Search PubMed⌕ Search

Biomedical subjects

L Rägo

Publications and source records attributed to L Rägo.

At least 37 records · Page 2Linked to original sources
PubMed1997

The effect of cholecystokinin tetrapeptide on respiratory resistance in healthy volunteers.

The effects of cholecystokinin tetrapeptide (CCK-4) on respiratory resistance were studied in 14 healthy volunteers by the registration of slow vital capacity and flow volume loop during forced respiration test. The administration of CCK-4 (50 micrograms) was performed in a double-blind and placebo-controlled design. Injections of CCK-4 induced prominent and time-limited paniclike symptoms in all healthy volunteers. Four volunteers (29%) experienced a panic attack. Subjective dyspnea was experienced by the majority of subjects at the peak of CCK-4 effect and seemed related to a diminution in vital capacity parameters; however, the forced respiration test did not reveal bronchoconstriction after CCK-4 challenge. Administration of CCK-4 also induced a short-lasting increase in heart rate and skin blood flow. This study suggests that dyspnea induced by CCK-4 is not related to changes in respiratory resistance.

Adult↗
PubMed1997

Different molecular forms of cholecystokinin and CCKB receptor binding in the rat brain after chronic antidepressant treatment.

Cholecystokinin (CCK) is a neuropeptide recently implicated in affective disorders. This study aimed at measuring the levels of different molecular forms of CCK and the binding characteristics of CCKB receptors in the rat brain after three weeks of treatment with four different antidepressants, imipramine, amitriptyline, desipramine, and citalopram (all at the dose of 10 mg/kg once per day i.p.). Chronic treatment with imipramine and desipramine had a significant immobility-reducing effect in the Porsolt's swim test. The effect of amitriptyline, albeit in the same direction, was not significant, and citalopram had no effect in this test. In the elevated plus-maze test of anxiety, all drugs tended to increase the number of open arm entries and the ratio open/total arm entries, but only the effects of imipramine were statistically significant. None of the treatments affected the total levels of CCK or the levels of CCK-8-sulphated, CCK-8-nonsulphated, CCK-5, or CCK-4 in the frontal cortex. There was no effect of the treatments on CCKB receptor binding in the frontal cortex, hippocampus, or striatum. Imipramine and amitriptyline, however, increased the affinity of CCKB receptor binding in the hypothalamus. Thus, no consistent effect of chronic antidepressant treatment on the CCK-ergic neurotransmission in the rats was found.

Animals↗
PubMed1997

Overflow of noradrenaline and dopamine in frontal cortex after [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine] (DSP-4) treatment: in vivo microdialysis study in anaesthetized rats.

The changes in the extracellular concentration of endogenous noradrenaline and dopamine in the frontal cortex following pretreatment with noradrenergic neurotoxin DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine] were studied by in vivo microdialysis in rats anaesthetized with chloral hydrate. Noradrenaline and dopamine levels in frontal cortex were detected only when the uptake inhibitor, nomifensine (10 microM) was present in dialysis fluid. Under those conditions, the Na+ channel agonist veratridine and a depolarising concentration of potassium chloride (60 mM), applied locally through the microdialysis probe, increased the overflow of noradrenaline. Tetrodotoxin had an opposite effect. These results indicate that most of the noradrenaline probably arose from exocytotic release. Noradrenaline efflux in the frontal cortex of DSP-4 pretreated rats (52 +/- 6.1 fmol/sample) did not differ significantly from that of the control animals (69 +/- 4.9 fmol/sample). Dopamine efflux was not changed either (64 +/- 9.6 and 62 +/- 3.9 fmol/sample, respectively). The alpha 2-adrenoceptor antagonist, atipamezole (3 mg/kg i.p.), increased the overflow of noradrenaline in the frontal cortex of saline-treated rats by 100%, whereas in DSP-4 treated rats the increase was only around 30%. The overflow of dopamine was not changed under the conditions described. The effect of atipamezole in DSP-4 treated rats may be of smaller magnitude due to the diminished pool of releasable noradrenaline or due to a downregulation of presynaptic alpha 2-adrenoceptors in the frontal cortex. The perfusion of 60 mM KCl at the end of the experiment unexpectedly produced equivalent increases in noradrenaline and dopamine content in dialysates of both vehicle and DSP-4 treated rats. We conclude that the uptake inhibitor, nomifensine, and atipamezole, which had a stronger effect in vehicle-treated animals, reduced the effect of KCl-stimulation and masked the true difference in changes of noradrenaline efflux. Post-mortem tissue concentrations of noradrenaline 7 days after DSP-4 administration (50 mg/kg) were significantly reduced in the frontal cortex (54%), hippocampus (62.5%) and to lesser extent in the hypothalamus (27%) as compared to vehicle-treated rats. Dopamine and 3,4-dihydroxyphenylacetic acid concentrations were not changed confirming the efficacy and selectivity of the DSP-4 lesion. These results demonstrate that one week after DSP-4 treatment the extracellular levels of noradrenaline and dopamine as assessed by in vivo microdialysis are not changed in the frontal cortex, but atipamezole-stimulated release of noradrenaline is decreased in DSP-4 treated rats.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed1997

