摘要:

AbstractThis article reviews the neurochemical results obtained in rats treated with pyritinol, a drug used clinically in the treatment of brain function deficits in old age. Pyritinol can be characterized as an indirectly acting cholinergic drug in the CNS, although its precise mechanism and its primary site of action remains to be elucidated. Direct interactions with muscarinic receptors and influences on catecholaminergic or indolaminergic systems are unlikely. Other actions of pyritinol, i.e., increases in cerebral glucose utilization in rats and cerebral blood flow in man might be secondary to its activating actions on cholinergic neurons. Since pyritinol is reported to significantly improve memory and cognitive functions in patients, the results are considered as evidence that neurochemical measurements of cholinergic functions in animals provide useful and relevant information for these indications although, similar to other cholinergic drugs, the magnitude of its therapeutic effect remains limited.

ISSN:0272-4391    

DOI:10.1002/ddr.430180102

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY

摘要:

AbstractGardner, C.R.: Discriminative stimulus properties of the non‐sedative anxiolytic benzodi‐ azepine receptor ligand RU 32698. Drug Dev. Res. 18:ll–18, 1989.Rats were trained to discriminate RU 32698 (10 mg/kg p.o.) from vehicle using a fixed‐ratio 20 drug discrimination procedure. The characteristics of this cue were compared with that evoked by training rats to discriminate a low dose of chlordiazepoxide (CDZP, 5 mg/kg p.o.) from vehicle. Both cues were antagonized by the benzodiazepine inverse agonist FG 7142, and by the weak inverse agonist CGS 8216. Each training drug substituted for the cue induced by the other. Several benzodiazepine receptor ligands substituted for both cues at similar doses (zopiclone, zolpidem, ZK 91296, RU 43028), although there was a tendency for only partial generalization with ligands with only weak agonist activity (RU 39419, CGS 9896, RU 32514). CL 218872 partially substituted for the RU 32698 cue. Tracazolate partially substituted for both cues but buspirone showed little or no substitution for either cue. Thus, RU 32698 induces a cue via an action at benzodiazepine receptors. The RU 32698 cue is sensitive to low levels of agonism at benzodiazepine receptors and should be useful in the discovery of non‐sedative anxiolyt

ISSN:0272-4391    

DOI:10.1002/ddr.430180103

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY

摘要:

AbstractSix cognitive enhancer compounds, the new class of central nervous system (CNS)‐active drugs (vinpocetine, vincamine, dihydroergotoxine, nicergoline, piracetam, and meclofenoxate) were tested before acquired two‐way active avoidance response of spontaneously hypertensive (SH) rats had been disrupted by lowered environmental oxygen concentration (6% oxygen). Exposure to normobaric hypoxia reduced the number of conditioned avoidance responses (CAR) by 44%; at the same time the spontaneous locomotor activity of the animals (measured by the alteration in the number of intertrial crossings) was not considerably decreased, and latency times of conditioned responses were not lengthened significantly. The compounds tested showed protective effect against hypoxia‐induced performance deficit without stimulating spontaneous activity. Vinpocetine antagonized nearly completely CAR blockade in the 1.25‐5.0 mg/kg p.o. dose range, restoring the ratio of avoidance responses to normal level. Vincamine exerted activity at a dose of 20 mg/kg p.o. Dihydroergotoxine and nicergoline were effective at 10 mg/kg p.o., Piracetam and meclofenoxate showed moderate protective activity at 2,000 and 500 mg/kg p.o., respectively. For comparison, the effect of dopaminergic drugs of a different mechanism of action (amphetamine, apomorphine, bromocriptine, and methylphenidate) was also tested in a similar situation. Only amphetamine (at 1.0 mg/kg i.p.) and low doses of apomorphine (0.1 and 1.0 mg/kg) had a favorable effect against hypoxia‐induced CAR blockade; this effect was accompanied by an increase in locomotor activity. On the basis of these data, the relatively simple behavioral method applied by us, protection of acquired conditioned response against the disruptive effect of hypoxia in SH rats, seems suitable to detect nootropic

ISSN:0272-4391    

DOI:10.1002/ddr.430180104

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY

摘要:

