摘要:

AbstractTolerance to and withdrawal from drugs of dependence involves subjective symptoms and physical signs. Until recently, only physical signs associated with these phenomena could be assessed in animals. Recently, however, drug discrimination methodology has been used to bioassay for the occurrence of subjective events in animals; the work reviewed in this paper describes extensions of this general technique to test for subjective aspects of withdrawal from and tolerance to benzodiazepine drugs in rats. The durg dicrimination procedure reinforces differential responding where the controlling stimulus is the presence or absence of a drug‐produced internal stimulus. Although it is impossible to determine the quality (subjective nature) of such stimuli in animals, it is possible to operationally define relationships between classes of stimuli. With regard to the discriminative stimulus produced by pentylenetetrazol (PTZ), data to date show that anxiogenic drugs substitute for PTZ and anxiolytic drugs block the PTZ stimulus. Because in humans severe anxiety is a frequently seen component of withdrawal from dependence on benzodiazepine drugs, this laboratory initiated experiments to determine if animals trained to detect PTZ and then given chronic treatment with benzodiazepines would substitute a withdrawal state for thePTZ stimulus. Data reviewed in this paper show that following diazepam administration, treatment with the benzodiazepine antagonist Ro 15‐1788 (RO) produced a dose‐related PTZ‐like stimulus. When given to nondependent animals, RO neither substituted for nor blocked nor enhanced the PTZ stimulus. In additional studies, RO produced a PTZ‐like stimulus when administered once every 3 d in rats maintained chronically on diazepam. Further, rats given a 2‐d regimen of diazepam, 80 mglkgl8 hr, were subsequently tolerant to the PTZ‐blocking action of diazepam. These data demonstrate that the discrimination of PTZ is a useful procedure for assessing subjective aspects of tolerance to and withdrawal from benzodiazepin

ISSN:0272-4391    

DOI:10.1002/ddr.430110302

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

年代:1987

数据来源: WILEY

摘要:

AbstractHP 370 4,9‐Dibromo‐6‐(4 methyl‐1‐piperaziny(l)benzo((b)pyrrolo[3,2,1‐jk][1,4 benzodiazepine]demonstrated preclinical activity indicative of clinical atypical antipsychotic activity, which may provide an advantage over current therapeutic agents. It was effective in blocking apomorphine‐induced climbing behavior in mice (ED50= 4.1 mg/kg i.p.; 1.6 mg/kg p.o), locomotion caused by direct application of dopamine to the nucleus accumbens in rats (ED50= 15.4 mg/kg i.p.), intracranial self‐stimulation in rats (ED50= 10.1 mg/kg i.p.), and pole‐climb avoidance in rats (ED50= 4.0 mg/kg p.o. avoidance; 10.6 mg/kg p.o. escape failures). HP 370 was relatively inactive in blocking aporomorphine‐induced stereotypy in rats (50% at 40 mg/kg, 33% at 20 mg/kg i.p.), relatively inactive in causing catalepsy in rats (50% at 40 mg/kg i.p.)m and was completely inactive in blocking stereotypy caused by the direct application of dopamine to the corpus striatum of rats (up to 80 mg/kg i.p.). Chronic administration of HP 370 caused supersensitivity to apomorphine in the climbing mouse test and in dopamine‐induced locomotion in rats, but not in dopamine‐induced stereotypy in rats. Acute administration of HP 370 caused and increase in the numberof active dopamine neurons sampled in both the ventral tegmental area and substantia nigra of rats, whereas chronic administration resulted in singnificantly fewer dopamine neurons found in the ventral tegmental area with no change from control levels observed for the substantia nigra. In a measure of social interaction in rats, HP 370 significantly increased the time spent interacting without altering overall activity, suggesting favorable effects on negative symptomatology. No in vivo anticholinergic activity was seen in the physostigmine lethality test in mice. In vivo blockade of alpha noradrenergic receptors was suggested by the inhibition of norepinephrine lethality in rats (50= 0.6 mg/kg i.p.). HP 370 displays an in vivo profile consistent with that of an atypical antipsychotic agent and is predicted to be clinically effective with fewer side effects than curr

