed Research International 07/2014; 2014(5):927804. DOI:10.1155/2014/927804 · 1.58 Impact Factor
  • Source
    • "But, because AD patients in our study were administered atypical antipsychotics (risperidone; n ¼ 10 of 14) (Table 3), differences in pharmacologic actions of typical versus atypical antipsychotics consequently could have accounted for the observed serotonergic differences between both studies. The second study, from Lai et al. (2011), identified reduced 5- HT 1A receptors in hippocampal brain slices of a subgroup of depressed AD patients (n ¼ 14) compared with nondepressed AD patients (n ¼ 10) (p < 0.01). Both results agree with ours, indicating that generally decreased serotonergic neurotransmitter activity in the hippocampus might account for the neurochemical pathophysiology of depression in AD. 4.6. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Depression and aggression in Alzheimer’s disease (AD) are two of the most severe and prominent neuropsychiatric symptoms (NPS). Altered monoaminergic neurotransmitter system functioning has been implicated in both NPS, although their neurochemical etiology remains to be elucidated. Methods: Left frozen hemispheres of 40 neuropathologically confirmed AD patients were regionally dissected. Dichotomization based on depression/aggression scores resulted in depressed/nondepressed (AD+D/-D) and aggressive/nonaggressive (AD+Agr/-Agr) groups. Concentrations of dopamine, serotonin (5-HT), (nor)epinephrine ((N)E) and respective metabolites were determined using RP-HPLC. Results: Significantly lower 3-methoxy-4-hydroxyphenylglycol (MHPG) and higher homovanillic acid levels were observed in Brodmann area (BA) 9 and 10 of AD+D compared to AD-D. In AD+Agr, 5-hydroxy-3-indoleacetic acid (5-HIAA) levels in BA9, 5-HIAA/5-HT ratios in BA11, and MHPG, NE, and 5-HIAA levels in hippocampus were significantly decreased compared to AD-Agr. Conclusions: These findings indicate that brain region-specific altered monoamines and metabolites may contribute to the occurrence of depression and aggression in AD.
    Neurobiology of Aging 05/2014; 35(12):2691-2700. DOI:10.1016/j.neurobiolaging.2014.05.031 · 5.01 Impact Factor
  • Source
    • "Frozen tissues from various cortical regions (frontal cortex, anterior cingulate gyrus, hippocampus) were thawed on ice, dissected free of meninges and white matter, then homogenized with an Ultra Turrax homogenizer (10 s maximum setting) and washed in ice-cold Tris– HCl buffer to obtain brain homogenates for radioligand binding assays before storage at −80 °C. Frontal cortex consisted of tissues dissected from Brodmann areas 9 and 46 (dorsolateral prefrontal cortex), while hippocampal tissues consisted of sections incorporating CA1–CA3 as well as the dentate gyrus [33] "
    [Show abstract] [Hide abstract]
    ABSTRACT: Histamine H(3) receptor antagonists have been proposed as a novel therapeutic approach for the symptomatic treatment of Alzheimer's disease (AD). However, it is unclear whether there is a neurochemical basis for extending their potential use in vascular and mixed dementias. In this study, we measured cortical H(3) receptors in patients with subcortical ischemic vascular dementia (SIVD) and mixed SIVD/AD (MIX). Radioligand binding assays using [(3)H]GSK189254 were used to measure H(3) receptors in the postmortem frontal cortex, anterior cingulate gyrus and hippocampus of a cohort of longitudinally assessed SIVD, MIX and age-matched controls. H(3) receptor levels were unchanged in SIVD and MIX in all areas studied. Furthermore, frontal H(3) receptor densities negatively correlated with predeath assessment of cognition using Mini-Mental State Examination (MMSE) scores. Our data suggest that H(3) receptors are preserved in SIVD and MIX, thus supporting further assessments of H(3) antagonists as potential therapeutics in these dementias.
    Journal of the neurological sciences 11/2011; 315(1-2):110-4. DOI:10.1016/j.jns.2011.11.013 · 2.47 Impact Factor
Show more