High Vesicular Monoamine Transporter Binding in Asymptomatic Bipolar I Disorder: Sex Differences and Cognitive Correlates

Department of Psychiatry, University of Michigan, Ann Arbor, 48104-1687, USA.
American Journal of Psychiatry (Impact Factor: 12.3). 11/2000; 157(10):1619-28. DOI: 10.1176/appi.ajp.157.10.1619
Source: PubMed


It has been hypothesized that anomalies in monoaminergic function underlie some of the manifestations of bipolar disorder. In this study the authors examined the possibility that trait-related abnormalities in the concentration of monoaminergic synaptic terminals may be present in patients with asymptomatic bipolar disorder type I.
The concentration of a stable presynaptic marker, the vesicular monoamine transporter protein (VMAT2), was quantified with (+)[(11)C]dihydrotetrabenazine (DTBZ) and positron emission tomography. Sixteen asymptomatic patients with bipolar I disorder who had a prior history of mania with psychosis (nine men and seven women) and individually matched healthy subjects were studied. Correlational analyses were conducted to examine the relationship between regional VMAT2 binding, cognitive function, and clinical variables.
VMAT2 binding in the thalamus and ventral brainstem of the bipolar patients was higher than that in the comparison subjects. VMAT2 concentrations in these regions correlated with performance on measures of frontal, executive function. In addition, sex differences in VMAT2 binding were detected in the thalamus of the bipolar patients; the male patients had higher binding than the women. No sex differences in binding were observed in the healthy comparison group.
These initial results suggest that higher than normal VMAT2 expression and, by extension, concentration of monoaminergic synaptic terminals, may represent a trait-related abnormality in patients with bipolar I disorder and that male and female patients show different patterns. Also, VMAT2 concentrations may be associated with some of the cognitive deficits encountered in euthymic bipolar disorder.

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    • "Thalamic lesions have been associated with both mania and depression (Cummings, 1995). Furthermore, neurochemical abnormalities such as increased monoamine-producing neurons (Zubieta et al., 2000) and increased NAA have been reported in the thalamus in bipolar disorder (Zubieta et al., 2000; Deicken et al., 2001). Therefore, in this study, we investigated primarily thalamic MRS metabolite abnormalities in bipolar disorder. "
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    ABSTRACT: The neurobiology and neurochemistry of bipolar disorder and its different phases are poorly understood. This study investigated metabolite abnormalities in both unmedicated bipolar depression as well as mania using 2D (1)H magnetic resonance spectroscopy imaging (MRSI). MRSI data were obtained from 24 unmedicated bipolar disorder (BP) subjects (12 (hypo)manic (BPM)) and 12 depressed (BPD), and 20 closely matched healthy controls. 2D (1)H MRSI data were collected from a 15-mm axial slice placed along the anterior commissure-posterior commissure (AC-PC) line to measure brain metabolites bilaterally in the thalamus and also the anterior and posterior cingulate cortex (ACC and PCC). Brain Lac/Cr levels were significantly increased in the BP group as a whole compared to healthy controls. Glutamate abnormalities varied across bipolar state as well as brain region: significantly increased Glx/Cr values were found in the left thalamus in BPD, but BPM had decreased Glu/Cr and Glx/Cr levels in the PCC when compared to healthy controls and decreased Glu/Cr levels even when compared to the BPD subjects group. The findings of the study point to state-related abnormalities of oxidative and glutamate metabolism in bipolar disorder.
    Full-text · Article · Jun 2013
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    • "BD is distinguished from unipolar depression by the occurrence of manic or hypomanic symptoms during one or more episodes of the illness. Disturbances of gamma-amino butyric acid (GABA) (Benes and Berretta, 2001; Benes et al., 2000; Petty, 1995; Shiah et al., 1998), monoaminergic (Zubieta et al., 2000) and second messenger systems have been implicated in BD, but the underlying cellular mechanisms remain poorly understood (Belmaker, 2004). Neurobiological markers that are sensitive to the illness might provide a bridge between behavioral and neurobiological abnormalities (Lenox et al., 2002). "
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    ABSTRACT: Disruption of functional connectivity may be a key feature of bipolar disorder (BD) which reflects disturbances of synchronization and oscillations within brain networks. We investigated whether the resting electroencephalogram (EEG) in patients with BD showed altered synchronization or network properties. Resting-state EEG was recorded in 57 BD type-I patients and 87 healthy control subjects. Functional connectivity between pairs of EEG channels was measured using synchronization likelihood (SL) for 5 frequency bands (δ, θ, α, β, and γ). Graph-theoretic analysis was applied to SL over the electrode array to assess network properties. BD patients showed a decrease of mean synchronization in the alpha band, and the decreases were greatest in fronto-central and centro-parietal connections. In addition, the clustering coefficient and global efficiency were decreased in BD patients, whereas the characteristic path length increased. We also found that the normalized characteristic path length and small-worldness were significantly correlated with depression scores in BD patients. These results suggest that BD patients show impaired neural synchronization at rest and a disruption of resting-state functional connectivity.
    Full-text · Article · Mar 2013 · Clinical neuroimaging
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    • "MAT1 mRNA and protein expression in cell bodies in the adult mouse brain . Abnormalities in presynaptic neurotransmission might contribute to various neuropsychiatric phenotypes and in fact , research over the last several decades has documented the importance of VMAT2 in neurotransmission and neuropsychiatric disorders ( Erickson et al . , 1996 ; Zubieta et al . , 2000 , 2001 ; Little Fig . 5 . Absence of VMAT1 reduces hippocampal cell proliferation . To assess cell proliferation in the hippocampus , wild type ( WT , white bars , n = 8 ) and knock - out ( VMAT1 KO , black bars , n = 9 ) mice were sacrificed 24 h after the last BrdU injection . Values are expressed as the number of BrdU positive cells "
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    ABSTRACT: Vesicular monoamine transporters (VMAT) are involved in presynaptic storage and release of neurotransmitters. While it was thought initially that only VMAT2 is brain expressed and VMAT1 is present only in the periphery, recent data has challenged the exclusive expression of VMAT2 in brain. To further elucidate the role of VMAT1 brain expression and its potential role in neuropsychiatric disorders, we have investigated mice lacking VMAT1. Comparison of wildtype and knock-out (KO) mice using qPCR and immunohistochemistry documents the expression of VMAT1 in the brain. Deletion of VMAT1 leads to increased hippocampal apoptosis and reduced neurogenesis as assessed by caspase-3-labeling and BrdU-labeling. Behavioral data show that mice lacking VMAT1 have neurocognitive deficits. VMAT2 expression is not altered in VMAT1 KO mice, suggesting a distinct role of VMAT1. Our data support VMAT1 brain expression and suggest that VMAT1 plays a key role in survival of hippocampal neurons and thus might contribute to neurocognitive deficits observed in neuropsychiatric disorders.
    Full-text · Article · Nov 2012 · Neuroscience
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