Debrisoquine and S-mephenytoin hydroxylation polymorphisms in a Russian population living in Estonia.

OBJECTIVE: To investigate the CYP2D6 and CYP2C19 phenotypes and genotypes in a Russian population of Estonia. METHODS: Two hundred and eighteen unrelated healthy subjects of Russian origin were studied. All participants took 10 mg debrisoquine and 100 mg S/R-mephenytoin for phenotyping. The CYP2D6 genotype was analysed by PCR amplification for the CYP2D6*3 and CYP2D6*4 alleles and subjects with S/R-mephenytoin ratios of greater than 0.5 were genotyped with respect to CYP2C19*2 and CYP2C19*3 alleles. RESULTS: Seventeen subjects (7.8%) were classified as poor metabolisers of debrisoquine and 5 (2.3%) as poor metabolisers of S-mephenytoin. The frequency of CYP2D6*4 was 14.4% and that of CYP2D6*3 1.4%. Seven of 15 poor metabolisers of debrisoquine (47%) carried two defective CYP2D6 alleles (CYP2D6*3 or CYP2D6*4). Six of the 10 S-mephenytoin poor-metaboliser alleles (60%) carried either the CYP2C19*2 or CYP2C19*3. CONCLUSION: The frequencies of poor metabolisers of debrisoquine and S-mephenytoin among Russians were similar to those in other Caucasian populations. The CYP2D6 poor-metaboliser phenotype was predicted by PCR-based amplification for the CYP2D6*3 and CYP2D6*4 alleles with 47% accuracy. The frequency of the CYP2D6*4 allele was lower in Russians than in other Caucasian populations studied so far.

Adolescent↗
PubMed1997

Binding of pinoline on the 5-hydroxytryptamine transporter: competitive interaction with [3H] citalopram.

Pinoline (6-methoxy-1,2,3,4-tetrahydro-beta-carboline) is a naturally occurring compound in the mammalian body which inhibits 5-hydroxytryptamine (5-HT) uptake and exerts antidepressant-like behavioural effects in rats. The present study investigates the effects of pinoline on [3H]citalopram binding to the 5-HT transporter on rat brain. Our experiments revealed that pinoline inhibits [3H]citalopram binding with IC50 1255 +/- 167 nM and Ki 572 +/- 76 nM; Hill coefficient for inhibition was close to 1. In saturation experiments, pinoline co-incubated with [3H]citalopram, increased dose-dependently the Kd value but had no effect on the Bmax value of [3H]citalopram binding. Micromolar concentrations of pinoline did not have influence on the dissociation rate of specifically bound [3H]citalopram. Binding parameters of [3H]citalopram did not differ significantly in cerebral cortex and hippocampus of rats treated for 10 days with pinoline or vehicle. These results indicate that pinoline did not have any modulative influence on the activity of 5-HT transporter and it interacts competitively with citalopram on the substrate recognition site of the 5-HT transporter.

