Biomedical subjects
Publications and source records attributed to G Telegdy.
H-Phe-Ile-Tyr-His-Ser-Tyr-Lys-OH inhibited the extinction of active avoidance behavior 3 h and 6 h after administration and facilitated the learning of a T-discrimination task. The peptide antagonized ECS-induced amnesia, if the treatment was performed 1 h before the test session. These results suggest that H-Phe-Ile-Tyr-His-Ser-Tyr-Lys-OH can facilitate learning and memory processes.
Tolerance was induced in mice to the antinociceptive effect of heroin by repeated subcutaneous injections of this narcotic analgesic for 3 days. Pretreatment of mice with daily doses of oxytocin (2-200 micrograms/kg body wt.) resulted in an attenuation of heroin tolerance. A single oxytocin injection prior to the first challenge with heroin was as active in attenuating heroin tolerance as daily treatments with the neuropeptide. A single injection of oxytocin prior to the least heroin challenge also attenuated the expression of tolerance. The neuropeptide failed to modify the acute antinociceptive effect of heroin. It is concluded, therefore, that oxytocin interferes with mechanisms involved in the development and expression of tolerance to heroin.
The effects of oxytocin (OXT) and of dipeptides derived from the C-terminal portion of oxytocin (Z-prolyl-leucine and Z-prolyl-D-leucine) on the development of acute and chronic tolerance to, and dependence on morphine were tested in the mouse. Oxytocin and the dipeptides attenuated the development of acute and chronic tolerance to the antinociceptive effect of morphine and delayed the onset of the naloxone-precipitated withdrawal syndrome. Both oxytocin and Z-prolyl-D-leucine affected drug-induced behavioural responses related to dopamine (DA) in the brain. Thus, oxytocin potentiated the hypermotility induced by a large dose of apomorphine and decreased the supersensitivity of the DA receptors. Small doses of Z-prolyl-D-leucine inhibited the hypomotility elicited by a small dose of apomorphine and potentiated the hyperactivity induced by amphetamine. The data indicate that both oxytocin and Z-prolyl-D-leucine affect tolerance to and dependence on morphine. While oxytocin interacts mainly with postsynaptic DA-ergic neuronal elements, the dipeptide primarily affects DA-ergic neurotransmission at the presynaptic level.
The possible cataleptogenic or anticataleptic effects of cholecystokinin octapeptide sulphate ester (CCK-8-SE) and desulphated CCK-8 (CCK-8-NS) were evaluated in rats after intracerebroventricular (i.c.v.) administration. Neither CCK-8-SE nor CCK-8-NS induced any sign of catalepsy. When haloperidol, in a dose of 1.0 mg/kg (i.p.), and either CCK-8-SE or CCK-8-NS, in doses of 8, 80 or 800 pmol (i.c.v.), were applied at the same time, the peptides significantly decreased the total duration of catalepsy, the 80 pmol dose being the most effective. For the inhibition of catalepsy CCK-8-NS was the more active as it decreased catalepsy scores even 120 min after administration. Both peptides showed only transient effects on the fully developed catalepsy induced by haloperidol.
Male rats with hyperprolactinaemia, induced by adenohypophyseal homografts under the kidney capsule, were injected with haloperidol for 3 days and then subjected to treatment with morphine, administered twice in a day at increasing doses for 12 days. At the first treatment, morphine induced an antinociceptive effect that was more prolonged in homografted rats than in sham-operated controls. The pretreatment with haloperidol did not change the prolongation of morphine-induced antinociception in homografted rats. After 12 days of treatment with morphine, all animals were tested for the development of tolerance to the antinociceptive effect of morphine. Pituitary homografts resulted in an inhibition of the development of tolerance, while this effect was absent in homografted rats pretreated with haloperidol. At the end of the treatment with morphine, the naloxone-precipitated abstinence syndrome was studied. Homografted rats shown an attenuation of the withdrawal syndrome and pretreatment with haloperidol did not change this response. These results suggest an involvement of dopaminergic transmission in prolactin-induced changes in the development of tolerance to morphine, but not in the antinociceptive effect following an acute injection of morphine and in naloxone-precipitated withdrawal syndrome of the rat.
