Jonas Ekblom

Human fear conditioning is related to dopaminergic and serotonergic biological markers.

Biological markers for acquisition and extinction of fear conditioning were studied in 40 individuals selected for displaying either good or poor acquisition of fear conditioning. as estimated by the skin conductance response. Participants with a short serotonin transporter (5-HTT) promoter allele or low monoamine oxidase activity in platelets (trbc-MAO) displayed better acquisition than those with only long alleles or high trbc-MAO, whereas participants with a long dopamine D4 receptor (D4DR) exon III allele showed delayed extinction compared with those with only short alleles. The findings, that D4DR exon III and 5-HTT promoter genotypes and trbc-MAO activity are related to human fear conditioning, a basic form of associative learning, are consistent with animal studies suggesting a genetic contribution to fear conditioning. The authors suggest that in humans these genetic mechanisms are partly dopaminergic and serotonergic in origin.

Changes in uptake of vitamin B12 and trace metals in brains of mice treated with clioquinol

Clioquinol is a hydroxyquinoline antibiotic that has been associated with severe side-effects in the CNS. The syndrome caused by clioquinol treatment, subacute myelo-optic neuropathy (SMON), is considered as one of the worst drug disasters of this century. The precise biochemical mechanism behind SMON is not fully understood. Clioquinol can form strong lipophilic chelates with divalent cations and therefore it has been speculated that the drug may disturb the retention of vitamin B(12) through chelation of Co(2+). In the present study, the tissue distribution and uptake capacity of [57Co]cyanocobalamin were estimated in mice treated with clioquinol or saline. The concentrations of some trace metals were also determined in brain tissue. Accumulation of vitamin B(12) in the brain and its concentration in blood were decreased by clioquinol treatment. The mean concentrations of several trace metals were also lowered in the brain while the concentration of cobalt in the brain was not affected, suggesting that clioquinol does not bind to the cobalt in vitamin B(12). Moreover, a significant decrease in the levels of S-adenosylmethionine (SAM) was observed in the brain after clioquinol treatment. This may be a consequence of decreased vitamin B(12) levels. From these results, it can be concluded that chronic treatment with clioquinol may alter the tissue homeostasis of vitamin B(12) in the brain.

Elevated plasma semicarbazide‐sensitive amine oxidase (SSAO) activity in Type 2 diabetes mellitus complicated by retinopathy

Aims To measure plasma semicarbazide‐sensitive amine oxidase (SSAO) activities and detect retinopathy in Type 2 diabetes mellitus (DM).

Levels ofl-MethionineS-Adenosyltranferase Activity in Erythrocytes and Concentrations ofS-Adenosylmethionine andS-Adenosylhomocysteine in Whole Blood of Patients with Parkinson's Disease☆

In the present study, levels of S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) in whole blood as well as L-methionine S-adenosyltransferase (MAT) activity in erythrocytes were assayed in a series of 20 patients with Parkinsons disease and 12 healthy control subjects. A significant difference was found with regard to SAM levels between patients and controls, with the detected levels being 383.1 +/- 41.5 nM for the parkinsonian patients and 680.6 +/- 30.9 nM for the controls. With regard to SAH, we found no difference between the groups. The catalytic activity of MAT was increased by 30% in patients compared to controls, with the Vmax for methionine being 17.9 +/- 3.7 and 13.9 +/- 2.2 pmol/mg/h, respectively.

Insulin-like growth factor-1 receptors in human spinal cord: changes in amyotrophic lateral sclerosis

Neurotrophic factors are important for neuronal survival and maintenance in the adult nervous system. The regional distribution of insulin-like growth factor-1 (IGF-1) receptors in human spinal cords from controls and amyotrophic lateral sclerosis (ALS) patients was studied by immunohistochemistry and quantitative autoradiography. When comparing125I-IGF-1 binding in the different spinal levels of normal spinal cord the same distribution pattern was found in which the binding was highest in the central canal > dorsal horn > ventral horn > white matter. In the ALS cases although a general upregulation of IGF-1 receptors was observed throughout the spinal cord, significant increases were observed in the cervical and sacral segments compared to controls. IGF-1 receptor immunoreactivity showed a similar pattern to that for125I-IGF-1 binding, with immunoreactivity being found in the gray matter of the spinal cord and enhanced immunoreactivity occuring in ALS patients compared to controls. In agreement with the distribution of IGF-1 receptors, IGF-1 immunoreactivity was found within the gray matter of the spinal cord. The cartography of IGF-1 receptors in the normal spinal cord as well as the change of these receptors in diseased spinal cord may be of importance in future treatment strategies of ALS.