Animals↗
PubMed1996

Anxiogenic-like effect of the neuropeptide Y Y1 receptor antagonist BIBP3226: antagonism with diazepam.

The effect of the novel non-peptide neuropeptide Y Y1 receptor antagonist BIBP3226, N2-(diphenylacetyl)-N-[(4-hydroxy-phenyl)-methyl]-D-arginine amide, on exploratory behaviour of rats in the elevated plus-maze was studied. BIBP3226 (0.5 and 5 micrograms, i.c.v.) induced an anxiogenic-like effect at the higher dose tested. This effect was antagonised by diazepam (0.5 mg/kg). The anxiogenic-like effect of BIBP3226 was not related to a decrease in general locomotor activity. These findings support the hypothesis that neuropeptide Y Y1 receptor subtype is involved in anxiety regulation.

Animals↗
PubMed1996

Debrisoquin and S-mephenytoin hydroxylation phenotypes and CYP2D6 genotypes in an Estonian population.

The polymorphisms of debrisoquin (CYP2D6) and S-mephenytoin (CYP2C19) hydroxylation were studied in 210 unrelated healthy native Estonians by coadministration of mephenytoin and debrisoquin or dextromethorphan. Among the 210 volunteers 21 (10%) were poor metabolizers of debrisoquin/dextromethorphan and two (0.95%) were poor metabolizers of S-mephenytoin. By pooling these data with an earlier study on 156 Estonians, the prevalences of poor metabolizers of debrisoquin/dextromethorphan and poor metabolizers of S-mephenytoin were 7.6% and 2.2%, respectively. The CYP2D6 genotype of 151 subjects was analysed by allele-specific PCR amplification for the defect alleles CYP2D6A and CYP2D6B. All poor metabolizers of debrisoquin carried two defect CYP2D6-alleles. The phenotype (extensive or poor metabolizer) was in all subjects correctly predicted by the genotype. The frequencies of the defect alleles CYP2D6B and CYP2D6A among these 151 subjects (including 14 poor metabolizers-9.3%) were 21.5% and 2.3%, respectively. DNA from 6 subjects with very high CYP2D6 activity (debrisoquin MR < 0.1) was analysed by EcoRI RFLP to identify duplicated or amplified CYP2D6-genes. Two of the subjects were found to carry a duplicated CYP2D6L-gene. In conclusion, the distribution of genetically determined metabolic capacities of CYP2D6 and CYP2C19 in Estonian unrelated subjects did not differ significantly from that in other Caucasian populations. The CYP2D6 phenotype was predicted by PCR-based amplification for the CYP2D6A and CYP2D6B-alleles.

Adolescent↗
PubMed1992

The effect of chronic treatment with peripheral benzodiazepine receptor ligands on behavior and GABAA/benzodiazepine receptors in rat.

Rats were twice daily (2 x 10 mg/kg, i.p.) treated for three weeks with the peripheral benzodiazepine (BZ) receptor ligands Ro 5-4864 (4'-chlorodiazepam) and PK 11,195 (1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carbox ami de). After the first injection there were no differences between the drug-treated and control animals in behavioral tests. After 10 days treatment, the number of sniffings was increased in Ro 5-4864-treated rats. After the last injection, sniffings and ambulations were decreased in PK 11,195-treated animals. The number of rearings and groomings remained unchanged throughout the treatment, and there were no changes in the results in the elevated plus-maze test. Apparently these compounds are devoid of anxiolytic and anxiogenic effects at moderate doses. The effect of 72 a h withdrawal from the above mentioned chronic treatment on peripheral and central BZ receptors as well as on GABAA receptors was studied with receptor binding techniques using 3H-Ro 5-4864, 3H-flumazenil and 3H-muscimol, respectively, as ligands. The number of GABAA and central BZ receptors was lower after Ro 5-4864 treatment, as was the effect of progesterone-induced stimulation of 3H-muscimol binding. The number of peripheral BZ receptors was decreased after Ro 5-4864 and PK 11,195 treatments in the olfactory bulb but not in the cerebral cortex. The chronic treatment with peripheral BZ receptor ligands Ro 5-4864 and PK 11,195 produced only little behavioral effects. Ro 5-4864, often presented as an agonist of peripheral BZ receptors, was behaviorally inactive.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Effects of central and peripheral type benzodiazepine ligands on thyrotropin and prolactin secretion.