The effects of cholecystokinin octapeptide sulfate ester (CCK-8-SE) and nonsulfated cholecystokinin octapeptide (CCK-8-NS) were tested on feeding by rats in familiar and novel environment. In a familiar environment only intraperitoneally (IP) administered CCK-8-SE (0.8-24 nmole/kg) could inhibit 30 min food intake of 24 hr food-deprived rats, while the same doses of CCK-8-NS IP and both octapeptides (0.8-8000 pmole/rat) intracerebroventricularly (ICV) were totally ineffective. The effects of CCK-8-SE and CCK-8-NS on feeding were also tested in a novel environment, i.e., in an open field. The parameters of exploratory activity and food intake of 24-hr food-deprived rats were recorded simultaneously during a 15-min session. After IP injection, CCK-8-SE dose-dependently depressed the food intake, and the higher doses (8.0 or 24 nmole/kg) also decreased the open field parameters, including number of approaches to food. In the novel environment, 8.0 or 24 nmole/kg IP injected CCK-8-NS also depressed the food intake, whereas the incidence of grooming was enhanced after 8.0 nmole/kg CCK-8-NS. The most effective doses of both octapeptides increased the latency to first bite. For the open field test ICV treatment was also carried out with 8, 80 or 800 pmole doses of the octapeptides, and after 80 pmole CCK-8-SE ICV the food intake was decreased, and after 80 or 800 pmole CCK-8-SE and 800 pmole CCK-8-NS the food intake/approach parameter was depressed.(ABSTRACT TRUNCATED AT 250 WORDS)
The effects of intracerebroventricular administration of synthetic ovine corticotropin-releasing factor (CRF 1-41) have been investigated on the retention of passive avoidance behaviour, and on the dopamine, norepinephrine and serotonin contents of the hypothalamus, mesencephalon, amygdala, septum and striatum, as well as on the plasma corticosterone levels of hypophysectomized and sham-operated rats. Treatment with CRF 1-41 20 min before the first retention test, 24 hours after the learning trial, significantly facilitated the passive avoidance behaviour of hypophysectomized animals in a dose-dependent manner. No effect was found in sham-operated rats. No significant effects of a wide dose range of intracerebroventricularly injected CRF on the monoamine contents of limbic brain structures were detected. However, the same doses of CRF 1-41 increased the plasma corticosterone level in sham-operated rats. The data suggest that the release of CRF from neurons in the limbic system does not alter the monoamine contents in this system, although this peptide facilitates the retention of the passive avoidance behaviour of hypophysectomized rats.
In the present study the role of the central dopaminergic systems in the behavioral action of H-Phe-Ile-Tyr-His-Ser-Tyr-Lys-OH was investigated. The heptapeptide inhibited the extinction of active avoidance behavior if the treatment was performed intracerebroventricularly (icv) in a dose of 1 microgram, but was ineffective in a dose of 0.1 micrograms. If the peptide was injected into the nucleus accumbens septi (NAS) in a dose of 1 microgram, 0.1 micrograms or 0.01 micrograms it inhibited the extinction, but in the latter dose its effect was only a short one. H-Phe-Ile-Tyr-His-Ser-Tyr-Lys-OH in a dose of 1 microgram, 10 micrograms or 20 micrograms (icv) did not influence the turning activity of unilateral substantia nigra (USN)-lesioned animals. These results suggest that the NAS plays an important role in the behavioral action of H-Phe-Ile-Tyr-His-Ser-Tyr-Lys-OH and the heptapeptide has no direct dopamine receptor stimulatory or dopamine-releasing effect in the striatum.
The catalepsy induced by subcutaneously (sc.) and intracerebroventricularly (icv.) administered cholecystokinin octapeptide sulfate ester (CCK-8-SE) and desulfated cholecystokinin octapeptide (CCK-8-NS), and the effects of CCK-8-SE and CCK-8-NS on haloperidol-induced catalepsy, were investigated in mice. The results demonstrate the bimodal effect of CCK octapeptides in a catalepsy test. With sc. administration CCK-8-SE in the doses of 0.4 or 0.8 mumole/kg, but not CCK-8-NS at any dose, induced catalepsy. Furthermore, the catalepsy induced by CCK-8-SE was of short duration. With icv. administration only 40 pmole CCK-8-NS induced significant catalepsy. When 0.2, 0.4 and 0.8 mumole/kg sc. doses of CCK-8-NS or 0.4 pmole icv. dose of CCK-8-SE or CCK-8-NS was given in combination with intraperitoneal (ip.) administration of 1.0 mg/kg haloperidol, the total duration of catalepsy was suppressed. Finally, CCK-8-SE sc. when given in combination with haloperidol ip., exerted a biphasic, synergistic-antagonistic effect on the haloperidol-induced catalepsy.
