Taming Effects Research Articles

Adrenoceptor α2A signalling countervails the taming effects of synchronous cyclic nucleotide-elevation on thrombin-induced human platelet activation and aggregation

The healthy vascular endothelium constantly releases autacoids which cause an increase of intracellular cyclic nucleotides to tame platelets from inappropriate activation. Elevating cGMP and cAMP, in line with previous reports, cooperated in the inhibition of isolated human platelet intracellular calcium-mobilization, dense granules secretion, and aggregation provoked by thrombin. Further, platelet alpha granules secretion and, most relevant, integrin αIIaβ3 activation in response to thrombin are shown to be prominently affected by the combined elevation of cGMP and cAMP. Since stress-related sympathetic nervous activity is associated with an increase in thrombotic events, we investigated the impact of epinephrine in this setting. We found that the assessed signalling events and functional consequences were to various extents restored by epinephrine, resulting in full and sustained aggregation of isolated platelets. The restoring effects of epinephrine were abolished by either interfering with intracellular calcium-elevation or with PI3-K signalling. Finally, we show that in our experimental setting epinephrine likewise reconstitutes platelet aggregation in heparinized whole blood, which may indicate that this mechanism could also apply in vivo.

Taming effects with monadic typing

The familiar Hindley-Milner type system of the ML language family is extended with monad annotations to account for possible side effects of expression evaluation. This also allows effects to be effectively encapsulated by lexical scopes Γ with enforcement provided by type checking. A type-and-effects analysis supports type inference. Type soundness and completeness theorems establish the coherence of monadic type inference with the reference semantics of a small ML-style language.

Pharmacological Characterization of the Novel Anxiolytic β-Carboline Abecarnil in Rodents and Primates

beta-Carboline abecarnil was behaviorally and biochemically characterized as a new anxiolytic agent in rodents and primates in comparison with the benzodiazepine (BZ) anxiolytics. Oral treatment with abecarnil (0.5-10 mg/kg) showed a potent anticonflict activity in the water-lick test in rats. The minimal effective dose was lower than those of BZ anxiolytics, such as etizolam, diazepam, clotiazepam and tofisopam. Abecarnil also showed taming effects to suppress fighting and aggressive behaviors in mice and monkeys with little sedative and ataxic effects, in contrast to the BZ anxiolytics producing marked sedative and ataxic effects. Furthermore, abecarnil suppressed both the sedative and ataxic effects induced by diazepam. Abecarnil bound to rat cerebellar BZ1 receptors (Ki = 0.24 nM) with higher affinity than to rat spinal cord BZ2 receptors (Ki = 1.3 nM), whereas BZ derivatives bound to both the receptors with a low and equal affinity. GABA-ratios of abecarnil were 1.9 for the BZ1 receptors and 2.8 for the BZ2 receptors, and they were smaller than those of diazepam and flunitrazepam. Thus, in contrast to the BZ derivatives, abecarnil may act as a selective partial agonist at central BZ1 receptors, resulting in its potent anticonflict and taming effects with little sedative and ataxic effects.

Functional stereotactic neurosurgery for psychiatric disorders: an experience in Belgium and The Netherlands.

This chapter addresses the difficult and often contentious subject of psychosurgery which has been defined as “a neurosurgical intervention to sever fibres connecting one part of the brain with another, or to remove or destroy brain tissue with the intent of modifying or altering severe disturbance of behaviour, thought content or mood”. The authors have traced the historical development of psychosurgery and brought out the fact that it is those patients suffering from anxiety, depression and obsessive compulsive illness who throughout this history of psychosurgery have benefited most. They also refer to the “taming effects” of the old leucotomy (obsolete since the mid-1950’s) which had proved useful in the management of certain behaviour disorders of schizophrenia. This latter effect often left patients with severe blunting of personality, but the operation, judged in the context of the alternatives available at the time was better than nothing for this unfortunate group. It allowed 20% to return to life in the community. However, as the authors emphasize this became history with the discovery in the 1950’s of the major tranquilizers and effective pharmacological agents for the treatment of depression and anxiety which has transformed psychiatry. Nonetheless, some patients remain resistant to the newer treatments and it is this which keeps an interest in psychosurgery alive. The introduction of stereo-tactic techniques, increasingly accurate imaging techniques for target identification and precise lesions have all contributed to a very low morbidity of modern procedures. It is now well recognised that Psychiatrists and Neurosurgeons must work in close partnership to ensure the cases are appropriately selected.

