Recurrent panic attacks, anticipatory anxiety and phobic avoidance characterise panic disorder. The influence of genetic factors on liability to the disease has been the object of several linkage and ...association studies and appears to relate to an oligo-or polygenic rather than a monogenic mode of inheritance. Recently, an excess of high activity monoamine oxidase A (MAO-A) gene promoter alleles was found in female patients with panic disorder. An analysis of possible synergistic effects of the MAO-A gene promoter variant and the short serotonin transporter (5-HTT) gene promoter variant in panic disorder was performed in a German and an Italian sample (combined panic disorder n = 144, combined controls n = 175). There was no significant difference in odds ratios, suggesting that the observed increase of genetic liability by the long MAO-A gene promoter allele is not modified by the 5-HTT gene promoter polymorphism.
The cellular localization of adenosine A1 receptors in the CA1 region of the rat hippocampus was investigated using radioligand binding and lesioning methods in a quantitative autoradiographic study. ...Kainic acid injection reduced 3Hcyclohexyladenosine binding in the CA3 region by 40% and in the CA1 region by 30%. Transient cerebral ischemia reduced 3Hcyclohexyladenosine binding in the CA1 region by 50%, while no change was measured in the CA3 region. These findings suggest that adenosine A1 receptors are located presynaptically on axon terminals of CA3 pyramidal cells and postsynaptically on the dendrites of CA1 pyramidal cells in the CA1 region of rat hippocampus.
Excitotoxins L-beta-oxalyl-amino-alanine (L-BOAA) and 3,4,6-trihydroxyphenylalanine (6-OH-DOPA) have been investigated with regard to their potency to inhibit 3H alpha-amino-3-hydroxy-5-methyl-4- ...isoxazole-propionic acid (AMPA) binding in human hippocampus in a quantitative autoradiographic study. With dissociation constants (KD) of 3HAMPA binding and inhibition concentrations (IC50) of L-BOAA, 6-OH-DOPA and L-glutamate obtained from saturation and displacement experiments inhibition constants (Ki) for the inhibition of 3HAMPA binding in individual hippocampal subregions could be calculated. They were between 5.2 +/- 2.9 and 35.1 +/- 39.9 microM for L-BOAA and 39.1 +/- 26.8 and 59.4 +/- 44.1 microM for 6-OH-DOPA. L-BOAA was equally potent as the endogenous agonist L-glutamate with Ki's between 13.1 +/- 3.9 and 21.4 +/- 12.1 microM (n = 4, mean +/- S.D.). Limbic system symptoms like cognitive deficits, mood disturbances and vivid dreams observed in patients with the motor neuron disease neurolathyrism may thus well be mediated by agonistic action of L-BOAA at AMPA glutamate receptors in hippocampus.
Neurodegenerative diseases show an increase in prevalence and incidence, with the most prominent example being Alzheimer's disease. DNA damage has been suggested to play a role in the pathogenesis, ...but the exact mechanisms remain elusive. We enrolled 425 participants with and without neurodegenerative diseases and analyzed DNA damage in the form of micronuclei in buccal mucosa samples. In addition, other parameters such as binucleated cells, karyolytic cells, and karyorrhectic cells were quantified. No relevant differences in DNA damage and cytotoxicity markers were observed in patients compared to healthy participants. Furthermore, other parameters such as lifestyle factors and diseases were also investigated. Overall, this study could not identify a direct link between changes in buccal cells and neurogenerative diseases, but highlights the influence of lifestyle factors and diseases on the human buccal cytome.
Depressed patients often do not respond to the first antidepressant prescribed, resulting in sequential trials of different medications. Personalised medicine offers a means of reducing this delay; ...however, the clinical effectiveness of personalised approaches to antidepressant treatment has not previously been tested. We assessed the clinical effectiveness of using a predictive algorithm, based on behavioural tests of affective cognition and subjective symptoms, to guide antidepressant treatment. We conducted a multicentre, open-label, randomised controlled trial in 913 medication-free depressed patients. Patients were randomly assigned to have their antidepressant treatment guided by a predictive algorithm or treatment as usual (TaU). The primary outcome was the response of depression symptoms, defined as a 50% or greater reduction in baseline score of the QIDS-SR-16 scale, at week 8. Additional prespecified outcomes included symptoms of anxiety at week 8, and symptoms of depression and functional outcome at weeks 8, 24 and 48. The response rate of depressive symptoms at week 8 in the PReDicT (55.9%) and TaU (51.8%) arms did not differ significantly (odds ratio: 1.18 (95% CI: 0.89-1.56), P = 0.25). However, there was a significantly greater reduction of anxiety in week 8 and a greater improvement in functional outcome at week 24 in the PReDicT arm. Use of the PReDicT test did not increase the rate of response to antidepressant treatment estimated by depressive symptoms but did improve symptoms of anxiety at week 8 and functional outcome at week 24. Our findings indicate that personalisation of antidepressant treatment may improve outcomes in depressed patients.
The inhibition of 3Hnitrobenzylthioinosine (3HNBI) binding to human parietal cortex membranes by adenosine transport inhibitors, adenosine receptor agonists and antagonists and dihydropyridines was ...investigated. While the adenosine transport inhibitors inhibited 3HNBI binding with Ki values in the low nanomolar range and the adenosine A1 receptor agonist, cyclopentyladenosine, with a Ki in the low micromolar range, no IC50 values could be obtained for the adenosine receptor antagonists at concentrations up to 100,000 nM. Among the dihydropyridines (+)-nimodipine was the most potent with a Ki of 201 +/- 55 nM. Inhibition of adenosine transport thus may contribute to the clinical effects of nimodipine in the central nervous system.
The antispastic agent and N-methyl-D-aspartate (NMDA) receptor antagonist memantine has recently been proposed as a neuroprotective drug for use in patients with dementia syndromes with primarily ...temporal lobe pathology, e.g. senile dementia of Alzheimer type or dementia in Parkinson's disease. In a quantitative autoradiographic study in human post mortem hippocampus, memantine was able to inhibit binding of the noncompetitive NMDA-antagonist 3HMK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate) with inhibition constants between 3 and 10 microM, being about a factor of 10 more potent than the dissociative anaesthetic and NMDA receptor antagonist (+/-)ketamine. As these inhibition constants are well within the therapeutic concentration range of memantine, antagonism of endogenous glutamate at limbic NMDA receptors may be one molecular mechanism by which memantine is beneficial in dementia syndromes.
The excitotoxic amino acid domoate causes anterograde amnesia and memory deficits while the excitotoxin
l-β-oxalyl-amino-alanine (L-BOAA) is considered the causative agent of the motoneurone ...disorder, neurolathyrism. Employing quantitative autoradiography we investigated the potency of domoate and L-BOAA to inhibit
3Hkainate binding in human hippocampus. Domoate inhibited binding of
3Hkainate with inhibition constants between 5.8 ± 2.8 nM (deep layers of gyrus parahippocampalis) and 200.9 ± 247.8 nM (CA1 region of hippocampus). It was about a thousandfold more potent than L-BOAA with inhibition constants between 2.1 ± 0.5 μM (superficial layers of gyrus parahippocampalis) and 51.0 ± 41.9 μM (
CA
2
3
region of hippocampus). Interestingly, L-BOAA showed lowest affinity to
3Hkainate binding sites in those regions in which domoate showed highest affinity (e.g.
CA
2
3
) and vice versa (e.g. CA1). These data further support the notion that the neurological symptoms observed after domoate intoxication are due to an excitotoxic action at kainate receptors and provide evidence for heterogeneity of kainate receptors in human hippocampus.
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