摘要:

AbstractLigands for benzodiazepine receptors produce one of three types of effects: (1) diazepamlike; (2) opposite to diazepam; or (3) no direct effects, but blockade of the effects of the other ligands. Data refiewed in this paper demonstrate that the imidazodiazepine Ro 15‐4513 produces direct neuronal and behavioral effects of the type opposite to those of diazepam. These include electrophysiological and behavioural seizures, anxiety‐like behaviors, inhibition of aggression, and facilitation of learning and memory. In addition to its direct effects, Ro 15‐4513 also blocks the effects of benzodiazepines, barbiturates, and ethanol. This antagonism has been reported for a broad range of experimental approaches including biochemical, physiological, and behavioral measures. Because direct effects of Ro 15‐4513 are, in many cases, opposite to the effects of these sedative drugs, these direct effects may account for at least part of the ability of Ro 15‐4513 to antagonize sedative drugs. However, for some measures, such as exploratory activity and operant response rate, even under conditions in which the effect of Ro 15‐4513 is the same as that of the sedative drugs, Ro 15‐4513 still antagonizes the effects of the sedative drugs. Blockade of the effects of Ro 15‐4513 by both agonists and antagonists at the benzodiazepine receptor strongly supports the hypothesis that all of the effects of Ro 15‐4513 occur due to its action at the benzodiazepine receptor. Blockade of ethanol by very low concentrations of Ro 15‐4513 substantiates the role of the benzodiazepine receptor‐chloride ionophore complex in mediating neurobiological effects of ethanol and has stimulated efforts to develop alcohol antagonists with greater specif

ISSN:0272-4391    

DOI:10.1002/ddr.430130402

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

年代:1988

数据来源: WILEY

摘要:

AbstractIncreasing exposure of pregnant mothers to various industrial solvents due to voluntary abuse or involuntary exposure in the work place is raising the possibility of production of teratological effects in the offsprings. Ethanol, which can be broadly categorized as a solvent and which is also extensively abused, is well known for its teratological deragements in humans, termed as “fetal alcohol syndrome” as well as in animals. Benzene and its derivatives (xylene and toluene), alcohols, glycols and glycol ethers, and other solvents have also been reported to produce various types of teratogenic effects in animal (e.g., mice, rats, and rabbits) studies. In the case of toluene, some teratogenic anomalies have been reported in three children of mothers exposed to pure toluene vapor throughout the pregna

ISSN:0272-4391    

DOI:10.1002/ddr.430130403

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

年代:1988

数据来源: WILEY

摘要:

AbstractThe neurochemical and behavioural profile of Lu 17‐133, (±)‐trans‐4‐[3‐(3,4‐dichlorophenyl)‐indan‐1‐yl]‐1‐piperazineethanol has been characterized and compared with that of a series of inhibitors of biogenic amine uptake. Lu 17‐133 inhibits the uptake of dopamine and noradrenaline in the nanomolar range, but it has only a weak effect on serotonin uptake. Blockade of receptors for dopamine (D‐1, D‐2), noradrenaline (α1, α2), histamine (H1), acetylcholine (muscarinic), and serotonin (5‐HT2) was absent or seen only at micromolar concentrations. The biochemical profile is close to that of GBR 13.069, GBR 12.921, and Lu 19‐005 (INN name, Indatraline). Lu 17‐133 shows only weak behavioural effects. In high doses, it potentiates apomorphine and 5‐HTP and reverses the effect of tetrabenazine in mice. It has minimal stimulatory property, as it increases very weakly the locomotor activity in mice and does not induce stereotypy (either low‐component or oral stereotypy) in rats. It does not induce ipsilateral circling behaviour in 6‐OHDA‐lesioned rats, although in combination with scopolamine, a full ipsilateral rotation is seen. Lu 17‐133 has no anticataleptic effect and does not generalize to the discriminative stimulus properties induced by d‐amphetamine. Experiments have shown that there is no clear correlation between inhibitory effect on dompamine uptake and in vivo effects in the models detecting dopamine‐stimulating compounds; nor is there any obvious correlation between effects in different in vivo test models. The neurochemical and behavioural characteristics of Lu 17‐133‐inhibition of dopamine‐ and noradrenaline‐uptake in vitro with low stimulatory properties in vivo mak

ISSN:0272-4391    

DOI:10.1002/ddr.430130404

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

年代:1988

数据来源: WILEY

摘要:

AbstractThe effects of adrenergic beta‐receptor blockers on the hyperphagia produced by diazepam were studied in free‐feeding rats. The hyperphagia produced by 1.0 mg/kg subcutaneous (s.c.) diazepam, was antagonised by dl‐propranolol (6.0 mg/kg s.c.) and 1‐propranolol (6.0 mg/kg s.c.), but not by d‐propranolol (6.0 mg/kg s.c.). Intracerebroventricular administration of dl‐propranolol (50, 100, and 200 μg) failed to antagonise this hyperphagia. Other specific β1and β2blockers, metoprolol (10.0 mg/kg s.c.), and butoxamine (10.0 mg/kg s.c.) also did not antagonise this hyperphagia. It is suggested that some intrinsic property other than β‐blockade, tranquilising, or local anesthetic activity is responsible for this antagonism caused by s.c. administration of dl