P-22 - Taming effects of abecarnil, the benzodiazepine BZ-1 receptor partial agonist, in rodent and primate.

P-22 - Taming effects of abecarnil, the benzodiazepine BZ-1 receptor partial agonist, in rodent and primate.

Behavioral effects of suriclone: A new antianxiety drug of Cyclopyrrolone derivative

The effects of suriclone were investigated in various behavioral tests and compared with those of diazepam (DZP) and loraze-pam (LZP). Suriclone, upon single administration, was as potent as LZP, but less potent than DZP in increasing the lever press response in the punished period of a conflict schedule established by combining foot shock and food reward in rats, and suriclone was much longer in duration of action than DZP and LZP. The anticonflict effect of suriclone was markedly potentiated with repeated administration (10 mg/kg/day for 14 days), and this effect was equipotent as DZP. Muricide and hyperemotionality in rats induced by either olfactory bulbecto-my or midbrain raphe lesions were suppressed by suriclone. Suriclone was much more potent than DZP and comparable to LZP in these effects. In preventing maximal electroshock- and pentetrazol-induced convulsions in mice, suriclone was much less potent than DZP and LZP. In potentiating thiopental, ether and ethanol anesthesia in mice, as well as in impairing rotarod performance in mice and rats, suriclone was much less potent than DZP and LZP. These results indicate that the pharmacological properties of suriclone are similar to those of benzodiazepines, and are characterized by potent anticonflict and taming effects with much weaker anticonvulsant, anesthesia-potentiating and ataxic effects.

Taming effects of p-chlorophenylalanine on the aggressive behavior of septal rats

Septal irritability and shock-induced aggression were suppressed by the administration of p-chlorophenylalanine (PCPA) to septal rats. The levels of septal irritability and shock-induced fighting were significantly lower in septal, PCPA-treated rats than in nontreated septal rats. Since both parameters of septal aggression were reduced by PCPA, and while PCPA has no effect on shock-induced fighting of unlesioned rats under similar parameters, it appears that both forms of aggression may function through a common neural mechanism.

Pharmacological Studies on Triazine Derivatives V. Sedative and Neuroleptic Actions of 2-Amino-4-[4-(2-Hydroxyethyl)-Piperazin-1-Yl]-6-Trifluoromethyl-s-Triazine (Tr-10)

Pharmacological properties of 2-amino-4-[4-(2-hydroxyethyl)-piperazin-1-yl]-6-trifluoromethyl-s-triazine (TR-10) were investigated in mice and rats. Chlorpromazine served as a reference compound. TR-10 expressed in general the pharmacological profiles as neuroleptics ascertained by anti-methamphetamine activity, supression of conditioned avoidance response, taming effects, decrease in exploratory behavior and cataleptogenic activity. Among these effects, anti-methamphetamine action was most potent. Different from chlorpromazine, TR-10 showed a similar pharmacological activity pattern in the intraperitoneal and oral routes of adminisstration as depicted from ED50/LD50 values. Although the effects relevant to neuroleptics were less potent than chlorpromazine, such were seen with TR-10 at lower doses than those causing muscle relaxation. TR-10 significantly depressed the spontaneous motor activity but showed no anti-convulsant action in mice. Hypothermic action, potentiating effects of hypnotics and α-adrenergic blocking action, characteristic to chlorpromazine, were very weak for TR-10. TR-10 also showed low toxicity in mice (LD50═820 mg/kg p.o., 465 mg/kg i.p.) compared with that of chlorpromazine (LD50 ═370 mg, kg p.o., 228 mg/kg i.p.).

Pharmacological studies of triazine derivatives. IV. General pharmacological actions of 2-(benzylidenehydrazino)-4-tert-butyl-6-piperazino-s-triazine (TR-35) (author's transl)

General pharmacological actions of 2-(benzylidenehydrazino)4-tert-butyl-6-piperazino-s-triazine (TR-35) were examined. TR-35 showed a moderate sedative, muscle-relaxant, and anti-convulsant actions in mice and these effects were more potent than those of meprobamate. Basic anti-inflammatory agents such as mepyrizole or diphenamisol also showed these properties, Although TR-35 expressed taming effects in mice and rats, it had no depressant action against conditioned avoidance response and methamphetamine-induced hypermotility. As for autonomic nervous system or smooth muscle, TR-35 seemed to have a weak ganglion blocking and faint smooth muscle directing actions. Little effect was also observed on blood pressure of urethane anaesthetized rat.

Effects of handling before central 6-hydroxydopamine treatment on subsequent emotionality and neurochemical changes in rats

Five minutes of daily handling 6 days prior to intracisternal 6-hydroxydopamine (60HDA) treatment did not alter the magnitude or the time course of rage known to occur in rats after this method of chronic depletion of brain norepinephrine (NE) and dopamine (DA). However, handling produced an apparent protective effect against the ability of 60HDA to deplete brain DA and, possibly, NE. Since previous work has shown that this same handling regimen, instituted after the production of 60HDA-induced rage, has pronounced taming effects, these findings collectively show that handling is a potentially important variable to control in experiments concerned with the behavioral and neurochemical effects of this drug.

ChemInform Abstract: THE SYNTHESIS AND PHARAMCOLOGY OF A NOVEL BENZODIAZEPINE DERIVATIVE, 1‐(BETA‐METHYLSULFONYLETHYL)‐5‐(O‐FLUOROPHENYL)‐7‐CHLORO‐1,3‐DIHYDRO‐2H‐1,4‐BENZODIAZEPIN‐2‐ONE (ID‐622)

The pharmacological profiles of a new benzodiazepine derivative, 1-(beta-methylsulfonylethyl)-5-(o-fluorophenyl)-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one (ID-622), were shown. In anti-convulsant test, ID-622 was more potent than diazepam and medazepam when tested with pentylenetetrazol or bemegride, but was less potent than diazepam tested with strychnine or MES in mice. Taming effects of ID-622 were more potent than diazepam in both electroshock- and isolation-induced fighting mice tests, but were less potent in both septal rats and O.B. rats tests. ID-622 had only a weak influence on the spontaneous locomotor activity, and did not cause the righting reflex loss. In EEG, ID-622 increased fast activity and depressed hippocampal I-waves and amygdala after-discharge in cats. Acute toxicity of ID-622 was very low.

Taming effects of handling on 6-hydroxydopamine induced rage

The purpose of this experiment was to determine the importance of handling to the expression of hyperemotional behaviors, i.e., rage, known to occur after chronic depletion of brain norepinephrine (NE) and dopamine (DA) following central injection of 6-hydroxydopamine (6-OHDA) in rats. Five min of handling per day for 6 consecutive days reduced resistance to capture as well as the magnitude and frequency of startle responding following one 300 μg injection of 6-OHDA intracisternally. Both 6-OHDA-handled and 6-OHDA-unhandled rats showed comparable levels of brain NE, DA, serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA), comparable resting levels of plasma corticosterone, and comparable adrenal weights. These data demonstrate the importance of handling to the expression of 6-OHDA-induced rage and emphasize the importance of controlling for handling as a variable which can significantly affect the assessment of rage by behavioral criteria in this animal model of hyperemotionality.

