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Biomedical subjects

L Oreland

Publications and source records attributed to L Oreland.

At least 91 records · Page 5Linked to original sources
PubMed1995

Effect of the GABA-transaminase inhibitor vigabatrin on exploratory behaviour in socially isolated rats.

Elevation of the brain levels of the major inhibitory neurotransmitter gamma-aminobutyric acid (GABA) by inhibiting the GABA-catabolizing enzyme GABA-transaminase (GABA-T) is known to induce a number of functional effects including changes in behaviour. Vigabatrin (gamma-vinyl GABA, GVG) is an anti-epileptic drug that increases brain GABA levels by an irreversible inhibition of GABA-T. Using the elevated plus-maze model of anxiety and the open-field behaviour test, the effects of GABA-T inhibition and social isolation on rat exploratory behaviour were investigated. Social isolation for 1 week did not induce any change in the exploratory-behaviour of adult rats. However, rats socially isolated for 2 weeks, showed suppressed exploratory behaviour in the elevated plus-maze test. In both groups of differentially housed rats, treatment with vigabatrin at a dose of 250 mg/kg, i.p., significantly reduced the anxiety level in the plus-maze test. In the open-field test, vigabatrin tended to increase the exploratory behaviour only in the group of isolated rats. The results may suggest that vigabatrin has a better anxiolytic-like effect in the isolated rats than that in the socially housed rats.

4-Aminobutyrate Transaminase↗
PubMed1995

Decreased cytochrome-c oxidase activity and lack of age-related accumulation of mitochondrial DNA deletions in the brains of schizophrenics.

Defects in mitochondrial energy production have been implicated in several neurodegenerative disorders, such as Parkinson disease and amyotrophic lateral sclerosis. To study the contribution of mitochondrial defects to Alzheimer disease and schizophrenia, cytochrome-c oxidase (COX) activity and levels of the mtDNA4977 deletion in postmortem brain tissue specimens of patients were compared with those of asymptomatic age-matched controls. No difference in COX activity was observed between Alzheimer patients and controls in any of five brain regions investigated. In contrast, schizophrenic patients had a 63% reduction of the COX activity in the nucleus caudatus (P < 0.0001) and a 43% reduction in the cortex gyrus frontalis (P < 0.05) as compared to controls. The average levels of the mtDNA4977 deletion did not differ significantly between Alzheimer patients and controls, and the deletion followed similar modes of accumulation with age in the two groups. In contrast, no age-related accumulation of mtDNA deletions was found in schizophrenic patients. The reduction in COX activity in schizophrenic patients did not correlate with changes in the total amount of mtDNA or levels of the mtDNA4977 deletion. The lack of age-related accumulation of the mtDNA4977 deletion and reduction in COX activity suggest that a mitochondrial dysfunction may be involved in the pathogenesis of schizophrenia.

Aged↗
PubMed1995

Role of N-methyl-D-aspartic acid and cholecystokinin receptors in apomorphine-induced aggressive behaviour in rats.

We studied the aggressive behaviour induced by repeated treatment with apomorphine, a dopamine agonist (0.5 mg/kg s.c. twice daily, 10 days), in rats. The first signs of defensive aggressiveness appeared on the third day of apomorphine treatment and were generally seen on the 7th day. Aggressiveness induced by a challenge dose of apomorphine (0.5 mg/kg s.c.) on the 11th day was antagonized by haloperidol (0.05 and 0.1 mg/kg i.p.) and clozapine (10 mg/kg i.p.). An antagonist of N-methyl-D-aspartate (NMDA)-gated channels, dizocilpine (MK-801), also blocked the aggressive behaviour at 0.25 and 0.5 mg/kg i.p. but caused ataxia. When dizocilpine (0.25 mg/kg i.p.) and apomorphine were coadministered for 10 days, aggressive behaviour did not develop. At 0.025 mg/kg i.p., dizocilpine even accelerated the appearance of apomorphine-induced aggressive behaviour, which manifested on the 3rd day in all rats. In a separate study, a 7-day treatment with dizocilpine (0.25-1 mg/kg i.p.) of rats, sensitized by a prior 10-day apomorphine treatment, did not reverse the established aggressive behaviour. The coadministration of apomorphine and cholecystokinin (CCK) -A or -B antagonists, devazepide or L-365,260 (0.01-2.5 mg/kg i.p.) respectively, neither affected development of apomorphine-induced aggressive behaviour nor intensity of aggressiveness in the sensitized rats. In binding studies neither density nor affinity of striatal dopamine D2 receptors was changed by acute or chronic apomorphine treatment. The number of [3H]pCCK-8 binding sites in the frontal cortex increased already after a single injection of apomorphine.(ABSTRACT TRUNCATED AT 250 WORDS)

Aggression↗
PubMed1995

Platelet and brain GABA-transaminase and monoamine oxidase activities in patients with complex partial seizures.