ISSN:0272-4391    

DOI:10.1002/ddr.430130405

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

年代:1988

数据来源: WILEY

摘要:

AbstractA series of test compounds were studied for their ability to inhibit and block the head‐twitch response to either intraperitoneal (i.p.) 5‐hydroxytryptophan (5‐HTP) or intravenous (i.v.) mescaline in rats. Both responses were found to be sensitive to serotonin S2antagonists, and there was very good agreement between the inhibitory doses in both tests, particularly for the selective serotonin S2antagonists ritanserin and seganserin. However, these two compounds did not block the 5‐HTP response, although they completely abolished the mescaline response. In contrast, the mixed serotonin‐dopamine‐norepinephrine antagonist risperidone was a potent blocker of both responses. The use of various antagonists and the combination treatments of ritanserin with haloperidol or prazosin indicated that the 5‐HTP response is abolished when potent serotonin S2antagonism is associated with antagonistic activity on either dopamine D2o

ISSN:0272-4391    

DOI:10.1002/ddr.430130406

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

年代:1988

数据来源: WILEY

摘要:

Abstract5‐Hydroxytryptamine (5‐HT) increases heart rate in the spinal‐transected cat by acting on 5‐HT1‐like receptors, since this effect is not modified by ketanserin or MDL 72222 but is blocked by methysergide [Saxena et al., 1985]. These 5‐HT1‐like receptors in the cat heart have been further characterized in this investigation using compounds that have high affinities for 5‐HT1binding site subtypes. Like 5‐HT, the putative 5‐HT1‐like receptor agonists 5‐carboxamidotryptamine (5‐CT; nanomolar affinities for 5‐HT1A, 5‐HT1B, and 5‐HT1Dsubtypes) and N‐(3‐acetylaminophenyl) piperazine (BEA 1654; preferential and nanomolar affinity for 5‐HT1Asite) elicited dose‐dependent tachycardia. The doses needed to increase heart rate by 50 beats·min−1were calculated to be 84 ± 6, 4 ± 1 and 21,720 ± 5,200 nmol·kg−1for 5‐HT, 5‐CT, and BEA 1654, respectively. 8‐Hydroxy‐2‐(di‐N,N‐n‐propylamino)tetralin (8‐OH DPAT; selective nanomolar affinity for 5‐HT1Asite) and 5‐methoxy‐3‐(1,2,3,6‐tetrahydro‐4‐pyridinyl)‐1H‐indole (RU 24969; preferential nanomolar affinity for 5‐HT1Bsite) had little activity. Among antagonists that have nanomolar affinities for all four (5‐HT1A, 5‐HT1B, 5‐HT1C, and 5‐HT1D) 5‐HT1binding site subtypes, methiothepin, followed by methysergide, showed potent activity against tachycardia induced by 5‐HT, 5‐CT, and/or BEA 1654; metergoline was poorly effective. Mesulergine, which has highest affinity for 5‐HT1Cbinding subtype, also showed antagonist activity, but this effect was less than that of methiothepin or methysergide. It was concluded that the functional 5‐HT1‐like receptors mediating cardioac

ISSN:0272-4391    

DOI:10.1002/ddr.430130407

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

年代:1988

数据来源: WILEY

摘要:

AbstractThe ED50s for reversal of mouse aggression were determined for nine beta adrenergic receptor blockers: metoprolol, nadolol, pindolol, propranolol, acebutolol, penbutolol, labetalol, timolol, and atenolol. Propranolol and penbutolol generated linear doseresponse curves, suggesting easy access to brain. To determine if beta blockade was actually occurring at the receptor level, upregulation of beta receptors after 10 days of chronic treatment with the ED50s was determined in the limbic system as well as other areas of brain. These areas included: olfactory bulbs, hypothalamus, septum, amygdala, cortex, midbrain, cerebellum, pons, and medulla. Upregulation occurred in all areas of the brain in animals treated with propranolol and penbutolol, suggesting that at the dose required to block aggressing in fighting mice, beta receptors were also effectively blocked. With other drugs (timolol, atenolol, pindolol, metoprolol, nadolol, and acebutolol) the ED50s produced localized upregulation of beta receptors, but nothing consistent in the limbic areas. The beta blocker labetalol at the ED50for reversal of mouse aggression produced virtually no upregulation of brain receptors, suggesting no correlation between antiaggression and beta blockade.

ISSN:0272-4391    

DOI:10.1002/ddr.430130408

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

年代:1988

数据来源: WILEY

摘要:

AbstractIntravenous tazadolene elevated the threshold stimulus for rabbits to respond to electrical tooth‐pulp stimulation. Systemic tazadolene also increased the latency for mice to lick their paws in the hot‐plate analgesic test. However, tazadolene did not alter the mouse tail flick, a spinal reflex most sensitive to analgesics acting at spinal sites. Tazadolene analgesia was not antagonized by naloxone. Intracranial (i.c.), but not intraspinal (i.s.), injections of tazadolene were more effective than systemic injections in producing analgesic effects in the hot‐plate test. It is concluded that tazadolene is a centrally‐acting, non‐narcotic

ISSN:0272-4391    

DOI:10.1002/ddr.430130409

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

年代:1988

数据来源: WILEY

ISSN:0272-4391    

DOI:10.1002/ddr.430130401

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

年代:1988

数据来源: WILEY