Effects of psychotropic drugs on methamphetamine-induced behavioral excitation in grouped mice

When 7 mice injected with methamphetamine (5 mg/kg, s.c.) were placed together into a box with a limited space maintained at 28-30 degrees C, the grouped mice showed extreme behavioral excitation consisting of 2 typical features: fighting behavior with squeak and hyperactive behavior characterized by running and jumping. The effects of various drugs tested, according to the minimal effective doses (mg/kg, p.o.) which inhibited fighting behavior and hyperactive behavior respectively, were: haloperidol, 0.1 (fighting)--0.25 (hyperactivity); clothiapine, 1 - 1; perphenazine, 1 - 1; thiothixene, 1 - 5; chlorpromazine, 5 - 10; diazepam, 5 - 100; reserpine, 100 - 100; phenoxybenzamine, 200 - 200 (no effect). Major tranquilizers except rauwolfia alkaloids completely inhibited both types of excited behavior at low doses, as compared with the taming effects of the drugs on footshock-induced fighting episodes in pairs of mice. On the other hand, minor tranquilizers suppressed only fighting behavior, showing little effect on hyperactive behavior. None of the antidepressants, adrenergic blocking agents and other drugs showed antagonism to both types of excited behavior. The results indicate that this method may be useful for the evaluation of psychotropic drug effects in grouped mice.

Taming effect of nonnarcotic analgesics on the septal syndrome in rats

A series of nonnarcotic analgesics (aspirin, mefenamic acid, phenylbutazone, aminopyrine and methampyrone) as well as chlordiazepoxide and trazodone were administered to septal rats to examine the effects of these drugs on the hyperreactivity and viciousness characteristic of this syndrome. All the nonnarcotic analgesics tested showed taming effects, as did chlordiazepoxide and trazodone. To examine whether this effect was due to an antiinflammatory action of the nonnarcotic analgesics, acute and chronically prepared septal rats were treated with these drugs at different time periods following lesioning. No noticeable difference of the effect of these drugs existed between acute and chronic groups. The nonnarcotic analgesic drugs have a taming action on septal rats which appears to be independent of an antiinflammatory component.

Clozapine (W-801)の行動薬理学的ならびに脳波学的研究

The behavioral and electroencephalographic effects of Clozapine were investigated in mice, rats and rabbits, and compared with chlorpromazine and perphenazine. Clozapine showed in general the pharmacologic properties characteristic to neuroleptics, such as decrease in exploratory behavior, suppression of conditiond avoidance response, taming effects, anti-methamphetamine and so on. These effects were less potent and shoter in duration than those of chlorpromazine and perphenazine. Clozapine, however, lacked cataleptogenic propeties and depressed the EEG arousal responses induced not only by auditory but also by mesencephalic reticular stimulation, differently from chlorpromazine and perphenazine.

STRUCTURE-ACTIVITY RELATIONSHIP OF s-TRIAZOLO-1,4-BENZODIAZEPINES IN CENTRAL NERVOUS DEPRESSANT ACTION

A variety of the central depressant effects of 1, 4-benzodiazepines have been well documented (1–3). Shimamoto and Takaori (4), and Nakajima et al. (5) also have reported the potent sedative, taming, muscle relaxant and anti-convulsive properties of 1-alkyl-carbamoyl-1, 4-benzodiazepin-2-ones synthesized by Usui et al. (6). Most of the chemical studies in this area have been devoted to syntheses of the derivatives of 1, 4-benzodiazepines with relatively simple substituents at 1, 2 or 3 position or in phenyl ring as exemplified by chlordiazepoxide, diazepam, oxazepam and nitrazepam. On the other hand, Meguro and Kuwada (7) in this Chemical Laboratories have synthesized a number of novel 6-phenyl-4H-s-triazolo-[4, 3a] [1, 4] benzodiazepines with a tricyclic ring system.The present report deals with the anticonvulsive, muscle relaxant, sedative and taming effects of these novel compounds in small experimental animals. In these respects, it was proved that several derivatives including 8-chloro-6-phenyl-4H-s-triazolo-[4, 3a] [1, 4] benzodiazepine (D-40TA) and 1-methyl-8-chloro-6-phenyl-4H-s-triazolo [4, 3a] [1, 4] benzodiazepine (D-65MT) were more effective in the central depression than diazepam and nitrazepam.