The cold-stimulated thyrotropin (TSH) levels in the rat were decreased by clonazepam (a central type benzodiazepine agonist), diazepam (a mixed agonist), FG 7142 (an inverse central type agonist) and Ro 5-4864 (a peripheral type agonist), clonazepam being the most potent and Ro 5-4864 the least active. Clonazepam and diazepam also decreased while FG 7142 increased prolactin (PRL) levels. Ro 5-4864 did not have any significant action. Clonazepam (1 and 5 mg/kg) and diazepam (15 mg/kg but not 25 mg/kg) decreased even the TRH-induced PRL levels. Only Ro 5-4864 (25 mg/kg) decreased TRH-induced TSH secretion but not significantly. The actions of central type compounds were antagonized by flumazenil but not by PK 11195. The weak effects of Ro 5-4864 were not antagonized by either antagonists. While the peripheral type benzodiazepine agonist only weakly affected the secretion of anterior pituitary hormones, the central type inhibition of TSH appears to be mediated through the hypothalamic TRH and that of PRL rather through the anterior pituitary gland. The sedating (or agitating in case of FG 7142) effect of high doses of benzodiazepine ligands may contribute to the changes in TSH and PRL levels.

Animals↗
PubMed1992

Effects of central and peripheral type benzodiazepine ligands on growth hormone and gonadotropin secretion in male rats.

The action of central and peripheral type benzodiazepine ligands on growth hormone, luteinizing hormone and follicle stimulating hormone levels in serum were studied in male rats. Graded doses of Ro 5-4864, that binds to the peripheral type benzodiazepine receptors, clonazepam, a fairly pure central type agonist and diazepam, a mixed-type agonist, were given intraperitoneally. Also a benzodiazepine partial inverse agonist, FG 7142, was investigated. Clonazepam increased growth hormone levels at 0.2 mg/kg while higher doses were not active. Diazepam (5-25 mg/kg) was not effective. FG 7142 (15 mg/kg) and Ro 5-4864 (25 mg/kg) decreased growth hormone levels. Flumazenil, a central-type antagonist, reversed at least partially the effects of clonazepam and FG 7142, suggesting an effect through GABA-benzodiazepine complex. Elevation of growth hormone could be associated with anxiolysis and decrease of growth hormone with enhanced anxiety. Clonazepam (0.2-5 mg/kg) and diazepam (5-25 mg/kg) increased luteinizing hormone concentrations, but only the effects of 1 mg/kg of clonazepam and 5 mg/kg of diazepam reached statistical significance. Even FG 7142 caused a modest increase of luteinizing hormone at 5 mg/kg, but Ro 5-4864 rather decreased luteinizing hormone, although not significantly. Flumazenil (25 mg/kg) antagonized partially the effects of diazepam and clonazepam. Effects of Ro 5-4864 and FG 7142 were not modified by flumazenil or PK 11195, a peripheral-type mixed antagonist/agonist. Luteinizing hormone stimulation by benzodiazepine ligands may be a pituitary action while inhibition could be caused by the activation of the central GABAergic system. Serum follicle stimulating hormone levels were not significantly altered by central or peripheral type benzodiazepine agonists or antagonists.

Animals↗
PubMed1991

Correlation between exploratory activity in an elevated plus-maze and number of central and peripheral benzodiazepine binding sites.