ISSN:0272-4391    

DOI:10.1002/ddr.430110303

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

年代:1987

数据来源: WILEY

摘要:

AbstractHP 370, 4,9‐dibromo‐6‐(4‐methyl‐1‐piperazinyl)benzo[b]pyrrolo[3,2,1‐jk][1,4] benzodiazepine, a compound that has an atypical antipsychotic profile in vivo, was tested for activity in a number of neurotransmitter receptor binding and uptake assays and compared with serveral typical and atypical antipsychotic compounds. The in vitro profile of HP 370 was most similar to that of clozapine, with the notable exception that HP 370 was inactive as an inhibitor of quinuclidinyl benzilate (QNB) binding (IC5010−5). HP 370, like clozapine, was a relatively weak and nonselective inhibitor of dopamine (DA) receptor subtypes, whereas sulpiride, another compound reported to be atypical, is a very selective but weak inhibitor of dopamine‐2(D2) receptors. HP 370 and clozapine inhihited WB4101 binding with high affinity, indicating α1‐adrenergic receptor blockade. Neither HP 370 nor the standard neuroleptic compounds inhibited flunitrazepam or gamma‐aminobutyric acid (GABA) binding. HP 370, Clozapine, and sulpiride were inactive as inhibitors of norepinephrine (NE), DA, and 5HT uptake, whereas HP 370 AND clozapine were weark inhibitors of GABA uptake. Based on this in vitro data, the mesolimbic site‐selectivity of HP 370 seen in vivo cannot be explained by anticholinergic GABA‐mimetic activity in the DA‐parative results point to a distinct advantage of an atypical neuroleptic, without the antocholinerg

ISSN:0272-4391    

DOI:10.1002/ddr.430110304

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

年代:1987

数据来源: WILEY

摘要:

AbstractThe direct effects of platelet activating factor (PAF) (2.5 nM) on isolated guinea pig heart were studied: first, on Langendorff model perfused hearts, using the radiolabelled microspheres technique, we found that PAF reduced the myocardial flow homogenously. Secondly, using isolated “working” heart preparations, the direct effects of PAF on the coronary and aortic flows, heart rate, and systolic ejection volume were evaluated. PAF markedly reduced coronary and aortic flows. Systolic ejection volume (SEV) was significantly decreased and the reduction, which was maximal at 3 min, persisted at 20 min. Some of the direct cardiac effects of PAF were antagonized by addition of GBE to the medium (10 mg/l). These data demonstrate the direct effects of PAF on cardiac function. The possible of PAF in the mediation of the episodes of coronary spasm may be sugges

ISSN:0272-4391    

DOI:10.1002/ddr.430110305

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

年代:1987

数据来源: WILEY

摘要:

AbstractThe cardioselective beta‐adrenoceptor antagonist bisoprolol ((±)−1‐[4‐(2‐isopropoxyethoxy‐ymethyl)‐phenoxy]3‐isopropylamino‐2‐propanol‐hemifumarate, EMD 33512) was studied for its effects on cardiac performance in ten anesthetized open‐chest pigs. Radioactive labelled microspheres (15 ± 1 μm) were used to determine regional blood flows. In doses of 4, 16, 64, 256, and 1,024 μg · kg−1(arterial plasma concentrations 1.65 ± 0.07 to 569 ± 22 ng · ml−1) the drug caused dose‐dependent decreases in cardiac output (4–31%,P<.05) that were primarily due to a negative chronotropic action as heart rate, which had already been slowed down by 9% (p<.05) after the lowest dose, decreased up to 22% (p<.05). Stroke volume was not significantly affected at any dose, although it tended to decrease after the highest dose of hisoprolol (−10%,p<.05). Myocardial it tended to reflected by maxLVdP/dt, fell dose dependetly from 12% (after 4μg · μg·Kg−1,P<.05) up to 46% (after 1,024 μg ·−1,P<.05). Raising the heart rate to predrug levels revealed that this reduction in maxLVdP/dt was not related to the bradycardic action of the drug. Mean arterial blood pressure decreased slightly (<15%,P<.05) after the highest three doses, but a larger fall was prevented by a mild vasoconstriction of the systemic arterial vascular bed as systemic vasular resistance increased up to 28% (P<.05). Pulmonary artery pressure was not affected, because pulmonary vasuclar resistance increased with the highest doses. Left ventricular blood flow, which had already decreased significantly with the lowest dose (11%,PB<.05), also decreased dose dependently (up to 44% after 1,024 μg · kg−1,P<.05). These decreases were equally distributed over all myocardial layers as the endolepi blood flow ratio (1.13 ± 0.04) was not affected. Myocardial 02consumption was not affected by the lowest dose, but decreased progressively up to 43% (P<.05) with the higher doses. These changes occurred parallel to those in blood flow as myocardial O2extraction did change. Cerebral blood flow was well preserved but decreases in perfusion of some other organs and tissues (kidneys, stomach, and skeletal muscle) were similar to those in cardiac output.In conclusion, bisoprolol has a cardiovascular profile similar to that of other beta‐adrenoceptor agents. The finding that no serious adverse cardiovascular affects are observed over a wide dose range warrants further

