Comparative studies of somatostatin-14 and some of its fragments on passive avoidance behavior, open field activity and on barrel rotation phenomenon in rats

Behavioral effects of somatostatin-14, and some of its fragments [somatostatin(3–8), somatostatin(9–14), somatostatin(7–10)] after intracerebroventricular (ICV) administration have been investigated in male rats. In a passive avoidance learning test, somatostatin-14 (0.6 nM) given immediately after the learning session increased the avoidance latency at 24 hr after the injection, when compared to a somatostatin(3–8) (0.6 nM)-treated group. However, compared to a saline-treated group, the peptides did not significantly influence the avoidance latency. Somatostatin-14 administered in higher dose (6.0 nM) decreased the avoidance latency compared to the saline-treated group, while its fragments did not influence it. In an open field behavioral test, immediately after the 24-hr passive avoidance test, 6 nM of somatostatin-14 decreased the rearing activity, while the fragments did not influence this behavior. Somatostatin-14 produced barrel rotation in a dose-related manner, but after the injection of a high dose of the peptide (12 nM) all of the animals died in cardiorespiratory failure (apnea, pulmonary oedema). The fragments did not produce barrel rotation.     

Preventive effect of cholecystokinin octapeptide on experimental amnesia in rats

The effect of intracerebroventricular (ICV) administration of cholecystokinin octapeptide (CCK-8) on electroconvulsive shock (ECS)-induced amnesia in passive avoidance response was studied in rats. In normal rats, CCK-8 in doses from 1 ng to 1 microgram had no effect on the response when injected before the training trials, immediately after foot shock or before the first retention test. However, proglumide, a CCK-8 receptor blocker, induced marked amnesia when injected in doses from 0.1 to 10 micrograms before the training trials and in doses of 1 and 10 micrograms before the first retention test, though not subsequent to foot shock. ECS given immediately after the foot shock caused amnesia in the 24 hr and 48 hr retention tests, which could have been prevented by CCK-8 injected in doses of 10 ng to 1 microgram prior to the training trials, of 10 ng to 1 microgram following ECS and of 0.1 and 1 microgram before the first retention test. In addition, the effects of CCK-8 and proglumide became pronounced following chronic ICV infusion, using an osmotic minipump, for 7 days at a dose of 1 ng/day and 10 ng/day, respectively. The amnesia induced by proglumide was not affected by arginine vasopressin (AVP), while AVP in doses of 10 ng and 100 ng given 30 min before the training trials prevented ECS-induced amnesia. The antiamnesic effect of AVP was abolished by simultaneous administration of proglumide. On the other hand, AVP-antiserum produced marked amnesia which could be antagonized by CCK-8. However, the antiamnesic effect of CCK-8 was not suppressed by AVP-antiserum.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pre-electroconvulsive shock administration of calcium channel blockers reduces retrograde amnesia induced by ECS

Effect of pre-electroconvulsive shock (ECS) administration of calcium channel blockers (CCBs) like verapamil, diltiazem, nifedipine, nimodipine, flunarizine and cinnarizine on retrograde amnesia induced by ECS was examined using passive avoidance paradigm in rats. The groups (Gr 1-7) of adult, male Wistar rats received true ECS with CCBs (5mg/kg; i.p) or vehicle (10 ml/kg; ip) and other groups (Gr 8-14) received sham ECS with CCBs (5mg/kg; i.p) or vehicle (10 ml/kg; i.p). The anti-amnestic activity of CCBs were evaluated using the passive avoidance paradigm in rats. Results showed that, the baseline latencies for all the groups did not differ significantly. Rats receiving true ECS produced significantly lower latencies. There was increase in the post ECS step through latencies of the rats administered CCBs before ECS. Therefore, pre-ECS administration of calcium channel blockers might reduce retrograde amnesia produced by ECS without altering seizure duration.     

Dopamine and norepinephrine stimulate somatostatin release by median eminence fragments invitro

The effect of catecholamines on somatostatin release by median eminence (ME) fragments was evaluated using an $\text{in}$$\text{vitro}$ incubation system. Adult male rats were used as tissue donors. Somatostatin release was readily detected during short-term incubations (10 and 30 minutes). Dopamine (DA) significantly stimulated somatostatin release during a 30 minute incubation period at the two doses tested (0.6 and 6 μM). Under similar conditions, norepinephrine (NE) stimulated somatostatin release only at the 6 μM dose. Using a shorter incubation period (10 min) and a 6 μM dose, only DA stimulated somatostatin release. The effects of DA and NE were specifically blocked by the $\text{in}$$\text{vitro}$ addition of pimozide or phentolamine, respectively, suggesting that dopaminergic and noradrenergic receptors may be present in the somatostatinergic terminals of the ME. The results indicate that both DA and NE may be involved in the regulation of somatostatin secretion.     