Two groups of rats were selected from a small animal population on the basis of their exploratory activity in an elevated plus-maze model of anxiety. One group had a considerably lower and the other one a higher exploratory activity than the average total population. These subgroups were termed "anxious" and "non-anxious", respectively. In both groups central benzodiazepine binding sites in various brain structures were labelled with 3H-flunitrazepam. Peripheral benzodiazepine binding sites labelled in vitro with different tritiated ligands were also studied in several peripheral organs including blood platelets and lymphocytes. "Anxious" animals had a significantly lower number of 3H-flunitrazepam binding sites in the cerebral cortex but not in the hippocampus and cerebellum. In this subgroup 3H-Ro 5-4864 binding to peripheral benzodiazepine recognition sites was also lower than in the other one in adrenals, kidneys, platelets and lymphocytes. In the heart no differences of 3H-Ro 5-4864 binding between subgroups studied were found. Although in "anxious" rats 3H-diazepam and 3H-PK 11195 binding was significantly lower only in lymphocytes, a somewhat decreased binding to these ligands was also present in platelets. No significant differences in the affinity were found between the two groups throughout the experiments described. The results indicate that behavioral anxiety in rats is correlated not only with the lower number of central benzodiazepine receptors but also with a lower density of peripheral benzodiazepine binding sites in several peripheral organs including platelets and lymphocytes.

Adrenal Glands↗
PubMed1991

The effect of medetomidine on GABA and benzodiazepine receptors in vivo: lack of anxiolytic but some evidence of possible stress-protective activity.

Medetomidine, a new selective alpha 2-adrenoceptor agonist, potentiated bicuculline seizures in mice. In vivo pretreatment with medetomidine in mouse cerebral cortex reduced dose-dependently (2.5-100 micrograms/kg) GABA-potentiated 3H-flunitrazepam binding. The affinity of 3H-muscimol was also reduced by medetomidine. This effect of medetomidine on GABA-potentiated benzodiazepine binding was reversed by pretreatment with atipamezole (1 mg/kg), a specific alpha 2-antagonist. In an elevated plus-maze model of anxiety medetomidine (0.5-10 micrograms/kg) was inactive both in rats and mice and did not antagonize the behavioural effects of an anxiogenic beta-carboline, DMCM. However, at lower doses medetomidine (10 but not 50 micrograms/kg) antagonized the swimming stress caused increase of central benzodiazepine binding sites (labeled with 3H-Ro 15-1788) in mouse cerebral cortex. The increase of peripheral benzodiazepine binding sites on brain and heart cryostat cut slices caused by stress was also antagonized by pretreatment with medetomidine. The behavioural and biochemical data obtained in this study are evidence that medetomidine does not have anxiolytic effect but may have, in lower doses, stress-protective activity.

Animals↗
PubMed1990

Thymopentin antagonizes stress-induced changes of GABA/benzodiazepine receptor complex.

Intraperitoneal administration of thymopentin, a thymopentin II-derived pentapeptide, had no stable and evident effect in the two anxiety models (elevated plus-maze and licking-conflict test) studied. However, in the elevated plus-maze test thymopentin antagonized the behavioral effects of DMCM, a beta-carboline derivative with anxiogenic properties. Further, it was demonstrated that the licking-conflict test procedure itself produced a significant elevation of plasma corticosterone levels, increased the number of [3H]flunitrazepam and decreased the number of [3H]muscimol binding sites in rat hippocampus. The forced-swimming stress similarly to the licking-conflict test also caused an increase in hippocampal [3H]flunitrazepam binding sites. Although ineffective behaviorally in the tests for anxiety, thymopentin pretreatment effectively reversed the changes in corticosterone levels caused by the licking-conflict test. Moreover, it normalized the changed number of benzodiazepine and GABA receptors after stressful stimuli. It is well known that not all anxiolytic drugs (i.e. buspirone) are equally active in behavioral tests for anxiety. According to our data we propose that thymopentin has stress-protective activity. As in vivo and in vitro thymopentin did not change [3H]-flunitrazepam and [3H]muscimol binding, the direct effect of this peptide on the GABA-benzodiazepine-Cl- ionophore receptor complex is unlikely. The action of this peptide on GABA release and/or metabolism can be suggested.

