G. Telegdy

Decreased serotonin turnover in the dorsal hippocampus of rat brain shortly after adrenalectomy : Selective normalization after corticosterone substitution

Pargyline-induced accumulation of serotonin (5-HT) was used as an index of 5-HT turnover rate in the dorsal hippocampus. One hour after bilateral removal of the adrenals, 5-HT turnover was significantly reduced when compared to that of the sham-operated controls. A low dose of corticosterone given immediately after adrenalectomy restored the 5-HT response, while the same dose of dexamethasone was ineffective. Pretreatment with dexamethasone blocked the 5-HT response to corticosterone in the acutely adrenalectomized rat. The specificity of the 5-HT response in the hippocampus corresponds to the properties of the glucocorticoid receptor system in rat hippocampal neurons.

Inhibition of seizures induced by picrotoxin and electroshock by cholecystokinin octapeptides and their fragments in rats after intracerebroventricular administration

The anticonvulsive activity of cholecystokinin octapeptide sulphate ester (CCK-8-SE), non-sulphated cholecystokinin octapeptide (CCK-8-NS) and three different N- and C-terminal fragments were investigated against seizures induced by picrotoxin and electroshock in rats after intracerebroventricular administration. Doses of 0.8 and 80 pmol of CCK-8-SE and CCK-8-NS significantly enhanced the latency of seizures induced by picrotoxin and shortened the duration of the clonic phase of the seizures induced by electroshock. Only CCK-8-SE shortened the recovery time and only 0.8 pmol of CCK-8-SE could shorten the duration of the tonic phase of convulsions induced by electroshock. Doses of the octapeptides of 8000 pmol were ineffective, with the exception of CCK-8-NS in the picrotoxin test. Of the fragments tested, the C-terminal tetrapeptide, CCK-5-8, enhanced the latency of seizures induced by picrotoxin in a dose of 0.8 pmol, and had a dose-dependent biphasic effect on the duration of the clonic phase of seizures induced by electroshock. Intracerebroventricular administration of diazepam enhanced only the latency of tremor and clonic seizures induced with picrotoxin in a dose of 40 nmol. Twelve nmole of diazepam shortened the clonic phase of convulsions induced by electroshock. The peptides tested were much more active than diazepam, and their effective doses were comparable to the amounts of cholecystokinin octapeptide found in brain structures.

On the mode of action of an oxytocin derivative (Z-Pro-D-Leu) on morphine-dependence in mice.

The dipeptide Z-Pro-D-Leu appears to attenuate the development of physical dependence on morphine in mice, as measured by the stereotyped jumping response after naloxone challenge. Injected subcutaneously, 50 μg Z-Pro-D-Leu was required to produce this effect, while a hundred times smaller amount injected into the cerebral ventricles was sufficient to produce the same effect. In morphine-naive mice, 50 μg of the dipeptide did not change the dose-response curve for morphine, measured by the antinociceptive effect of the opiate on a hot-plate test. Although Z-Pro-D-Leu per se did not induce antinociception in the doses tested (50, 100 and 200 μg), the larger doses potentiated the effect of morphine. As a possible mode of the central action, the effect of the dipeptide on the levels of noradrenaline (NA) dopamine (DA) and serotonin (5-HT) in the brain has been measured. Two hours after a single acute injection of Z-Pro-D-Leu (50 μg), the level of NA in the lower brain stem (pons + medulla) was significantly reduced. Daily administration of the dipeptide for 3 days resulted in decreases in the levels of NA and DA in the brain stem. In morphine-dependent mice, the 5-HT and DA levels in the brain stem were reduced 30 min after naloxone challenge. The data support the idea that Z-Pro-D-Leu inhibits the development of morphine-dependence by a mechanism of action in the central nervous system. This effect seems to be distinct from an antagonism between the dipeptide and morphine at the receptor level. It is likey, on the other hand, that the effect is related to an influence of the dipeptide on monoaminergic neurotransmission in the brain stem.

Hereditary diabetes insipidus in rats: Altered cerebral indolamine and catecholamine metabolism

Compared to heterozygous Brattleboro animals, homozygous (diabetes insipidus) rats exhibited higher steady-state levels of serotonin in the mesencephalon, septum and striatum. These differences disappeared upon the administration of pargyline, suggesting accumulation of serotonin. The norepinephrine level was higher in the mesencephalon, while the disappearance rate (alpha-met hyl-p-tyrosine) was accelerated in the septum and decreased in the hypothalamus. The lower striatal dopamine level was associated with a decreased disappearance rate. The data suggest that the altered monoamine metabolism might be associated with the known endocrine and behavioral disturbances of the homozygous rats.

