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Biomedical subjects

M I Fekete

Publications and source records attributed to M I Fekete.

At least 19 recordsLinked to original sources
PubMed1995

Diurnal alteration in opiate effects on the hypothalamo-pituitary-adrenal axis: changes in the mechanism of action.

Opioid control of the hypothalamo-pituitary-adrenocortical axis has a characteristic circadian rhythm (Kiem, Kanyicska, Stark and Fekete, 1987). To elucidate the mechanisms leading to circadian alterations of opioid control of the hypothalamo-pituitary-adrenocortical axis, and to look for the receptor type at which the p.m. inhibitory action of opioids occurs, we examined the effect of morphine at different doses and the interaction between naloxone and morphine at different times of day in intact male Wistar rats. In the morning: morphine (10 and 30 mg/kg s.c.) significantly increased corticosterone secretion, while 3 mg/kg s.c. had no effect. Naloxone in a dose of 2.5 mg/kg i.p. significantly antagonized the corticosterone-releasing effect of morphine, suggesting that the secretion of corticosterone induced by morphine is mediated via mu-opioid receptors. In the afternoon: basal plasma corticosterone levels were higher than those in the morning, and morphine caused a significant corticosterone increase only at the dose of 30 mg/kg, and had no effect in the dose of 10 mg/kg. Morphine significantly decreased corticosterone levels in the dose of 3 mg/kg. This inhibitory action lasted approximately 3 h after morphine injection and was able to inhibit the circadian evening rise of corticosterone. The effect of morphine and the interaction between naloxone and morphine on prolactin secretion remained unchanged from a.m. to p.m.; naloxone (2.5 mg/kg i.p.) which inhibited the 30 mg/kg morphine-induced corticosterone rise in the morning failed to antagonize the 3 mg/kg morphine-induced decrease of corticosterone secretion in the afternoon. A high dose of naloxone (10 mg/kg i.p.) effectively prevented the 3 mg/kg morphine-induced p.m. inhibition of corticosterone secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Autoradiographic localization and quantitative determination of specific binding sites of anxiolytic homophthalazines (formerly called 2,3-benzodiazepines) in the striato-pallido-nigral system of rats.

Homophthalazines (2,3-benzodiazepin-derivates, such as tofisopam, nerisopam, girisopam) constitute a drug family with strong anxiolytic and antipsychotic potencies. By autoradiography, all of these drugs showed a specific distribution pattern of binding sites exclusively in brain areas which relate to the striato-pallido-nigral system, while no specific label was found in any other brain areas in the rat. Quantitative analyses of the autoradiograms by computerized densitometry, as well as by a receptor binding assay on 32 microdissected brain areas showed very high concentrations of tritiated homophthalazines in the glubus pallidus, caudate nucleus, putamen and the substantia nigra. Relatively high density of binding sites was measured in the nucleus accumbens, the olfactory tubercle, the entopeduncular nucleus and the subthalamic nucleus. Concentrations measured in the cerebral cortical areas, cerebellum or brainstem nuclei did not differ from the background. No significant differences were found between the homophthalazines investigated in terms of the distribution patterns or density of binding sites.

Animals↗
PubMed1993

A novel specific binding site for homophthalazines in the rat brain.

The specific binding sites of a homophthalazine, girisopam, in rat brain have been localized by qualitative and quantitative autoradiography. This substance exerts strong anxiolytic and antipsychotic effects both in rodents and in humans. High labeling was present in all major components of the extrapyramidal system, such as the caudate-putamen, globus pallidus, subthalamic nucleus, substantia nigra, and the extrapyramidal portion of the accumbens nucleus and the olfactory tubercle, while specific labeling was not seen in any other brain areas including the cerebral cortex, thalamus, cerebellum or brainstem areas. This novel distribution of girisopam is consistent with its antipsychotic effect and anxiolytic properties and may provide a morphological basis for further studies to elucidate the mechanisms of action of homophthalazines in the central nervous system.

Animals↗
PubMed1992

A novel specific binding site for anxiolytic homophthalazines in the rat brain.