Structure-activity relationship of s-triazolo-1,4-benzodiazepines in central nervous depressant action.

A variety of the central depressant effects of 1, 4-benzodiazepines have been well documented (1-3). Shimamoto and Takaori (4), and Nakajima et al. (5) also have reported the potent sedative, taming, muscle relaxant and anti-convulsive properties of 1-alkylcarbamoyl-1, 4-benzodiazepin-2-ones synthesized by Usui et al. (6). Most of the chemical studies in this area have been devoted to syntheses of the derivatives of 1, 4-benzodiazepines with relatively simple substituents at 1, 2 or 3 position or in phenyl ring as exemplified by chlordiazepoxide, diazepam, oxazepam and nitrazepam. On the other hand, Meguro and Kuwada (7) in this Chemical Laboratories have synthesized a number of novel 6-phenyl-4H-s-triazolo-[4, 3a] [1, 4] benzodiazepines with a tricyclic ring system. The present report deals with the anticonvulsive, muscle relaxant, sedative and taming effects of these novel compounds in small experimental animals. In these respects, it was proved that several derivatives including 8-chloro-6-phenyl-4H-s-triazolo-[4, 3a] [1, 4] benzodiazepine (D-40TA) and 1-methyl-8-chloro-6-phenyl-4H-s-triazolo [4, 3a] [1, 4] benzodiazepine (D-65MT) were more effective in the central depression than diazepam and nitrazepam.

新向精神薬，Oxazolazepamの薬理学的研究(第I報)

Oxazolazepam showed marked taming effects in mice, hamsters, rats and monkeys. These effects were comparable to those of chlordiazepoxide. Oxazolazepam was somewhat more potent against convulsions induced by megimide and pentetrazol and convulsion of E1-strain mouse but was less potent against convulsions induced by strychnine and electro shock than chlordiazepoxide. On the decrease of spontaneous locomotor activity, muscular relaxation, ataxia and loss of righting reflex in mice and tolerance of taming effects in hamsters, oxazolazepam was definitely less effective than chlordiazepoxide. On the conditioned avoidance response in rats, emesis produced by apomorphine in dogs and tremorine induced symptoms in mice, oxazolazepam was not significantly inhibitory.

Taming effects of para-chlorophenylalanine on septal rats

Para-Chlorophenylalanine, a specific depletor of the brain serotonin, injected in doses of 100–300 mg/kg, attenuates the irritability and vicious behavior of rats with septal lesions. The relationships between this effect and the depletion of brain amines are discussed.

A Modern Devil-Baby

There is a theory that woman first evolved and used the fairy story, that combination of wisdom and romance, in an effort to tame her mate and to make him a better father to her children. The stories finally became a rude creed, or rather rule of conduct, which softened the treatment men accorded to women. In support of this theory it is pointed out that in the typical fairy story the heroine is often disguised under a repulsive and ugly mask and the man is destroyed by seductive beauties. The old woman, the mother-in-law to the maker of the tale-let us observe in passingis too often a wicked witch who gives men bad advice, and, above all, the stepmother is the incarnation of all wickedness. These first pitiful efforts of women became so widespread and so powerful that we have not yet escaped their influence. We had a remarkable experience at Hull House this year of the persistence of one of these tales which has doubtless had its taming effects through the centuries upon recalcitrant husbands and fathers. It burst upon us one day in the persons of three Italian women who, with an excited rush into Hull House, demanded to see the devilbaby. No amount of denial convinced them that it was not there, for they knew exactly what it was like, with its cloven hoofs, its pointed ears, and its diminutive tail. It had been able to speak as soon as it was born and was most shockingly profane. For six weeks the messages, the streams of visitors from every part of the city and suburbs to this mythical baby, poured in all day long and so far into the night that the regular activities were almost swamped. The Italian version, with a hundred variations, dealt with a pious Italiangirl married to an atheist who vehemently tore a holy picture from the bedroom wall, saying that he would quite as soon have a devil in the house as that, whereupon the devil incarnated himself in the child. As soon as the devil-baby was born, it ran about the