The effect of beta-(Tyr9)melanotropin-(9-18) on active avoidance behavior, electroconvulsive shock-induced amnesia and T-discrimination learning of rats

The effect of beta-(Tyr9)melanotropin-(9-18) was investigated on active avoidance behavior, electroconvulsive shock (ECS)-induced amnesia and T-discrimination learning in rats. The decapeptide inhibited the extinction of active avoidance behavior. It was also able to block ECS-induced amnesia if the treatment was performed immediately, or 4 hr or 20 hr after the ECS. In the T-discrimination paradigm the peptide facilitated spatial discrimination learning and reversal learning. These results suggest that beta-(Tyr9)melanotropin-(9-18) can influence learning and memory processes in different behavioral tests.     

A study of the relationships between carbon tetrachloride-induced lipid peroxidation and liver damage in rats pretreated with vitamin E

The relationships between the peroxidation of musomal lipids and the early liver damage have been investigated in rats pretreated with progressively higher doses of α-tocopherol (vit. E) and intoxicated with various amounts of carbon tetrachloride.Pretreatment of rats with vit. E at 25 $\text{mg}\text{100g}$ body wt. has minor effects on both the peroxidation of musomal lipids and the liver triglyceride accumulation in rats poisoned with CC1₄ at 250 $\text{μl}\text{100g}$ body wt. However, a decrease of the peroxidative reaction and of the liver steatosis occurs when the rats are pretreated with progressively higher doses of vit.E. A close correlation exists between the two phenomena, when the intoxication is accomplished with CC1₄ at 250 $\text{μ1}\text{100 g}$ body wt. Also, the musomal concentration of α-tocopherol is strictly correlated to both the decrease of musomal lipoperoxidation and the decrease of liver triglyceride accumulation. The CCl₄-induced impairment of musomal glucose-6-phosphatase and the incorporation of ¹⁴C from ¹⁴CC1₄ into liver musomal lipids are not affected by vit. E pretreatment.The extent of musomal lipoperoxidation is not correlated to the liver triglyceride accumulation when vit. E-pretreated rats are given CC1₄ at 25 or 2.5 $\text{μ1}\text{100 g}$ body wt. However, a correlation between lipoperoxidation and liver steatosis occurs when non-pretreated rats are challenged with the three different doses of the halogenated hydrocarbon.     

Effects of intracerebroventricular administration of neurotensin,substance P and calcitonin on gastrointestinal motility in normal and vagotomized rats

The effects of intracerebroventricular (ICV) vs. intravenous (IV) injection of neurotensin, substance P and calcitonin on intestinal myoelectrical activity were examined in fed rats. ICV administered neurotensin and calcitonin restored the ‘fasted’ pattern of intestinal activity, i.e. the migrating myoelectric complex (MMC) at a dose as low as 12 and 0.2 pmol, respectively, whereas substance P only reduced significantly ($\text{P < 0.01}$) the duration of the postprandial pattern when injected ICV (48 pmol).Administered systemically at doses 100 times higher than the smallest active doses by the ICV route, calcitonin induced a fasted pattern, while neurotensin and substance P did not modify the fed pattern.The effects of ICV administration of neurotensin and calcitonin were abolished after vagotomy but the shortening effect of substance P on the duration of the postprandial pattern was still present.It is concluded that these three neuropeptides act centrally to control the pattern of intestinal motility in fed rats by shortening the ‘fed’ pattern for substance P and by restoring the MMC pattern for calcitonin and neurotensin, this last effect being mediated by the vagus.     

Effect of sex hormones on the growth and multiplication of tetrathyridia of Mesocestoides corti (Cestoda: Cyclophyllidea) in mice

The number of tetrathyridia in the peritoneal cavities of mice increases exponentially with time. Thirty days post infection more larvae are in the cavities than in the livers. After that the increase of intraperitoneal populations continues, whereas the number of tetrathyridia in the livers remains more or less constant.Exogenous testosterone propionate, 10 $\text{μg}\text{g}$, twice a week, for 5 weeks, increases significantly the total volumes of tetrathyridial populations in the peritoneal cavities, whereas oestradiol benzoate, 5 $\text{μg}\text{g}$ or 10 $\text{μg}\text{g}$, also for 5 weeks, accelerates the rate of growth and multiplication of coelomic tetrathyridia to a much lesser extent, but increases significantly the infection of the livers.     

Evidence for central neuropeptidergic control of rumination in sheep

Effects of intracerebroventricular (ICV) vs. intravenous (IV) administration of tetragastrin, pentagastrin, CCK₈ and gastrin 17 on rumination were investigated in conscious sheep. Administered at 26 pmoles/kg ICV both tetra and pentagastrin induced a premature short (15–27 min) period of rumination only $\text{24±7}$ and $\text{23±9}$ min after food distribution in place of $\text{112±44}$ min in controls. Similar but less pronounced effects were observed for ICV administration of an equimolar dose of gastrin 17 whereas CCK₈ did not promote an early peciod of rumination despite its anorectic effects. Administered intravenously tetra and pentagastrin but not gastrin 17 caused early rumination only for 10 times higher doses. It is concluded that gastrin 17 and its C-terminal tetrapeptide may play a physiological role in the central control of rumination in sheep.     