Follow-up of plasma semicarbazide-sensitive amine oxidase activity and retinopathy in Type 2 diabetes mellitus

Plasma activity of the enzyme semicarbazide-sensitive amine oxidase (SSAO) is high in diabetes. Production of angiotoxic substances (an aldehyde, hydrogen peroxide, and ammonia) in vessel walls is catalysed by SSAO, suggesting a role for SSAO in the development of complications of diabetes. The objective of the present study was to follow up plasma SSAO activity (measured radiometrically), HbA(1c) (using ion exchange chromatography), and retinopathy (by fundus photography) after 2.8 years, in 34 patients with Type 2 diabetes. We also measured urinary levels of an SSAO substrate, methylamine, by fluorometric high-performance liquid chromatography (HPLC). As at baseline, plasma SSAO activity was now higher in subjects with retinopathy (mean 19.5) than in subjects without retinopathy (mean 16.0), 95% confidence interval (CI) for difference 0.6-6.3 nmol benzylamine ml(-1) plasma h(-1). SSAO activity had not changed significantly since baseline, mean difference -1.65 and 95% CI for difference -3.76 to 0.46 nmol benzylamine ml(-1) plasma h(-1). Mean HbA(1c) level remained higher for patients with retinopathy (now 7.9%) compared to those without retinopathy (6.1%), 95% CI for difference 0.6-3.0%. Comparing baseline and the present study, retinopathy was nonproliferative; level had worsened for five and improved for two patients. Urinary methylamine/creatinine ratio was lower in the group of patients with retinopathy (mean 0.99) than in those without retinopathy (mean 1.78), 95% CI for difference 0.1-1.5 microg mg(-1). The results of the present study are compatible with a role for SSAO in the development of diabetic retinopathy.

Chronic pharmacological treatment with certain antidepressants alters the expression and DNA-binding activity of transcription factor AP-2

Several of the genes in the serotonergic and the dopaminergic systems have consensus binding sites for the AP-2 transcription factor family in their regulatory regions. Imbalances in these systems have been implicated in many psychiatric disorders, including depression and bipolar affective disorder. We have made an effort to further elucidate the molecular mechanisms of drugs used for affective disorders. Recently, we analyzed the effects of chronic treatment with certain antidepressants on AP-2 in rat brain. The present study demonstrates that chronic administration of three different classes of antidepressants modulates the DNA-binding activity of AP-2 in the rat brain. Chronic administration of citalopram (10 mg/kg), imipramin (10 mg/kg) and lithium-chloride (40 mg/kg) significantly decreased DNA-binding activity of AP-2. Furthermore, citalopram (10 mg/kg) and imipramin (10 mg/kg) significantly decreased the amount of AP-2alpha protein as determined by ELISA. In addition, citalopram (10 mg/kg) significantly decreased the amount of AP-2beta protein. In contrast, chronic administration of lithium-chloride (40 mg/kg) did not affect the amount of the two AP-2 isoforms. An increased understanding of the function of transcription factors and their involvement in human disease, such as depression, could make it possible in the future to selectively modulate relevant target genes directly.

Reactive gliosis and monoamine oxidase B

A double-staining method was applied to cryosections of human spinal cord from patients who died with amyotrophic lateral sclerosis (ALS) and corresponding controls in order to investigate cellular content of monoamine oxidase B (MAO-B). 3H-L-Deprenyl emulsion autoradiography was used in combination with histochemical methods for the detection of astrocytes and monocytes/microglia. In the ALS spinal cords an increased number of astrocytes as well as an increased content of MAO-B in reactive species of astrocytes was demonstrated. No significant 3H-L-deprenyl binding was observed in cells derived from the mesoderm, e.g. monocytes or microglia. Furthermore, a sub-population of reactive astrocytes that contained low levels of MAO-B was observed in spinal sections. These findings were further substantiated by studies performed on primary astrocyte cultures.

A regulatory monoamine oxidase a promoter polymorphism and personality traits

Monoamine oxidase type A (MAOA) has been implicated to be part of mechanisms underlying human temperament and psychiatric disorders. We hypothesised that a functional polymorphism in the 5′ untranslated region of the MAOA gene is associated with specific personality traits. In 371 healthy Caucasians, we estimated personality traits by the use of the Karolinska Scales of Personality (KSP), Scandinavian Universities Scales of Personality, Health-Relevant 5-Factor Personality inventory, Temperament and Character Inventory and the revised NEO Personality Inventory. In the same subjects, we analysed the genotype of a polymorphic region consisting of a variable number of a 30-bp repeat sequence located approximately 1.2 kb upstream of the MAOA gene. After correction for multiple testing, no statistically significant differences between MAOA genotype and personality were observed in men (n = 206) nor in women (n = 165). We conclude that the structure of this MAOA promoter region does not have a large impact on the expression of personality characteristics in the present Swedish population.

Increased binding of3H-L-deprenyI in spinal cords from patients with amyotrophic lateral sclerosis as demonstrated by autoradiography

The present investigation has applied quantitative autoradiography and histochemistry to study the regional distribution of MAO-B and its relation to the number of cells in respective regions. L-deprenyl binds irreversibly and quantitatively to the B-form of monoamine oxidase, MAO, and is an ideal3H-ligand to measure the MAO-B enzyme protein in tissues by means of in vitro autoradiography. The investigation is performed on spinal sections from five controls and five cases with amyotrophic lateral sclerosis (ALS) on cervical, thoracic and lumbar level. The highest density of3H-L-deprenyl binding was found around the central canal (lamina X). MAO-B was markedly increased (up to 2.5 times of values in controls) specifically in regions of neurodegeneration e.g. motor neuron laminae and corticospinal tracts. There was a high correlation between glial cell count and3H-L-deprenyl binding with a relation indicating enhanced MAO-B protein in glial cells within areas of neurodegeneration. In contrast the increased microglial cell number in ALS did not show any correlation with3H-L-deprenyl binding.