Effect of oxytocin on acute enkephalin tolerance in mice

Intracerebroventricular (i.c.v.) administration of a test dose of 0.5 microgram D-Met2-Pro5-enkephalinamide (ENK) resulted in analgesia. Acute tolerance developed if a tolerance-inducing high dose of 5 micrograms ENK was administered i.c.v. prior to the test dose. Tolerance appeared as a reduction of the analgesic effect of the test dose. Subcutaneous (s.c.) injection of oxytocin (OXT) inhibited the development of tolerance. It is suggested that OXT is able to modify the development of tolerance to enkephalins, which are ligands of delta-opiate rather than mu-opiate receptors.

The effect of somatostatin, its fragments and an analog on electroconvulsive shock-induced amnesia in rats

In the present study the effects of intracerebroventricularly [icv] administered somatostatin [linear and cyclic], somatostatin3-6, somatostatin7-10 and des AA1,2,4,5,12,13 [D-Trp8] somatostatin [ODT8-SS] were investigated on electroconvulsive shock [ECS]-induced retrograde amnesia in rats. The ECS significantly decreased the foot shock-induced avoidance latency, and thus caused retrograde amnesia. Somatostatin [linear and cyclic] in a dose of 0.6 nM had no action on the ECS-induced retrograde amnesia, while in doses of 3 nM and [cyclic only] 6 nM it significantly prevented it. Somatostatin3-6, somatostatin7-10 and ODT8-SS in doses of 0.6, 3 and 6 nM had no effect on the ECS-induced amnesia. These results indicate that the whole sequence of the original somatostatin molecule is needed to block the ECS-caused retrograde amnesia.

Neuropharmacological actions of the superactive agonist analog D-Trp-6-LH-RH after peripheral injection into mice

The neuropharmacological actions of the agonist analog D-Trp-6-LH-RH were investigated in several tests after subcutaneous administrations to male mice. The doses applied were in the range 1-1000 micrograms/kg. D-Trp-6-LH-RH doses of 10 micrograms/kg and higher induced significant analgesic effects in the hot-plate and tail-flick tests, and decreased the open-field parameters (ambulation, rearing, grooming). The 100 and 1000 micrograms/kg doses increased the latencies of picrotoxin-induced seizures, significantly inhibited apomorphine-induced cage climbing and also exerted a cataleptogenic effect. The results indicate that this agonist analog of LH-RH has an inhibitory effect on the central nervous system, and the mechanism of its action may involve dopaminergic transmission and/or endogenous opiates.

Effects of β-/Tyr9/melanotropin-/9–18/ decapeptide on catecholamine disappearance and serotonin accumulation in discrete brain regions of rats

Abstract The effects of intracerebroventricular administration of a 1.0 ug dose of Tyr-Phe-Arg-Trp-Gly-Ser-Pro-Pro-Lys-Asp /DC-11-18/ on the α-methyl-p-tyrosine /α-MPT/-induced catecholamine disappearance and the pargyline-induced serotonin accumulation in the hypothalmus, mesencephalon, amygdala, septum, cortex and striatum were studied. The dopamine disappearance was facilitated in the septum, while it was impeded in the striatum. The norepinephrine disappearance was lowered in the amygdala. The serotonin accumulation was inhibited in the hypothalamus and enhanced in the septum. The data indicate that this decapeptide is able to modify the activities of catecholamines and serotonin in different brain regions.

In vitro effects of a synthetic enkephalin analogue (D-Met2,Pro5)-enkephalinamide on the hypothalamus-pituitary — Testis function in rats

The effects of (D-Met2,Pro5)-enkephalinamide, a synthetic analogue of the natural opioid pentapeptides, were investigated on the hypothalamus-pituitary-testis axis using in vitro tissue and isolated cell incubation systems. (D-Met2,Pro5)-enkephalinamide in a concentration range 10(-7)--10(-5) M did not alter the testosterone production and the troph-hormone sensitivity of the isolated Leydig cells, or the gonadotroph hormone release and the luteinizing-hormone--releasing hormone (LH-RH) sensitivity of the isolated anterior pituitary cells. However 10(-5)--10(-5) M synthetic enkephalin analogue induced a dose-dependent inhibition of LH-RH content and release of the mediobasal hypothalamus, which was prevented by equimolar concentrations of naloxone.

Inhibition of haloperidol-induced catalepsy by cholecystokinin octapeptides after central administration to rats

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.