ISSN:0272-4391    

DOI:10.1002/ddr.430110306

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

年代:1987

数据来源: WILEY

摘要:

AbstractThe cardiac effects of SK&F 86466, an α2‐adrenoceptor antagonist currently under evaluation in humans as an antihypertensive agent, were investigated in rabbits. In the isolated working rabbit heart, SK&F 86466 had no effect on spontaneous heart rate, contractility, coronary flow, aortic flow, or left ventricular pressure at concentrations from 10−7to 3 × 10−5M. At higher concentrations, SK&F 86466 lowered heart rate, contractility, aortic flow, and left ventricular pressure to such an extent that the heart failed to perform work. Electrophysiologic studies of spontaneous actions potentials of sino‐atrial node cells revealed that from 10−9to 10−5M, SK&F 86466 had no effect on action potential generation. At 3X 10−5M, a 25% decrease in the rate of spontaneous action potentials was observed. This effect was accompained by a 1.3 V/sec decrease in + Vmaxand a 25% increase in APD50. These results suggest that: 1) SK&F 86466 has no direct cardiodepressant action in rabbits at pharmacologically relevent doses, and 2) the actions of SK&F 86466 on the heart are most likely due to an effect on inward

ISSN:0272-4391    

DOI:10.1002/ddr.430110307

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

年代:1987

数据来源: WILEY

摘要:

AbstractRats administered intraperitoneally with 1 mmol lithium carbonate/kg/day, 300 mg valproic acid/kg/day, and their combination for 12 days lithium treatment were found to increase the levels of γ‐aminobutyric acid (GABA) and its synthesizing enzymes, glutamic acid decarboxylase (GAD), in corpus striatum and midbrain regions. However, these elevated treatment alone increased GABA and GAD in the cerebral cortex and hippocampus regions. in adition, an increased cerebellar GABA concentration was observed. The combined treatment of lithium and valproic acid enhanced GABA and GAD levels in all brain regions, except for GABA and GAD in the pons‐medulla. A statistically significant synergistic effect of the two drugs was noticed in elevating GABA and GAD levels in the corpus striatum, cerebral cortex, and midbrain region. Furthermore, the elevated levels remained stable even 2 days after cessation of the combined therapy. The observed stable and synergistic increase in the regional GABA and GAD suggested a possible role of facilitated GABAergic transmission in the mechanism of therapeutic action of lithium and valproic acid combination in the treatment of m

ISSN:0272-4391    

DOI:10.1002/ddr.430110308

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

年代:1987

数据来源: WILEY

摘要:

AbstractCGS 17867A (2‐(4‐chlorophenyl)‐2,5,6,7,8,9,‐hexahydor‐3H‐pyrazolo [4,3,‐c]quinoline‐3‐one‐hydrochloride salt) is a tetrahydorpyrazoloquinoline related to the benzodiazepine (BZ) receptor agonist, CGS 9896. The compound is an effective inhibitor of [3H]flunitrazepam binding to the central BZ receptor (IC50 = 1.0 nM). Activity at the GABA‐A receptor and chloride channel components of the BZ receptor complex indicate a profile predictive of a partial agonist. CGS 17867A is orally active, block PTZ discriminative stimuli, produces an increase in conflict responding, and generalizes to CGS 9896 discriminative stimuli, indicating potential anxiolytic efficacy comparable to that of diazepam. This compound is more potent than diazepam in protecting rats against pentylenetetrazol‐induced convulsions and is effective in delaying the development of kindled seizures. Only moderate protection is noted against picrotoxin‐induced convulsions and no effect is produced by CGS 17867A against maximal electroshock‐ or strychnine‐induced convulsions. An absence of muscle relaxant properties is suggested by the inability of CGS 17867A to impair rotorod performance or to generalize to diazepam discriminative stimuli. Unlike CGS 9896, CGS 17867A does not antagonize diazepam‐induced rotorod deficit or diazepam discriminative stimuli. CGS 17867A potentiates ethanol‐induced rotorod impairment only at dosesin excess of those producing therapeutic efficacy, in contrast to the BZs, which induce both effects at comparable doses. Mice treated chronically with CGS 17867A do not show any tolerance or withdrawal effects upon subsequent testing. CGS 17867A produces a preclinical profile indicative of a partial BZ receptor agonist. The compound has anxiolytic and anticonvulsant potential and a reduced propensity to produce the limi

ISSN:0272-4391    

DOI:10.1002/ddr.430110309

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

年代:1987

数据来源: WILEY

摘要:

AbstractThe purpose of this study was to determine if the depression of calcium‐dependent glutamate release from synaptosomes derived from the rat amygdala is specific to neuroleptics. To this end the effects of nine nonneuroleptic agents and nine previously untested neuroleptic agents (or isomers) on nondependent and calcium‐dependent glutamate release were determined by gas‐chromatographic and radioisotopic methods. All of the neuroleptics except reserpine depressed calcium‐dependent release at 10−7M with only a weak, inconsistent reduction of nonspecific release. None of the nonneuroleptic agents at concentrations of 10−6M 10−5M produced depression of calcium‐dependent release withoutalsostrongly depressing nonspecific release. Reserpine was without effect on release at concentrations as high as 10−7M. Also shown was that the representive neuroleptics Haloperidol, chlorpromazine, and clozapine depressed the calcium‐dependent release of glutamine‐derived glutamate to a greater extent over glucose derived glutamate. These data suggest that the specific depression ofstimulus‐coupledglutamate release is not a characteristic of noneuroleptic compounds, but is highly associated with neuroleptics of the phenothiazine o

ISSN:0272-4391    

DOI:10.1002/ddr.430110310

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

年代:1987

数据来源: WILEY

摘要:

AbstractIn the present study, the possible functional modifications of both D‐1 and D‐2 dopamine (DA) receptor subtypes have been studied following chronic treatment with DA antagonists that selectively act on a single class of DA receptors. Particularly, the functional state of D‐1 and D‐2 receptors has been evaluated by measuring SKF 82526‐stimulated and bromocriptine‐inhibited adenylate cyclase activity in different brain regions of rats treated with saline, SCH 23390, or (−)sulpiride for 35 days.The results indicate that in striatum, nucleus accumbens, and substantia nigra, chronic blockade of D‐1 DA receptors by SCH 23390 induces up‐regulation of D‐1 receptors without changing the functional activity of D‐2 receptors. Likewise, chronic blockade of D‐2 DA receptors by (−)sulpiride causes an up‐regulation of D‐2 but not D‐1 DA receptors in striatum, nucleus accumbens, and substantia nigra. SCH 23390 or (−)sulpiride did not modify the functional activity of either D‐1 or D‐2 DA receptors located in frontal cortex and hippocampus. In conclusion, these results indicate that treatment with selective D‐1 or D‐2 DA receptor blockade for 5 weeks induces a receptor‐specific up‐regulation which involves the DA receptors located in the nigrostriatal system but n

ISSN:0272-4391    

DOI:10.1002/ddr.430110311

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

年代:1987

数据来源: WILEY