Animals↗
PubMed1990

Stress-protection action of beta-phenyl(GABA): involvement of central and peripheral type benzodiazepine binding sites.

Forced swimming stress caused a significant increase in the density of central type benzodiazepine binding sites in rat cerebral cortex and hippocampus. The number of peripheral type benzodiazepine binding sites was also enhanced on blood platelets. The affinity of neither central nor peripheral type benzodiazepine binding sites was changed considerably after swimming stress. Pretreatment of rats with beta-(phenyl)GABA (100 mg/kg), a GABAB agonist, almost completely eliminated the described changes of the both types of benzodiazepine binding sites caused by swimming stress. In an elevated plus-maze model of anxiety beta-(phenyl)GABA itself was inactive but like diazepam effectively counteracted the behavioural effects of DMCM, a beta-carboline derivative with anxiogenic properties. The possible involvement of benzodiazepine receptors in the mechanism of action of beta-(phenyl)GABA is discussed.

Animals↗
PubMed1989

Central- and peripheral-type benzodiazepine receptors: similar regulation by stress and GABA receptor agonists.

Central- and peripheral-type benzodiazepine (BD) receptors were labelled either by 3H-flunitrazepam or 3H-Ro 5-4864 in vitro after stress and in vivo administration of GABAA and GABAB agonists. A significant increase in the density of cerebral cortex and kidney BD binding sites was observed in rats after forced swimming stress. Similar changes in both type of BD receptors were also followed when naive (stressed) and handling-habituated (unstressed) rats were used. Stress in both models was unable to change the affinity of BD receptors in cerebral cortex, but significantly lowered it in kidneys. Acute treatment of rats with muscimol (1.5 mg/kg) or (-)baclofen (5 mg/kg) resulted in marked increase in the affinity of BD binding not only in cerebral cortex but also in kidneys. After (-)baclofen treatment the number of BD binding sites was lowered in the structures studied. In a separate study mice selected according to their behavioral response to (-)baclofen (1 mg/kg) were studied. Two weeks after the selection it appeared that baclofen responders were behaviorally more "anxious" than baclofen nonresponders. The number of BD binding sites was reduced in cerebral cortex, cerebellum, heart and kidneys in baclofen responders as compared to baclofen nonresponders. In several cases the changes in peripheral BD binding sites were even more pronounced than those in central ones. The data presented here evidence that peripheral- and central-type BD receptors are regulated similarly by GABA and some models of stress. The physiological mechanisms involved in similar regulation of central- and peripheral-type BD receptors are yet unknown.

Animals↗
PubMed1988

Behavioral differences in an elevated plus-maze: correlation between anxiety and decreased number of GABA and benzodiazepine receptors in mouse cerebral cortex.

In an elevated plus-maze model of anxiety mice treated with the benzodiazepine inverse agonist DMCM (0.5-1.5 mg/kg i.p.) spent significantly less time on the open arms and showed the decreased number of open arm entries. The opposite i.e. increased time spent on the open arms and the higher number of open arm entries was registered after diazepam (1.5 mg/kg). The results are consistent with the results obtained in the other animal tests and support the idea that this procedure is suitable for detecting anxiolytic/anxiogenic effects of benzodiazepine receptor ligands. After testing of 84 mice in an elevated plus-maze substantial differences were detected between the individuals. According to the behavioral response two subgroups of animals with DMCM or diazepam like exploratory activity (as compared to the whole group data) termed as "anxious" or "non-anxious", respectively, were chosen for further binding studies. "Anxious" animals had significantly lower numbers of 3H-flunitrazepam and 3H-muscimol binding sites as compared to "non-anxious" animals in cerebral cortex but not in cerebellum. No differences in the affinity were found between the two groups studied. The results indicate that behavioral anxiety in mice is in correlation with the decreased number of GABA and benzodiazepine receptors in cerebral cortex.

Animals↗