AbstractA preclinical anxiolytic profile of the pyrimidinylpiperazinyl imide compound Wy‐47,846, is presented. In an effort to achieve an orally active, nonbenzodiazepine anxiolytic agent, the compound Wy‐47,846 was synthesized and examined in various preclinical neurochemical, psychopharmacological and neurophysiological tests. Wy‐47,846 displayed high affinity at the 5‐HT‐1A receptor binding site (Ki = 16.7 nM) and had weak‐to‐modest affinities for D‐2 and 5‐HT‐2 receptors. Wy‐47,846 also was effective in binding to the 5‐HT‐1A site in ex vivo receptor binding studies, but did not alter D‐2 binding under these conditions. Wy‐47,846 was also weak to inactive at displacing adrenergic (alpha‐1, alpha‐2, and beta), cholinergic, histamine H‐1, opiate, and benzodiazepine receptor radioligands from their respective binding sites. Wy‐47,846 reduced 5‐HT‐2 receptor binding following subacute (3 week) treatment. In both shelf‐jump and discrete trial conditioned avoidance tests, Wy‐47,846 reduced avoidance responding while increasing escape responses. No sedative effects were noted at behaviorally active doses. Like other nonbenzodiazepine anxiolytics, Wy‐47,846 also did not release the suppression of punished responding in shock‐suppressed drinking nor in Geller‐Seifter conflict experiments. Wy‐47,846 also potently inhibited serotonergic neuronal activity in the dorsal raphe nucleus, suggesting agonist activity at the 5‐HT‐1A receptor and increased noradrenergic neuronal activity in the locus coeruleus by an unknown mechanism. These findings support the characteriza

ISSN:0272-4391    

DOI:10.1002/ddr.430180105

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY

摘要:

AbstractRats (N = 9) were trained to discriminate the antipsychotic drug haloperidol (0.05 mg/kg i.p.) from drug vehicle (0.25% acetic acid in 0.9% saline) using a water‐reinforced, fixed‐ratio 10 response operant procedure. Acquisition of discrimination required a mean of 45 trainingsessions (median value of 38 sessions). The discriminative stimulus was dose‐dependent with an ED50value of 0.008 mg/kg. The total number of responses per 10‐min test session was significantly reduced at all doses of haloperidol that produced haloperidol lever selection. The antipsychotic drug chlorpromazine substituted for the haloperidol discriminative stimulus (ED50= 0.38 mg/kg). The indirect dopaminergic agonists amphetamine (1.0 mg/kg) and cocaine (10 mg/kg) fully blocked the haloperidol discriminative stimulus. Taken together, these initial results suggest that the discriminative stimulus produced by haloperidol is mediated, at least in part, by an interaction with dopamine re

ISSN:0272-4391    

DOI:10.1002/ddr.430180106

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY

摘要:

AbstractMany of the currently used anticonvulsants possess a host of undesirable pharmacological properties. Several non‐opioid antitussives bind to high‐affinity [3H]dextromethorphan sites in brain and have novel anticonvulsants activity. Because these compounds may be useful in the treatment of some epilepsies, either alone or as adjuncts. Behavioral effects of these as well as clinically used anticonvulsant drugs were studied under a standard preclinical test of sedative‐hypnotic/anxiolytic activity which generally yieds positive results with standard anticonvulsants. Lever‐press responses of male Sprague‐Dawley rats were maintained under a multiple schedule of food presentation in which responses in one component were suppressed by brief electric shock (punishment) whereas responses in an alternate component were not punished. The drug doses tested were the ED50and 2 X ED50for anticonvulsant activity against maximal electroshock‐induced convulsions. The non‐opioid antitussive anticonvulsants, carbetapentane, caramiphen, dextromethorphan, as well as diphenylhydantoin, did not increase punished responding, Nonpunished responding was unaffected by ED50does levels of these compounds. In contrast, diazepam increased punished responding to 800% of control levels and increased nonpunished responding at 1 mg/kg. Responding was typically decreased by the highest doses of all drugs studied except diphenylhydantion. Thus, the non‐opioid antitussive anticonvulsants were devoid of significant behavioral effects at the ED50does and did not possess the anxiolytic activity of benzodiazepine or barbiturate