The effects of graded doses of cholecystokinin octapeptide sulphate (CCK-8-S) and non-sulphated CCK-8 (CCK-8-NS) on the development of tolerance to the hypothermic effect of ethanol were investigated in mice. The animals were pretreated with daily doses of CCK-8-S, CCK-8-NS (0.003-30 nmol/animal s.c.) or vehicle, followed two hours later by the i.p. administration of ethanol (4 g/kg). The same treatments were repeated on three consecutive days. The hypothermic response to ethanol administration gradually diminished, this phenomenon being accepted as indicating the development of tolerance to ethanol. Both CCK-8-S and CCK-8-NS inhibited the development of tolerance. While CCK-8-S resulted in a linear dose-response effect (0.3-30 nmol/animal), CCK-8-NS gave rise to a bell-shaped curve with effective blocking doses of 0.3-3 nmol/animal. There was no difference in colonic temperature between peptide and vehicle-treated, ethanol-naive animals, indicating that the peptide did not change the initial sensitivity to ethanol.
In this study the effects of beta-(Tyr9)MSH-9-18 administered intracerebroventricularly (icv) or into the nucleus accumbens septi (NAS) were investigated on active and passive avoidance behavior of rats. This hypothalamic decapeptide in a dose of 1.0 microgram (icv) inhibited the extinction of active avoidance behavior however, in a dose of 0.1 microgram (icv) it was ineffective. The peptide injected into the NAS in a dose of 0.1 microgram had a same inhibitory effect but in a dose of 0.01 microgram this inhibitory effect was only a short lasting one. In the passive avoidance behavior the peptide in a dose of 1 microgram and 0.1 microgram (icv) significantly increased the passive avoidance latency, but in a dose of 0.01 microgram it was ineffective. If the same doses of the decapeptide were injected into the NAS the peptide was ineffective. These results suggest that the NAS doses not play a role in the memory effect of beta-(Tyr9)MSH9-18 and memory compound does not participate in the NAS mediated effect of the decapeptide on the active avoidance behavior.
In most laboratories CCK-8(s) has been found to be the biologically active form of CCK-8 in the CNS. The role of CCK-8(ns) has scarcely been investigated and is poorly understood. CCK-8(s) exerts a transmitter and/or modulator role in this projection. CCK-8(ns), on the other hand, profoundly affects DA-ergic neurotransmission in the nigrostriatal DA-ergic projection. The octapeptide modulates the turnover and release of DA from this neuron population. DA-mediated behavioral reactions are also modulated by CCK-8(ns). We should emphasize that the biological importance of CCK-8(ns) in the CNS has hitherto generally been neglected. Our results point to the equivalence of CCK-8(s) and CCK-8(ns) in the CNS in most biological tests. In some cases the latter compound is the more potent one. In most of these tests the C-terminal fragment (tetragastrin = CCK-4) also proved to be active. It is most likely that a brain receptor population exists which can bind both forms of CCK-8 and even CCK-4. Nevertheless, the CNS could contain binding sites which bind only CCK-8(s) as a ligand. We have found that an unidentified sulfotransferase of the brain can sulfate CCK-8(ns) and thereby provide a ligand for the special receptors of CCK-8(s). It is likely that CCK modulates the turnover and release of DA, and vice versa. Theoretically, different biochemical mechanisms could exist for interactions between CCK octapeptides and DA. We have focused our investigations on the enzymic sulfation-desulfation processes of both CCK-8 and DA and have devised a hypothetical model for the possible interactions. Both CCK-8(ns) and DA could be sulfated in vivo, this enzymic reaction generally requiring active sulfate (PAPS). These two compounds could compete for the limited pool of PAPS, and thus CCK-8 and DA could mutually regulate their levels in the same cell by influencing one of the metabolic (DA) or synthetic (CCK-8(s)) pathways. CCK-8(s) also might provide the O-sulfate group for DA by enzymic transformation, and, conversely, DA-O-sulfate may sulfate CCK-8(ns) in a similar way. These trans-sulfation processes could also mutually determine the concentrations of DA and CCK-8 co-existing in one cell. Experiments to prove these models are planned.
The dose-related effects of cysteamine treatment on hypothalamic and striatal neurotransmission were investigated. Cysteamine pretreatment with a dose of 150 mg/kg slightly increased the dopamine, and markedly decreased the noradrenaline, content of the hypothalamus in a dose-related manner. The serotonin levels of the hypothalamus and striatum were not affected. Cysteamine pretreatment with a higher dose (300 mg/kg sc) slightly increased the uptake of noradrenaline into hypothalamic slices. The drug did not influence dopamine and serotonin uptake into hypothalamus and striatal slices. These results suggest that cysteamine decreases rather selectively the noradrenaline content of the hypothalamus.