UNLABELLED: The activities of gamma-aminobutyrate aminotransferase (GABA-T) and monoamine oxidase (MAO-A and -B) were measured in blood platelets from 27 patients and hippocampal tissues from eight (GABA-T) and ten (MAO) patients with complex partial seizures. The activity of platelet GABA-T was found to be higher in the epileptic patients (43.37 +/- 13.53 pmol/min/mg protein, P < 0.005) in comparison with that found in 14 healthy volunteer subjects (29.59 +/- 13.14 pmol/min/mg protein). This difference was most pronounced in patients treated with carbamazepine (CBZ) (P < 0.01) and phenytoin (PHT) (P < 0.01). Contrary to the platelets, the activity of GABA-T in the hippocampi from the epileptic patients (6.937 +/- 2.204 nmol/min/mg protein) did not differ significantly from that found in seven non-epileptic control cases (7.158 +/- 0.951 nmol/min/mg protein). The increase in GABA-T activity in the blood platelets from the epileptic patients could not be explained by a direct effect of the antiepileptic compounds, since there were no changes in the activities on exposure to PHT, CBZ or VPA in vitro, either of blood platelets or of brain tissue. With regard to platelet MAO, no difference in the activity was found between the two groups, whereas the MAO-B activity in the hippocampi was significantly higher in the epileptic patients (3.51 +/- 1.32 nmol/mg/mg protein) than in the control cases (1.21 +/- 0.73 nmol/mg/mg protein) (P < 0.0004). There was no difference in MAO-A activity in the hippocampi between epileptic patients and controls. CONCLUSION: In the hippocampi from patients with complex partial seizures the activities of the mitochondrial enzymes GABA-T and MAO-A were similar to those found in control subjects. The activity of MAO-B, however, was significantly higher indicating that there is an increased proportion of reactive astrocytes in epileptic hippocampus.

4-Aminobutyrate Transaminase↗
PubMed1995

Decreased methionine adenosyltransferase activity in erythrocytes of patients with dementia disorders.

ATP:1-methionine S-adenosyltransferase (EC 2.5.1.6, MAT) activity was analyzed in erythrocytes from nine patients with a clinical diagnosis of probable Alzheimer's disease (Pro.AD), four with possible Alzheimer's disease (Pos.AD), three with mild cognitive dysfunction (MCD) and two with dementia of vascular origin (VD), and 10 age-matched control subjects. Significantly lower kinetic parameters (Vmax and Km towards methionine) for MAT were observed in all the dementia cases. In the subgroup of Pro.AD patients who also had low plasma levels of vitamin B12 (B12), the reduction in MAT Km was significantly correlated with an increase in the serum levels of homocysteine, while no such correlation was observed in all the other dementia groups. Treatment for 6 months of this subgroup of Pro.AD patients with B12 (1 mg x 7 days + 1 mg/week, i.m.), S-adenosylmethionine (SAM, 200 mg twice daily, p.o.) and folate (2.5 mg every 2 days, p.o.) caused a significant decrease in homocysteine in parallel with a significant increase in Km for MAT. These findings support the hypothesis that aberrations in the B12 dependent transmethylation reactions might be involved in the pathogenesis of dementia, and suggest that the evaluation of erythrocyte MAT activity may be a useful marker for the detection of such an aberration.

Age Distribution↗
PubMed1995

Impaired exploratory behaviour after DSP-4 treatment in rats: implications for the increased anxiety after noradrenergic denervation.

The effect of DSP-4, a neurotoxin selectively affecting the projections of the locus coeruleus, upon exploratory behaviour of rats was studied in a complex exploration test, including a choice between open and enclosed areas and both inquisitive and inspective exploration elements. One week after DSP-4 (50 mg/kg i.p.) administration, the neurotoxin-treated rats did not explore a novel open area to any extent on the first exposure to the apparatus; however, on the third day of testing, these animals began to explore the area and the novel objects. Diazepam (0.5 mg/kg) treatment did not change the behaviour of control rats, but significantly increased the exploratory activity of the DSP-4-treated animals. LY 288513, a selective CCKB receptor antagonist (0.01 mg/kg), prevented the increase in exploratory activity in the DSP-4-treated rats, but increased the exploratory activity of controls on the third exposure to the test situation. The results of this investigation suggest that DSP-4 treatment reduces neotic behaviour by increasing neophobia rather than by decreasing exploratory drive. The divergence reported between the relative potencies of CCKB receptor antagonists in exploratory activity and other anxiety tests may in part be due to the effects of these drugs on exploratory drive.

