Postmortem stability of monoamines, their metabolites, and receptor binding in rat brain regions.
ABSTRACT The effects of postmortem delay, time of storage, and freezing, thawing, and refreezing tissue samples were studied in postmortem rat brain using conditions that reflect the handling of postmortem human brain before neurochemical analysis. The levels of monoamines and metabolites in the striatum and cingulate and occipital cortex were measured using alumina extraction and HPLC methods. Binding of raclopride to dopamine D2, SCH-23390 to dopamine D1, ketanserin to serotonin 5-HT2, 8-hydroxy-2-(di-n-propylamino)tetralin to serotonin 5-HT1A, and cholecystokinin (CCK)-8 to CCK-B sites was measured in tissue homogenates from the striatum or fronto-parietal cortex. An 18-h postmortem delay before dissection and storage resulted in region-specific changes in monoamine and metabolite levels. Binding to striatal D1 and frontoparietal cortex CCK-B sites was reduced over the course of a 27-h postmortem delay. Binding to D2 and 5-HT sites was relatively stable. Storage of tissue for up to 8 months also resulted in region-specific changes in monoamine and metabolite levels. No changes in receptor binding were seen after long-term storage. Freezing, thawing, and refreezing tissue samples resulted in increased levels of striatal 3,4-dihydroxyphenylacetic acid and decreased binding to striatal D2 sites. These results demonstrate time-, temperature-, and storage-dependent regional differences in the stability of monoamines and their metabolites and in binding to various receptor sites. These differences in stability and binding should be accounted for to interpret accurately the effects of neurological disorders on neurotransmitter dynamics in postmortem human brain tissue.
- SourceAvailable from: Kine-Susann Dervola[Show abstract] [Hide abstract]
ABSTRACT: PCB 180 is a persistent non-dioxin-like polychlorinated biphenyl (NDL-PCB) abundantly present in food and the environment. Risk characterization of NDL-PCBs is confounded by the presence of highly potent dioxin-like impurities. We used ultrapure PCB 180 to characterize its toxicity profile in a 28-day repeat dose toxicity study in young adult rats extended to cover endocrine and behavioral effects. Using a loading dose/maintenance dose regimen, groups of 5 males and 5 females were given total doses of 0, 3, 10, 30, 100, 300, 1000 or 1700 mg PCB 180/kg body weight by gavage. Dose-responses were analyzed using benchmark dose modeling based on dose and adipose tissue PCB concentrations. Body weight gain was retarded at 1700 mg/kg during loading dosing, but recovered thereafter. The most sensitive endpoint of toxicity that was used for risk characterization was altered open field behavior in females; i.e. increased activity and distance moved in the inner zone of an open field suggesting altered emotional responses to unfamiliar environment and impaired behavioral inhibition. Other dose-dependent changes included decreased serum thyroid hormones with associated histopathological changes, altered tissue retinoid levels, decreased hematocrit and hemoglobin, decreased follicle stimulating hormone and luteinizing hormone levels in males and increased expression of DNA damage markers in liver of females. Dose-dependent hypertrophy of zona fasciculata cells was observed in adrenals suggesting activation of cortex. There were gender differences in sensitivity and toxicity profiles were partly different in males and females. PCB 180 adipose tissue concentrations were clearly above the general human population levels, but close to the levels in highly exposed populations. The results demonstrate a distinct toxicological profile of PCB 180 with lack of dioxin-like properties required for assignment of WHO toxic equivalency factor. However, PCB 180 shares several toxicological targets with dioxin-like compounds emphasizing the potential for interactions.PLoS ONE 08/2014; 2934495. · 3.53 Impact Factor
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ABSTRACT: Using high pressure liquid chromatography, we find more brainstem 5‐HT and 5‐HIAA in suicides compared with nonpsychiatric, sudden death controls throughout the rostrocaudal extent of the brainstem DRN and MRN. This suggests that 5‐HT synthesis in suicides is greater within all DRN subnuclei and the MRN compared with controls.Synapse 06/2013; · 2.43 Impact Factor
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ABSTRACT: Panic disorder is characterized by a progression of panic symptom severity with repeated attacks. Repeated panic episodes evoke heightened anticipatory anxiety, phobic avoidance and are typically associated with comorbid symptoms of depression. Due to the heterogeneity of the disorder, reliable neurochemical correlates attending panic have not been identified. However, variable neuropeptide interfacing with major and minor transmitter systems may modulate individual vulnerability to panic and account for variable panic profiles. The extensive colocalization of cholecystokinin (CCK) with other neurotransmitters, including dopamine (DA), enkephalin (ENK) and GABA, in specific central sites may influence various aspects of anxiety and panic. The behavioral correlates attending panic likely follow from variable neurochemical release and conditioning/sensitization. Clinicians maintain that recurrent panic attacks are spontaneous (unexpected, uncued) and fail to acknowledge the wealth of information implicating a prominent role for stressful life events in panic. Conditioning and sensitization of both behavior (e.g., fear-motivated) and neurochemical events (e.g., DA and CCK) in response to uncontrollable stressors parallel the diverse heterogeneity of panic amongst clinical samples. Cholecystokinin-4, pentagastrin, lactate acid, and CO2 induce panic attacks that are dependent on subjective history, expectancy measures and panic profiles. Panic disorder is associated with chronic illness and familial sick-role modeling exacerbates the course of the illness. The current review outlines the evidence in support of a conditioning/sensitization model for panic, a model that may explain the variable efficacies of pharmacological interventions.The Open Psychiatry Journal 12/2007; 1.