Radioligand binding studies were performed in order to elucidate the mechanism of action of anxiolytic-neuroleptic homophthalazines. Rat striatal membrane preparations were found to bind 3H-EGIS 6775 [3H-GYKI-52 322, 3H-(1-(4-aminophenyl)-4-methyl-7,8-dimethoxy-5H-homophthalazine)] in a specific and displaceable manner. Several other brain regions tested were devoid of similar binding activity. Saturation analysis revealed that binding affinity was in the 10(-8)-10(-7) M range. Binding was enhanced by Mg2+ ions and, to a smaller extent by Ca2+ ions. The binding principle was sensitive to heat or trypsin treatment. This specific binding site appears, according to competition studies, different from the receptors whose presence in the rat striatum has been reported earlier.

Animals↗
PubMed1991

Prolactin response to morphine in intact and adrenalectomized lactating rats.

To examine the hypothesis that the increased adrenocortical activity during lactation induced the loss of the prolactin (PRL) -releasing effect of morphine, we studied the effect of morphine in adrenalectomized (ADX) and sham-operated primiparous lactating Wistar rats. Animals were adrenalectomized 4 days after delivery. On day 11 of lactation (7 days after ADX), pups were separated from their mother 2 h before morphine or haloperidol injection. Intravenous injection of 5 mg/kg morphine did not change plasma PRL levels in the sham-operated lactating rats, but it resulted in a significant increase of plasma PRL levels in ADX lactating animals, with or without corticosterone replacement. Catalepsy following 10 mg/kg i.v. morphine was also markedly enhanced in ADX lactating animals. The PRL response to 0.5 mg/kg haloperidol was higher in ADX lactating animals than that in the controls. Morphine given 2 h after haloperidol treatment resulted in a further increase of plasma PRL in ADX, but not in the sham-operated lactating animals. These results suggest that adrenal hyperfunction may lead to a loss of sensitivity to morphine during lactation.

Adrenalectomy↗
PubMed1991

Inhibition of suckling-induced prolactin release by dexamethasone.

The effect of dexamethasone (DEX) treatment (400 and 200 micrograms/kg BW 21 and 2 h before suckling stimulus, respectively) on suckling- and domperidone (DOMP)-induced PRL release was investigated in freely moving, primiparous lactating rats. DEX completely blocked suckling-induced plasma PRL release without affecting DOMP-induced release of the hormone suggesting a central action of DEX. The effect was transient because it could not be detected on the second day of testing. The effect of DEX implanted in three different brain areas on suckling- and DOMP-induced PRL release was also tested. Implants surrounding the hypothalamic paraventricular nuclei and dorsal hippocampus failed to affect PRL release induced by suckling stimulus. Surprisingly, DEX suppressed PRL release induced by suckling stimulus when it was implanted into the medial basal hypothalamus. These findings demonstrate that DEX is a potent inhibitor of the suckling-induced PRL release. They also indicate that the site of action of DEX is not at the anterior pituitary gland or the paraventricular nuclei and hippocampus because DEX treatment and DEX implants had no effect on plasma PRL levels induced by DOMP and suckling stimulus, respectively. Our data suggest that the effect of DEX is mediated through a region of the medial basal hypothalamus. The observed transient block in suckling-induced PRL release may be physiologically relevant during stress in lactating mothers for conserving pituitary stores of the hormone needed for milk production or being able to adapt to a rapid change in osmoregulation.

Animals↗
PubMed1991

Adrenergic and dopaminergic regulation of circulating beta-endorphin-like immunoreactivity in hypertension.