Adrenergic Agents↗
PubMed1995

Effects of the histamine H3 agonist (R)-alpha-methylhistamine and the antagonist thioperamide in vitro on monoamine oxidase activity in the rat brain.

The effects of an H3 agonist, (R)-alpha-methylhistamine (alpha-MeHA), and an H3 antagonist, thioperamide, on monoamine oxidase (MAO) activity in rat hypothalamus were studied in vitro. Thioperamide was more potent in inhibiting MAO-B than MAO-A activity; MAO-B activity in rat hypothalamic homogenates was competitively inhibited by thioperamide with a Ki value of 175 micronM. From this in vitro experiment, the conversion of N-telemethylhistamine to N-tele-methylimidazoleacetic acid may be inhibited by thioperamide, suggesting that thioperamide may affect the regulation of histamine metabolism within histaminergic neurons. In contrast with the results obtained with thioperamide, alpha-MeHA inhibited MAO-A more potently than MAO-B activity; the Ki values for MAO-A and -B of hypothalamic homogenates were estimated to be 1.1 and 3.3 mM, respectively. The weak inhibitory effect of alpha-MeHA for MAO-B does not seem to be a major cause of changes in N-tele-methylhistamine concentrations.

Animals↗
PubMed1994

Effects of chronic treatment with the GABA-transaminase inhibitor vigabatrin on exploratory behaviour in rats.

Vigabatrin (gamma-vinyl GABA, GVG) is an irreversible inhibitor of the enzyme GABA-transaminase (GABA-T) GABA-T is the enzyme responsible for the catabolism of the major inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the mammalian brain. Previously, a single administration of vigabatrin at a dose of 50 mg/kg was found to produce an anxiolytic-like effect on exploratory behaviour in rats and a decrease in the locomotor activity, 2 and 4 h after the injection and, presently, 24 h after the injection. Using an elevated plus-maze and open field tests, we investigated whether or not chronic administration of vigabatrin at the same dose (50 mg/kg/day, i.p.) for 14 and 28 days induces tolerance with regard to these effects. The anxiolytic-like effect of vigabatrin was found to persist in the elevated plus-maze test, as was the case with diazepam (5 mg/kg/day, i.p.), 24 h after the last injection. However, in the plus-maze and open field tests, the effects of vigabatrin and diazepam on the general locomotor activity were not found to be decreased.

4-Aminobutyrate Transaminase↗
PubMed1994

Monoamine oxidase-B in motor cortex and spinal cord in amyotrophic lateral sclerosis studied by quantitative autoradiography.

The distribution of MAO-B was studied by using an in vitro quantitative autoradiographical method in the post-mortem spinal cord and motor cortex from control and ALS cases. 3H-L-deprenyl was used as a radiotracer. Sections stained with thionine were used to count glial cells. In both control and ALS spinal cords, high density of 3H-L deprenyl binding was observed around the central canal, in the substantia gelatinosa and other grey matter regions. In the ALS cases a pronounced and statistically significant increase of MAO-B was observed in the corticospinal tract, the motor neuron areas and in the ventral white matter. An increase in the number of glial cells in spinal cords from ALS cases was also evident. Moreover, the concentration of MAO-B was highly correlated with glial cell counts in thionine stained sections in various regions of the spinal cord, both in controls and ALS cases. An elevated level of 3H-L-deprenyl binding, in ALS cases, was observed in all the individual laminae of the pre- and post-central gyri of the cerebral cortex. There was no difference in MAO-B concentration between the two groups in the occipital cortex. A substantial increase in the concentration of MAO-B was observed in the white matter of ALS cases. Reactive gliosis has been shown to be associated with neurodegenerative disorders and experimental lesions in animals. The most likely explanation for the increase of MAO-B in ALS and in other neurodegenerative disorders seems to be that the increase is a consequence of the reactive gliosis associated with these disorders.

Amyotrophic Lateral Sclerosis↗
PubMed1994

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.

Amyotrophic Lateral Sclerosis↗
PubMed1994

Increase in brain GABA-transaminase activity after chronic ethanol treatment in rats.