In dose studies, cysteamine pretreatment in a dose of 200 mg/kg or 300 mg/kg (subcutaneously, s.c.) markedly decreased the hypothalamic noradenaline content, but did not influence the dopamine and serotonin contents. In time studies, pretreatment with cysteamine in a dose of 300 mg/kg (s.c.) led to markedly decreased hypothalamic noradrenaline contents 4 hr, 8 hr and 12 hr after treatment. These results suggest that cysteamine treatment selectively decreases the hypothalamic noradrenaline content in dose- and time-related manners.
Endogenous hyperprolactinaemia was induced in intact male rats by transplantation of pituitaries under the kidney capsule. Five days later the utilization of noradrenaline (NA) and dopamine (DA) in individual brain nuclei and changes of plasma prolaction (PRL) were measured. Inhibition of catecholamine synthesis by alpha-methyl-p-tyrosine (alpha-MPT) was used to measure utilization. Hyperprolactinaemia increased the utilization of NA in the locus coeruleus, the cell-body region of the dorsal noradrenergic bundle (DNB), but decreased it in some terminal projections of the same pathway (e.g. the cingulate gyrus). DA utilization was increased by hyperprolactinaemia in the eminentia mediana. In the nigrostriatal DA-ergic projection, hyperprolactinaemia decreased the utilization of DA in the cell-body region (substantia nigra) and increased it in the terminal projection (nucleus caudatus). In the ventral tegmental area (mesolimbic DA-ergic projection), hyperprolactinaemia decreased the utilization of DA. It is concluded that hyperprolactinaemia affects neurotransmission in the hypothalamus and also in specific extrahypothalamic pathways (e.g. DNB, nigrostriatal and mesolimbic DA-ergic projections) and that these changes may correlate with some behavioural effects of the pituitary hormone.
The effects of intraperitoneally (ip.) and intracerebroventricularly (icv.) administered sulfated and nonsulfated cholecystokinin octapeptide (CCK-8-SE and CCK-8-NS) and their N- and C-terminal fragments on the tail-pinch-induced feeding behavior of rats were investigated. After ip. administration, only CCK-8-SE inhibited tail-pinch-induced food intake. After icv. administration, both CCK-8-SE and CCK-8-NS, in doses of 800 pmole/rat, reduced the amount of food eaten. Of the CCK fragments tested icv., the sulfated N-terminal fragments, the middle portion of the CCK-8-sequence (the CCK-3-6 fragment), and the C-terminal tetrapeptide depressed the food intake of rats during tail-pinch, whereas the C-terminal tripeptide significantly increased it. The results suggest that CCK peptides inhibit tail-pinch-induced feeding by separate mechanisms, depending on the route of administration.
The effects of pretreatment with atropine, haloperidol and phenoxybenzamine on somatostatin-induced antiamnesia were investigated. Somatostatin itself blocked electroconvulsive shock (ECS)-induced amnesia. The receptor blockers per se had no influence on the ECS-induced avoidance latency. Atropine and haloperidol did not inhibit somatostatin-induced antiamnesia, whereas phenoxybenzamine blocked it completely. The results suggest that the central noradrenergic system plays an important role in the mediation of the antiamnesic action of somatostatin.
Experiments were performed to examine the acute effects of cholecystokinin octapeptides and fragments on the active and passive avoidance behaviour of rats following peripheral and central administration. Both the sulphated (CCK-8-SE) and non-sulphated cholecystokinin octapeptide (CCK-8-NS) and also the COOH-terminal tetra-, penta-, hexa- and heptapeptides of cholecystokinin octapeptide facilitated the extinction of active avoidance behaviour and retention of passive avoidance behaviour. This latter effect of cholecystokinin octapeptides was reversed by anxiolytic chlordiazepoxide pretreatment, showing that in these test situations cholecystokinin octapeptides are able to modify fear-motivation or arousal of the animals; their effect is at least partly similar to that of the neuroleptic substance haloperidol. Subcutaneous treatment with CCK-8-SE or CCK-8-NS appeared to be 3-10 times more effective than intraperitoneal treatment. Following intracerebroventricular administration, 100-300 times lower doses were needed to cause a behavioural effect similar to that after subcutaneous injection. Microinjection of CCK-8-SE or CCK-8-NS in the fmol dose range into the nucleus accumbens facilitated the extinction of active avoidance behaviour and attenuated the retention of passive avoidance behaviour, while microinjection of these peptides into the central amygdaloid nucleus caused opposite effects on these behavioural tests. It seems that the neuroleptic-like effects of cholecystokinin octapeptides are mediated through the nucleus accumbens, and the opposite action (non neuroleptic-like) through the central amygdaloid nucleus.