Effects of 6-thioguanine-containing RNA on in vitro protein synthesis

6-Thioguanine was administered to rats 12 hr after partial hepatectomy at a dose of 40 mg/kg of body weight; 6 hr later, polyadenylic acid-containing RNA was isolated and was used to measure initiation of protein synthesis $\text{in vitro}$ in a wheat germ system. $\text{In vitro}$ initiation was found to be 2.3-fold greater when 6-thioguanine-containing RNA was employed, than when polyadenylic acid-containing RNA isolated from untreated animals was used. The homopolymer, poly(TG), did not promote peptide synthesis in the wheat germ $\text{in vitro}$ system employed.     

Combined pharmacokinetic and pharmacodynamic studies on alprenolol and 4-hydroxy-alprenolol in man

The effects of orally (100 mg) and intravenously (10 mg) administered alprenolol on the heart rate of 4 exercising healthy volunteers were correlated with the plasma concentrations of alprenolol and its metabolite 4-OH-alprenolol. The metabolite was recovered in plasma after both routes of alprenolol administration and was eliminated from the body at the same rate as alprenolol ($\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}\text{? 3}\text{h}$). Infusion of 4-OH-alprenolol (10 mg) significantly reduced the heart rate during exercise. The results indicate that orally administered alprenolol forms the active metabolite 4-OH-alprenolol in sufficiently large amounts to significantly influence the effect of the parent drug. The “first pass” elimination of the oral alprenolol dose was about 90 per cent.     

Effect of ethanol upon isoproterentol stimulation of growth and secretion in the mouse parotid gland

Isoproterenol (0.3 mmole/kg body wt.), when injected into the mouse intraperitoneally, increases the weight by 35% and stimulates DNA synthesis 30-fold in the parotid gland. The induction of both hypertrophy and hyperplasia is completely inhibited by ethanol at a dose of 200 mmole/kg body wt. but is almost unaffected by 60 mmole/kg. The full inhibiton of both growth parameters is observed when ethanol is administered up to 5 hr after isoproterenol. Partial inhibition is observed when ethanol is given as long as 15 hr after isoproterenol. It contrast ethanol did not alter the secretion of α-amylase in response to isoproterenol. Ethanol had no effect upon the rise in cyclic GMP level caused by isoproterenol but augmented the rise in cyclic GMP In agreement with these $\text{in}$$\text{vivo}$ observations, low concentrations of ethanol activated adenylate cyclase $\text{in}$$\text{vitro}$, however guanylate cyclase activity was quite strongly inhibited. Although high levels of ethanol (300 mmole/kg) inhibited the induction of both ornithine decarboxylase and S-adenosylmethionine decarboxylase little inhibition was seen at 200 mmole/kg suggesting that the interference with polyamine metabolism is not the mechanism of the ethanol effect upon isoproterenol-induced parotid growth.     

Lack of opiate receptor involvement in centrally induced calcitonin analgesia.

Calcitonin (CT) injected into the brain ventricles (ICV) of conscious rabbits induced an analgesia not reversable by naloxone which could be repeatedly elicited (for 5 days), while tolerance to morphine developed. CT and morphine synergized $\text{in vivo}$ when administered ICV in combination. CT did not alter electrically-induced contractions of guinea-pig myenteric plexus-longitudinal muscle and no displace of ³H-dihydromorphine by CT was observed in brain opiate receptor preparations. We have concluded that the mechanism of centrally induced CT analgesia may be opiate-independent.     

Electroconvulsive shock and brain muscarinic receptors: relationship to anterograde amnesia

Rats were administered one electroconvulsive shock daily for 7 days (ECS X 7) and were killed 24 hours after the last treatment. Muscarinic cholinergic receptor number, as determined by [3H] quinuclidinyl benzilate [( 3H]QNB) binding, was significantly reduced in the cerebral cortex. A parallel group of rats was trained on a passive avoidance task 24 hours following the last ECS and tested for retention of the original avoidance response 24 hours later; these animals exhibited a profound amnesia. Animals tested 1 hour following training were not amnestic, indicating that learning was unimpaired. Animals trained 7 days following ECS X 7 were not amnestic and [3H] QNB binding changes were not demonstrable at this time. A single ECS which does not significantly affect cortical [3H] QNB binding, did not induce amnesia in rats trained 24 hours after the treatment and tested 24 hours later. The parallel, cumulative nature of ECS-induced muscarinic receptor down-regulation and ECS-induced anterograde amnesia suggests a possible causative relationship.     