The activity of gamma-aminobutyrate aminotransferase (GABA-T) was measured in the brains of rats treated both acutely and sub-chronically with ethanol. Previously, chronic treatment with ethanol for 90 weeks was found to increase the mean brain GABA-T activity by 20-45%. In the present study acute ethanol treatment (4 g/kg, i.p.) did not induce and change in the activity of brain GABA-T with the exception of a small increase in the cerebellum (8%) and, after repeated treatment with ethanol (4 g/kg/day, i.p.) for one and two weeks, no change in the activity of GABA-T was also found in any of the brain regions examined. Subchronic treatment with ethanol for 14 weeks, performed according to two different schedules involving a voluntary intake of ethanol in the drinking water, resulted in approximately a two-fold difference in ethanol intake. A mean increase of 50-85% in the activity of GABA-T was found in all the brain regions of rats with higher ethanol intake in comparison with the group of rats with lower ethanol intake. A bimodal distribution of brain GABA-T activity, however, was found in the ethanol-treated rats, with 60% of the rats having a two-fold increase and the remaining 40% having unchanged activities. The addition of pyridoxal phosphate to the incubation media increased the activity of brain mitochondria from ethanol-treated rats with high brain GABA-T, whereas there was a decrease in the activity in control rats and in ethanol-treated rats in which no increase in brain GABA-T had occurred. These results show firstly, that in a subpopulation of rats, subchronically treated with ethanol for 14 weeks, there was a two-fold increase in brain GABA-T activity, while in another subgroup no change occurred, and, secondly, that this increase in GABA-T activity was a consequence of a change in the response of the apoprotein to the addition of the cofactor pyridoxal phosphate.

4-Aminobutyrate Transaminase↗
PubMed1994

Mitochondrial enzyme deficiencies in Down's syndrome.

Defects in cytochrome oxidase (CO; complex 4) have recently been demonstrated in blood platelets and in brain tissue from patients with Alzheimer's disease (AD) with possible etiological implications. Because of pathogenetic similarities with AD, we have measured the activities of several mitochondrially localised enzymes in the blood platelets of individuals afflicted with trisomy-21 (Down's syndrome). The activities of monoamine oxidase, cytochrome oxidase, isocitrate dehydrogenase, and glutamate dehydrogenase were assayed in washed platelets from sixty caucasian, male and female control individuals (ages 18-60) and ten, young Down's Syndrome patients (ages 9-21). Significant reductions in the activities of monoamine oxidase, cytochrome oxidase, and isocitrate dehydrogenase were found. In all cases the average activities in Down's syndrome individuals were approximately two-thirds those of controls (DS/Controls = 0.68, 0.67, 0.64 respectively). The activity of the fourth enzyme studied, glutamate dehydrogenase, was found to be similar to controls. Results suggest that these reductions are a consequence of a generalised mitochondrial disturbance which may lie behind some pathogenetic aspect(s) of the disease.

Adolescent↗
PubMed1994

Anxiolytic-like effect of the GABA-transaminase inhibitor vigabatrin (gamma-vinyl GABA) on rat exploratory activity.

Vigabatrin (gamma-vinyl GABA, GVG) is an irreversible inhibitor of GABA-transaminase (GABA-T). This study addressed the question of whether or not the inhibition of GABA-T has an anxiolytic effect in rats. Diazepam (1.5 mg/kg) and GVG (50 and 500 mg/kg) increased the tendency of rats to explore in the elevated plus-maze test, whereas the effect of general locomotor activity was diminished. The sedative effect of GVG (500 mg/kg) was more pronounced 6 h than 2 h after IP administration. The present findings suggest that even a partial inhibition of GABA-T results in a reduction of anxiety measures in a novel environment.

4-Aminobutyrate Transaminase↗
PubMed1994

Cholecystokinin receptor binding in morphine analgesia: tolerance, withdrawal and abstinence.

The effect of morphine treatment on cholecystokinin (CCK) receptor binding in rat cerebral cortex was investigated. Subcutaneous implantation and removal of Alzet miniosmotic pumps, releasing morphine, permitted us to establish the phases of initial analgesia, tolerance to the analgesic action of morphine, morphine withdrawal and abstinence. CCK receptor binding in rat cerebral cortex never differed from the values obtained from animals implanted with saline-releasing minipumps. The results of the present study suggest that the putative changes in the interaction between opioidergic and CCKergic neurotransmission at different stages of morphine treatment and withdrawal are not caused by changes of CCK receptor binding properties.

Analgesia↗