The central alpha-2-adrenergic receptor agonist, clonidine (300 micrograms daily) significantly increased the plasma beta-endorphin-like immunoreactivity (beta ELI) in 12 patients with mild to moderate essential hypertension in a randomized, crossover study. A significant linear correlation between the increase in plasma beta ELI and the decrease in blood pressure (both systolic and diastolic) was found after clonidine administration. The role of the reduced central sympathetic tone, induced by alpha-2-adrenoceptor stimulation, in the elevation of circulating beta ELI can be suggested. The plasma beta ELI increased also significantly after the dopaminergic D-2 receptor agonist, bromocryptine treatment, (5 mg, daily) in 13 patients with borderline and mild essential hypertension in a randomized, crossover study. A significant drop in circulating noradrenaline and in arterial blood pressure and a significant linear correlation between the changes of plasma noradrenaline level and blood pressure was found after bromocryptine administration. There was no correlation between the rise in plasma beta ELI and the decrease in blood pressure after bromocryptine. The importance of the central sympathetic activity and not only a direct pituitary dopaminergic agonist effect on the beta-endorphin secretion can be stressed in the effect of bromocryptine on the immunoreactive beta-endorphin level.

Adult↗
PubMed1990

Modulation of rat brain cortical alpha 2-adrenoceptors by treatment with hydrocortisone for 10 days.

The role of glucocorticoids in the modulation of central alpha 2-receptor mechanisms was investigated by in vitro receptor binding studies. [3H]Clonidine and [3H]idazoxan were used as radioligands. The alpha 2-receptor subtypes and guanine nucleotide sensitivity were studied in homologue and heterologue displacement experiments following hydrocortisone treatment (25 mg/kg s.c.) for 10 days. High and low agonist affinity states of the alpha 2-receptor could be identified in 3H-antagonist-agonist and 3H-agonist-antagonist displacement experiments, which may correspond to different regulatory protein-nucleotide associated forms of the receptor. In the presence of 10 microM GTP, the high-affinity binding was depressed. Following hydrocortisone treatment, there was no detectable change either in the affinity or the binding site concentration of clonidine in homologue displacement ("cold saturation") experiments. The affinity of idazoxan, however, was depressed. The effect of GTP was similar to the controls in this experimental arrangement. In contrast, in heterologue binding studies the high-affinity binding site was not demonstrable and the amount of low-affinity binding increased following the hydrocortisone treatment. The high-affinity site reappeared in the presence of GTP. The change in GTP sensitivity suggests that the nucleotide regulatory system may be involved in the action of adrenal steroids on central alpha 2-receptoral mechanisms.

Adrenergic alpha-Antagonists↗
PubMed1990

Loss of the effects of clonidine on the growth hormone release and hypotensive action in long-term castrated rats: the possible role of testosterone on alpha-2-adrenergic mechanisms of clonidine.

The effect of testosterone on the growth hormone (GH)-releasing and hypotensive actions of clonidine was evaluated in vivo using male Wistar rats. Clonidine at various doses and by various routes (5 micrograms/kg, i.c.v.; 15 micrograms/kg, i.v., and 7, 15, 31, 125 and 250 micrograms/kg, i.p.) induced a significant increase in plasma GH levels in rats. Intracerebroventricular (5 micrograms/kg) injection of clonidine significantly decreased blood pressure. The effects of clonidine on the GH release and blood pressure were lost in long-term castrated rats, but were restored by testosterone replacement in the castrates. In addition, the hypotensive response to clonidine in testosterone-replaced castrated rats lasted longer than in the sham-operated rats. The injection of yohimbine (3 mg/kg, i.p.) strongly inhibited the secretion of GH induced by clonidine treatment in sham-operated animals, and its inhibitory action was significantly attenuated in castrates. In long-term castrated rats, basal blood pressure decreased significantly compared with that of sham-operated rats. This was also restored after testosterone administration to castrates. The results of the present study indicate that the alpha 2-adrenergic receptor-mediated effects of clonidine on the GH release and blood pressure might be dependent on the endogenous testosterone secretion.

Animals↗
PubMed1989

Prolactin response to fentanyl in depression.

Ten unmedicated female inpatients with major depression (DSM-III) and 10 healthy volunteer women were given an intravenous injection of 0.1 mg fentanyl at 9:00 AM and 9:00 PM on different days. The prolactin secretory response to this opioid agonist was investigated for 1 h with serial blood sampling. Repeated measures Analysis of Variance yielded a significant effect of fentanyl administration on prolactin secretion (p less than 0.0001), and there were elevated hormone responses in the evening (p less than 0.005). No group difference was seen between healthy volunteers and depressed patients, but four of the depressives showed the most blunted response, and three of these low responders committed suicide within 1 year.

Adult↗
PubMed1989

Opposite effects of chronic cortisol treatment on pre- and postsynaptic actions of clonidine in pithed rats.

1. Both clinical and experimental studies have shown that chronic elevation of plasma cortisol levels are attended by altered adrenergic receptor function. In the present study we examined the effects of chronic cortisol treatment (25 mg kg-1 day-1 for 7 days by minipumps) on the peripheral cardiovascular responses of pithed, adrenal demedullated vagotomized rats. 2. Chronic cortisol treated rats had higher basal diastolic blood pressures after being pithed, suggesting that sympathetic outflow is not required to sustain elevated peripheral resistance in glucocorticoid-induced hypertension. 3. Whereas alpha 1-adrenoreceptor-mediated diastolic blood pressure responses were unaltered, alpha 2-adrenoreceptor-mediated vasopressor responses were potentiated in pithed rats which were chronically treated with cortisol. 4. Elevation of plasma noradrenaline induced by the stimulation of the entire sympathetic outflow of pithed rats was not changed but the clonidine-induced presynaptic alpha 2-adrenoreceptor inhibition of noradrenaline release was attenuated by chronic cortisol treatment. 5. In conclusion, in adrenal demedullated pithed rats the responses mediated by peripheral pre- and postjunctional alpha 2-adrenoreceptors appeared to be affected oppositely after chronic cortisol treatment, suggesting that the pharmacologically homogeneous alpha 2-adrenoreceptor population may be modulated differently by chronic elevation of plasma glucocorticoids.

Adrenergic alpha-Agonists↗
PubMed1989

Possible involvement of the dopaminergic system in the mode of action of the potential antidepressant trazium esilate.

Trazium esilate (EGYT-3615) is structurally an as-triazino isoquinolinium salt which showed considerable activity in pharmacological tests characteristic for antidepressants (antagonism of tetrabenazine, potentiation of yohimbine, behavioral despair). The compound exhibited minimal sedative effect. Some findings suggest that it influences the central dopaminergic system. The drug potentiated actions of amphetamine such as stereotypy and hypermotility. It differentially blocked the hypothermic and the stereotypy inducing action of apomorphine. Trazium esilate also inhibited the cataleptic state provoked by bulbocapnine in mice. In higher dose it decreased the plasma prolactin level in rats. The compound potentiated the effect of norepinephrine on isolated vas deferens of the rat. Trazium esilate is a weak displacer on a1-, a2- and D2-receptors, however, it induced a2-receptor desenzitization after repeated treatment. It had no influence on rat brain cortical noradrenaline and striatal dopamine release evoked by high K+ concentration, but it increased the spontaneous dopamine outflow in rat striatum. The compound also elevated the striatal dopamine and DOPAC levels both after acute and chronic treatment.

Animals↗
PubMed1988

Effect of chronic morphine treatment on the adrenaline biosynthesis in adrenals and brain regions of the rat.

Phenylethanolamine-N-methyltransferase (PNMT) activity and tissue catecholamine content were examined after 13 days morphine treatment. Prolonged morphine treatment did not alter the PNMT activity in brain regions (A1/C1 and A2/C2 cell groups, medial basal hypothalamus, median eminence). However, the enzyme activity and the adrenaline content were increased in the adrenal medulla of male rats. In parallel, morphine treatment induced adrenal hypertrophy. In female or hypophysectomized male animals the chronic morphine treatment had no effect on adrenal weight but evoked the increase of PNMT activity. It is concluded that the morphine-induced increased adrenaline biosynthesis in the adrenal gland is not fully dependent on the intact pituitary-adrenal axis and may be mediated partly by a neural mechanism (increased splanchnic nerve activity) or by a direct effect of morphine.

Adrenal Glands↗
PubMed1988

Effect of adjuvant reserpine treatment on catecholamine metabolism in schizophrenic patients under long-term neuroleptic treatment.

The clinical and biochemical effects of adjuvant reserpine treatment were investigated in 12 chronic schizophrenic patients on long-term neuroleptic medication. The global severity of the symptoms using the Brief Psychiatric Rating Scale did not change significantly in the whole group, however, a moderate decrease in positive symptoms (factors though disturbance, activation and hostile-suspiciousness) was observed for 5 patients. Cerebrospinal fluid (CSF) noradrenaline levels showed a consistent decrease, but other biochemical parameters (CSF dopamine metabolites, platelet MAO and serum dopamine-beta-hydroxylase activities) did not change significantly. The changes of clinical symptoms and biochemical parameters did not show any correlation.

Adjuvants, Pharmaceutic↗
PubMed1988

Diurnal variation in fentanyl-induced hormone responses and side effects.

The prolactin (PRL) and thyrotropin (TSH) secretory response to the opioid agonist fentanyl (0.1 mg IV) was investigated with serial blood sampling in ten healthy women at 9 AM and 9 PM on different days. In five subjects saline control trials were also performed. A repeated-measures analysis of variance yielded a highly significant effect of fentanyl administration both on PRL and TSH secretion. In every case there were elevated hormone responses in the evening, and more drug-related subjective symptoms were reported at this time than before noon. These findings indicate a diurnal variation of opioid responsiveness, with lower sensitivity in the morning.

Adult↗
PubMed1988

Prolactin release induced by opiate agonists, effect of glucocorticoid pretreatment in intact and adrenalectomized rats.

Cortisol administered at a dose of 25 mg/kg 24 h before measurements decreased the prolactin secretion induced by intraventricularly given opioids (dynorphin, beta-endorphin, Met-enkephalin or D-Met-Pro-enkephalinamide). The effect of cortisol was depressed by actinomycin D pretreatment. The cortisol-induced inhibition of the action of morphine was facilitated in adrenalectomized animals; measuring the effects of increasing doses of cortisol a maximal inhibition was obtained at a dose of 5 mg/kg. The opioid-induced corticosterone secretion was not affected 24 h after a single administration of cortisol. The present results show that the cortisol-induced inhibition of opioid-induced prolactin secretion is dependent on protein synthesis and independent of changes in drug metabolism, and of the type of opiate receptor preferentially affected by the opiate agonists employed.

Adrenalectomy↗
PubMed1987

Diurnal variation in prolactin, adrenocorticotropin and corticosterone release induced by opiate agonists in intact and adrenalectomized rats.

Diurnal variations of the effectivity of beta-endorphin (beta-End), dynorphin (DYN), Met-enkephalin (Met-Enk), D-Met2-Pro5-enkephalinamide (D-Met-Pro-Enk) and morphine to induce prolactin (PRL) and adrenocorticotropin (ACTH)/corticosterone (CS) release in intact and adrenalectomized rats have been examined. The response to morphine (10 mg/kg s.c.), Met-Enk (200 micrograms/rat i.c.v.) and D-Met-Pro-Enk (0.5 microgram/rat i.c.v.) did not change with different times of the day, while that to beta-End (0.5 microgram/rat i.c.v.), DYN (1 microgram/rat i.c.v.) and U50-488H, a selective kappa agonist (10 mg/kg s.c.), showed a circadian rhythm in stimulating PRL release, with a higher increase in the afternoon (16.00-17.00 h) than in the morning (08.00-09.00 h). In adrenalectomized rats the loss of this circadian rhythm was shown. The CS release evoked by morphine, D-Met-Pro-Enk, Met-Enk and DYN was demonstrable only in the morning when the basal CS level was significantly lower than in the afternoon. The afternoon release of ACTH by morphine was higher than in the morning in adrenalectomized rats. beta-End and U50-488H were equally active in the morning and in the afternoon in increasing CS secretion. The present results suggest that the diurnal rhythm in the response of CS and PRL release to opioids is in relation with the glucocorticoid secretion.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