Hemolytically active components from P. parvum and G. breve toxins

Hemolytically active fractions were isolated from the toxins produced by the red-tide dinoflagellate $\text{Gymnodinium breve}$ (GBTX) and the chrysomonad $\text{Prymnesium parvum}$ (PPTX). High pressure liquid chromatography through bonded phase (ODS) silica columns using a gradient of methanol in chloroform yielded 6 major fractions from GBTX, 3 of which were hemolytic (HD₅₀=0.3?0.56 μg·ml^?1). None were ichthyotoxic. Of the 6 fractions obtained from PPTX, 4 were hemolytic (HD₅₀=0.013?2.8 μg·ml^?1) but only one (fraction 6) was ichthyotoxic. This fraction was ～ 2000 times more hemolytic than the crude PPTX (HD₅₀=33.2 μg·ml^?1). Analysis of their UV spectra indicates that the fractions within each group are closely related.     

Passive avoidance behavior: Opposite effects of oxytocin analogs with agonist and antagonist properties

Deamino-6-carba-oxytoxin (dC6O), a potent oxytocin analog considered to be resistant to some of the physiologically significant enzymic systems, and $\text{N-α-}\text{acetyl}\text{-[2-O-}\text{methyltyrosine}\text{]}\text{oxytocin}$ (AMTO), an analog acting as a competitive inhibitor of oxytocin on the rat uterus, were studied in rats trained in a passive avoidance task.Subcutanaeous administartion of dC6O (5–50 gmg·kg^?1) during different phases of the passive avoidance learning paradigm attenuated avoidance latencies; the results indicated that the drug induced state-dependent learning.AMTO (5–20 gmg·kg^?1) enhanced avoidance latencies when administered subcutaneously before training trials and/or before retention test trials. This effect occured in both males and females. The analogs did not influence exploratory behavior in open field.The results suggest that oxytoxin, in contrast to vasopressin, may impair memory processes. However, both analogs failed to influence the passive avoidance response when administered after training. This finding indicates that dC6O and AMTO did not influence the mechanism of memory consolidation whereas vasopressin and oxytoxin had a marked effect.     

l-Acetylmethadol (LAM) treatment of opiate dependence: plasma and urine levels of two pharmacologically active metabolites

The metabolic conversion of α-$\text{l}$-acetylmethadol (LAM) to α-$\text{l}$-noracetylmethadol (NAM) and α-$\text{l}$-dinoracetylmethanol (NNAM), has been studied in three opiate addicts being maintained on 100 mg of LAM three times weekly. Plasma levels of NAM and NNAM were established shortly after the initial dose of LAM. The plasma level of NNAM was substantially higher following repeated dosing than following the initial dose. The combined daily urinary excretion of LAM, NAM and NNAM was 6–8 times greater after repeated dosing than after the initial dose. Since NAM and NNAM, which are formed by the sequential N-demethylation of LAM are both considerably more active morphine-like agonists than is LAM itself, it is likely that the pharmacological effects of LAM are due to NAe NAM and NNAM. Variations in the rates of formation and elimination of NAM and NNAM may partially explain the variability in response seen in LAM maintenance therapy.     

Stereoselectivity in the metabolism of drobuline (d1-1-(isopropylamino) -4,4-diphenyl-2-butanol) a new anti-arrhythmic agent

The metabolism of drobuline has been examined in the dog, rabbit, rat, guinea pig and hamster. In the dog, unlike the other species, glucuronide conjugation is the major route of metabolism. The structure of the conjugate has been established as an O-glucuronide by isolation using HPLC following by field desorption mass spectral analysis. When the separate $\text{d}$- and $\text{l}$-isomers of drobuline were administered to a series of dogs the $\text{l}$-isomer reached plasma levels approximately three time higher than those of the $\text{d}$-isomer. Deuterium labeled drobuline was synthesized and resolved by multiple crystallizations of the malate salts. Racemic mixtures containing $\text{d}$₆-$\text{d}$ and $\text{h}$₆-$\text{l}$ drobuline and $\text{d}$₆-$\text{l}$ and $\text{h}$₆-$\text{d}$ drobuline were prepared and analyzed by GC-MS as the pentafluoropropionate derivatives. When either racemic mixture was administered to dogs (10 mg/kg, p.o.) the plasma levels of the $\text{l}$-isomer were found to be approximately three times those of the $\text{d}$-isomer. Using these deuterium labeled mixtures the disposition of the two isomers has been examined in the isolated perfused dog liver, in hepatocytes and isolated microsomes. The results indicate that the difference in plasma levels of the $\text{d}$- and $\text{l}$-isomers is not dependent upon stereospecific absorption or excretion but rather it is caused by metabolism of the $\text{d}$-isomer at a faster rate than that of the $\text{l}$-isomer.