ISSN:0272-4391    

DOI:10.1002/ddr.430180107

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY

摘要:

AbstractStudies were performed in anesthetized dogs to determine if topical application of phenol to the heart acutely alters postsynaptic function in addition to destroying efferent sympathetic nerves. Left ventricular dP/dt max as well as segment length shortening (%SL) and maximal rate of shortening (dL/dt max) in the circumflex perfusion territory were measured. Responses to left stellate ganglion stimulation (LSS) and intracircumflex injection of norepinephrine (NE, 0.10‐0.50 m̈g) were recorded before and after application of 85% phenol to the atrioventricular junction and to the circumflex artery and its branches (stage 1) as well as to the myocardial surface (stage 2). Responses of dP/dt max, %SL, and dL/dt max to the various dosages of NE were reduced by 40‐64%, 69‐75%, and 44‐61%, respectively, 1 hr after stage 1, indicating that application of phenol to the coronary arteries and arterio‐ventricular junction attenuated the postsynaptic response to adrenergic stimulation. No further changes occurred 1 hr after stage 2. Responses of dP/dt max and dL/dt max to LSS were reduced by 36% and 57%, respectively, after stage 1 and by 75% and 71% after stage 2. Because of high variability, the response of %SL to LSS were not affected by stage 1 or stage 2 application of phenol. In a secondo of 5 dogs, only stage 2 application of phenol was used. The blunting of the LSS response was similar to that seen with stage 1 followed by stage 2, but the NE response was unaffected. These data indicate that application of phenol to the coronary Vessels and to the atrioventricular junction acutely blunts both the postsynaptic response to afferent nerve stimulation, while application of phenol to the myocardial surface blunts only the response to efferent nerve stimulation. Thus, in acute animal studies, application of phenol to the myocardial surface may provide more reliable result on the effects of ventricular d

ISSN:0272-4391    

DOI:10.1002/ddr.430180108

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY

摘要:

AbstractCL 115,999 was found to be a very potent orally and transdermally active antihypertensive prostacyclin (PGl2) analog with a long duration of action. In conscious spontaneously hypertensive rats (SHR), CL 115,999 lowered mean arterial blood pressure (MABP) 16, 37, 47, and 54 mm Hg at 0.5, 1, 3, and 10 mg/kg orally, respectively. It lowered MABP 19, 28, and 50 mm Hg at 0.1, 0.3, and 1 mg/kg transdermally with durations of action of 2,>6, and>24 hr, respectively. In aorta‐coarcted, renin‐dependent, malignant hypertensive rats, and in deoxycorticosterone aceate (DOCA)‐salt‐induced (low renin) hypertensive rats, CL 115,999 at 3 mg/kg orally lowered MABP 54 and 66 mm Hg lasting longer than 6 and 5 hr, respectively. In conscious two‐kidney, one‐clip, Goldblatt hypertensive dogs, CL 115,999 decreased MABP 33 and 66 mm Hg at 1 (p.o.), and 0.5 (i.v.) mg/kg, respectively. CL 115,999 increased blood flows to renal, coronary, carotid, femoral, and superior mesenteric arterial beds in anesthetized dog when given intraarterially into the bed under study. These findings suggest that CL 115,999 produces potent vasodilation leading to lowering of blood pressure and may act like endogenous prostacyclin in the vasculatures and may be useful for the treatment of hypertension and other cardiovascular disease

ISSN:0272-4391    

DOI:10.1002/ddr.430180109

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY

摘要:

AbstractThe effect of novel potent CCK‐8 antagonists on a one‐trial passive avoidance response was investigated in the rat. Intracerebroventricular administration of L‐364,718 and CR 1409 in doses of 10 ng per rat or more and proglumide in doses of 100 ng per rat or more completely attenuated the passive avoidance response, when examined 24 hr after the injection. The effective doses of these antagonists did not cause any motility change, as tested by an open‐field situation at the same period of time after the central administration. The present findings, together with our previous results on an active avoidance response, suggests that endogenous CCK‐8 may be involved in memory

ISSN:0272-4391    

DOI:10.1002/ddr.430180110

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY

ISSN:0272-4391    

DOI:10.1002/ddr.430180101

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY