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B Zivkovic

Publications and source records attributed to B Zivkovic.

At least 19 recordsLinked to original sources
PubMed1994

Discriminative stimulus effects of alpidem, a new imidazopyridine anxiolytic.

Alpidem in an imidazopyridine derivative which binds selectively to the omega 1 (BZ1) receptor subtype. It is active in some, but not all, behavioural tests sensitive to benzodiazepine anxiolytics and has clinical anti-anxiety effects. However, in a previous study, it was shown that alpidem did not substitute for chlordiazepoxide in rats trained to discriminate this benzodiazepine. The present experiments were carried out to investigate the discriminative stimulus properties of alpidem in greater detail. In the first experiment rats learned to discriminate a dose of 10 mg/kg alpidem from saline. Acquisition of the discrimination was long and performance unstable. Chlordiazepoxide, clorazepate and zolpidem substituted only partially for alpidem but the effects of the training dose of alpidem were blocked by 10 mg/kg flumazenil. The second experiment established stimulus control more rapidly to a dose of 30 mg/kg alpidem. Alpidem induced dose-related stimulus control, and dose-related and complete substitution for alpidem was produced by zolpidem, abecarnil, CL 218,872, triazolam and suriclone. Partial substitution occurred with chlordiazepoxide, clorazepate and pentobarbital. In most cases, high levels of substitution were produced only by doses which greatly reduced response rates even though the training dose of alpidem produced only modest decreases in rates. Ethanol, buspirone and bretazenil produced very little substitution for alpidem and both flumazenil and bretazenil antagonised the effects of alpidem. In two further experiments alpidem was found to substitute for the stimulus produced by zolpidem (2 mg/kg) but not for that produced by ethanol (1.5 g/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Recent developments in the behavioral pharmacology of benzodiazepine (omega) receptors: evidence for the functional significance of receptor subtypes.

Recent research in molecular biology has demonstrated the complexity of GABAA receptors and shown that benzodiazepine (BZ-omega) receptor subtypes have a structural reality. It is therefore appropriate to ask whether the different pharmacological effects produced by benzodiazepines (anticonvulsant activity, anxiety reduction, motor incoordination, learning deficits, characteristic discriminative stimulus effects, tolerance and dependence) are associated with activity at different receptor subtypes. The present paper reviews the literature dealing with the behavioral effects of novel BZ (omega) receptor ligands relevant to the question of the functional significance of the BZ1 (omega 1) and BZ2 (omega 2) receptor subtypes. The only drugs currently available with a considerable degree of selectivity are alpidem and zolpidem. These compounds have relatively high affinity for GABAA receptors containing the alpha 1 subunit (corresponding to the BZ1 (omega 1) subtype) and very low affinity for receptors with the alpha 5 subunit (corresponding to one type of BZ2 (omega 2) receptor). Pharmacological effects observed with these, and other, less selective compounds allow several tentative conclusions to be drawn: (a) Little is known of the role of subtype selectivity in anxiolytic or amnestic effects but compounds with low intrinsic activity may reduce anxiety without giving rise to sedation or motor incoordination and BZ1 (omega 1) selective drugs appear to disrupt memory only at sedative doses; (b) Selectivity for BZ1 (omega 1) receptors may be associated with sleep-inducing activity but not with motor incoordination, suggesting that BZ2 (omega 2) receptors may be of particular importance in mechanisms of muscle relaxation; (c) The discriminative stimulus effects of different BZ (omega) receptor ligands are not identical and differences may be related to receptor selectivity; (d) Compounds with BZ1 (omega 1) selectivity and compounds with low intrinsic activity produce little or no tolerance and dependence. A wider range of selective compounds will be necessary to investigate these factors in detail and many different pharmacological profiles can be expected from drugs with selectivity and different levels of intrinsic activity.

Animals↗
PubMed1993

Repeated treatment with alpidem, a new anxiolytic, does not induce tolerance or physical dependence.

Alpidem is a new anxiolytic of imidazopyridine structure which has a high affinity for the omega 1 (BZ1) modulatory site of the GABAA receptor. The present study investigated whether tolerance and physical dependence develop after repeated treatment with alpidem, as is observed with benzodiazepines. Mice were given alpidem (100 mg/kg, p.o.) or diazepam (5 mg/kg, p.o.) twice daily for 10 consecutive days. Tolerance was assessed by measuring antagonism of pentylenetetrazole- and isoniazid-induced convulsions and bicuculline-provoked mortality, following repeated drug treatment. Decreases in the latency to isoniazid-induced convulsions and in the minimal convulsant dose of pentylenetetrazole were taken as an index of physical dependence and were evaluated at different times (3, 6, 14, 42, 67, 96 hr) after drug withdrawal or after flumazenil administration. In addition, changes in sensitivity to the convulsant effect of a beta-carboline (beta-CCM) were measured. Repeated treatment with diazepam produced tolerance to its anticonvulsant activities as indicated by shifts of the dose-response curves by a factor of 3-5. After discontinuation of diazepam treatment, spontaneous withdrawal occurred within 24 hr and lasted 67 hr as indicated by decreases in the threshold for convulsions induced by isoniazid and pentylenetetrazole. Flumazenil-induced withdrawal was observed in both isoniazid and pentylenetetrazole-induced convulsion models. Hypersensitivity of mice to the convulsant effect of beta-CCM also occurred. In contrast, repeated treatment with alpidem did not produce tolerance to its anticonvulsant effects and neither spontaneous nor flumazenil-induced withdrawal was observed in the pentylenetetrazole and isoniazid models. Moreover, withdrawal of alpidem did not induce any change in the convulsant activity of beta-CCM. These differences between alpidem and diazepam may be related to the low level of receptor occupancy during repeated treatment with alpidem because of its selectivity for omega 1 (BZ1) sites and to its moderate intrinsic activity.

Animals↗
PubMed1992

Differential development of tolerance to the depressant effects of benzodiazepine and non-benzodiazepine agonists at the omega (BZ) modulatory sites of GABAA receptors.

In a previous study, it was found that both the benzodiazepine hypnotic, midazolam, and the imidazopyridine hypnotic, zolpidem, which has selective affinity for a sub-population of omega (benzodiazepine, BZ) modulatory sites of GABA(A) receptors, produced similar decreases in rates of food-reinforced lever pressing in rats. However, during 10 days of repeated administration, marked tolerance developed to the depressant effect of midazolam but little tolerance developed with zolpidem. It was found in the present study that, with a within-subject design similar to that used previously, tolerance developed to the response rate-decreasing activity of the benzodiazepine, triazolam and the cyclopyrrolone, zopiclone but not to that of the triazolopyridazine, CL 218,872. In another experiment, using a between-groups design, tolerance developed to the effect of midazolam, even if the injections were not associated with daily test sessions, providing no evidence for a drug-environment interaction. The lack of tolerance to zolpidem was confirmed in two experiments. There was little indication of tolerance to the depressant effect of zolpidem, even after 19 days administration of daily doses, up to 30 mg/kg, a dose 10 times greater than that which completely suppressed responding. These results showed that the extent to which tolerance develops to the effects of drugs with affinity for omega (BZ) modulatory sites can show wide variations which may be related to differences in mechanisms of action.

Animals↗
PubMed1992

Activity of litoxetine and other serotonin uptake inhibitors in the tail suspension test in mice.

Compounds known to selectively inhibit the neuronal reuptake of serotonin are clinically effective antidepressants. However, in a number of the behavioral models used for detecting and analysing antidepressant action these drugs are inactive. The forced swimming test is not consistently sensitive to these drugs but it has recently been reported that a variation of this procedure, the tail suspension test in mice, is sensitive. The present study showed that five compounds previously shown to be selective serotonin uptake inhibitors--fluoxetine, zimeldine, paroxetine, indalpine, and litoxetine--produced dose-related decreases in immobility in the tail suspension test typical of the effects shown by other antidepressants. In separate experiments, fluoxetine, zimeldine, and indalpine decreased locomotor activity at doses similar to those that decreased immobility. In contrast, paroxetine and litoxetine had no effect on locomotion at the dose ranges active in the tail suspension test. These results confirm the sensitivity of the tail suspension test and indicate that serotonin uptake inhibitors probably decrease immobility and reduce locomotor activity through different mechanisms.

Animals↗
PubMed1992

Lack of tolerance and physical dependence upon repeated treatment with the novel hypnotic zolpidem.

Zolpidem is a new, short-acting hypnotic of imidazopyridine structure which binds selectively to a subpopulation of receptors involved in the action of benzodiazepines [omega 1 (BZ1) sites of the gamma-aminobutyric acidA receptors]. The present study investigated whether tolerance and physical dependence develop after repeated treatment with zolpidem as is observed with benzodiazepines. Mice were given zolpidem or the benzodiazepine midazolam (2 x 30 mg/kg, p.o.) for 10 consecutive days. Tolerance to central depressant effects (evaluated by recording spontaneous locomotor activity) and to anticonvulsant effects (measured against pentylenetetrazole-, electroshock- and isoniazid-induced convulsions) was assessed 42 hr after the last administration. A decrease in the latency to isoniazid-induced convulsions was taken as an index of physical dependence and was evaluated 3, 6, 14, 24, 42 and 67 hr after the end of chronic drug treatment. Repeated treatment with midazolam produced tolerance to its sedative and anticonvulsant activities as indicated by shifts of the dose-response curves by a factor of 3 to 5. Fourteen hr after discontinuation of treatment, spontaneous withdrawal was observed and lasted 3 days. When flumazenil was given 3 or 6 hr after the final midazolam injection, precipitated withdrawal was observed. In contrast, after repeated treatment with zolpidem, there was no change in its ability to produce sedative and anticonvulsant effects. Moreover, neither spontaneous nor flumazenil-induced precipitated withdrawal was observed in zolpidem-treated mice.

Animals↗
PubMed1991

Animal models of anxiety and the development of novel anxiolytic drugs.

1. The behavioural effects of classical anxiolytics such as barbiturates and benzodiazepines have been well characterised. However, recent research has been aimed at the development of novel anxiolytics without problems of sedation, muscle relaxation, amnesia and dependence. 2. A number of novel omega (benzodiazepine) receptor ligands with anxiolytic properties have been described including alpidem, bretazenil, suriclone and abecarnil. Although these compounds share some behavioural effects with older anxiolytic drugs, such as increasing punished drinking, they also show many differences. Their novel profiles may be related to low intrinsic activity or to selectivity for omega receptor subtypes. 3. The possibility that novel anxiolytics may be found among compounds active at serotonin receptors remains a strong hypothesis. Compounds, which, like buspirone, are active at 5HT1A receptors may be anxiolytic as may be antagonists at 5HT2 and 5HT3 receptors. All these compounds have behavioural effects which differ from those of benzodiazepines. 4. In order more effectively to screen for and develop novel anxiolytics it will be necessary to refine behavioural models in the light of feedback from the clinic.

Animals↗
PubMed1991

Tachykinins in the rat substantia nigra: effects of selective dopamine receptor antagonists.

The effects of sustained blockade of dopamine receptors by selective dopamine antagonists on the tachykinin (substance P and neurokinin A) content in the substantia nigra were examined. The treatment of rats for 14 days with D-1/D-2 dopamine receptor antagonist haloperidol (2 mg/kg) or selective D-2 antagonist sulpiride (100 mg/kg) produced a similar and significant decrease in nigral substance P and neurokinin A-like immunoreactivity content, about 32-36% and 27-28% of control respectively. In contrast, administration of SCH 23390 (1 mg/kg), a selective and potent D-1 dopamine receptor antagonist, failed to affect the levels of substance P and neurokinin A in the substantia nigra and did not change the sulpiride-induced reduction of the nigral tachykinin peptides. These results indicate that the D-1 dopamine receptors are not involved in the modulation of nigral substance P and neurokinin A content and suggest that the blockade of the D-2 dopamine receptor subtype exerts the same regulation of the tachykinin gene expression, in spite of the existence of three mRNAs encoding substance P and neurokinin A.

Amino Acid Sequence↗
PubMed1990

Differences in pharmacological profiles of a new generation of benzodiazepine and non-benzodiazepine hypnotics.

The hypnotics, quazepam (a benzodiazepine), brotizolam (a thienotriazolodiazepine), zopiclone (a cyclopyrrolone) and zolpidem (an imidazopyridine) have a common ability to bind to the benzodiazepine recognition site (omega receptor) within the GABAA receptor. For this reason we compared their pharmacological profiles in mice. All compounds shared anticonvulsant and central depressant effects. However, the sedative activity of zolpidem appeared at much lower doses than did the anticonvulsant and myorelaxant effects but the opposite was observed with the other hypnotics. In contrast to brotizolam, quazepam and zopiclone, zolpidem did not increase food intake in mice placed in a novel environment, indicating that this drug lacks disinhibitory activity. Moreover the efficacy of zolpidem at the GABAA receptor, as indicated by its activity against convulsions induced by the GABA synthesis inhibitor, isoniazid, was much greater than that of other hypnotics. These results suggest that the hypnoselective properties observed with zolpidem might be related to a high selectivity for the omega 1 recognition site of the GABAA receptor coupled with a very high intrinsic activity.

Animals↗
PubMed1990

The psychopharmacology of GABA synapses: update 1989.

Recent advances in the psychopharmacology of GABA synapses are reviewed. The usefulness of GABA mimetics in tardive dyskinesia and epilepsy has been confirmed, as has a dysfunction of GABA synapses in the etiopathology of these conditions. The antidepressant profile of GABA agonists in animal models for depression has been extended. The role of GABA receptors in the mechanism of action of antidepressants has been further delineated, with a parallelism occurring between the behavioral and biochemical response to antidepressant drug treatment in different animal models of depression.

Animals↗
PubMed1990

Pharmacological and behavioral profile of alpidem as an anxiolytic.

Pharmacological and behavioral studies in mice and rats have shown that the imidazopyridine alpidem possesses anxiolytic activity with a profile which is substantially different from that of benzodiazepines. Thus, in mice, alpidem inhibited marble-burying behavior and enhanced feeding under stressful conditions, as did benzodiazepines; in contrast to these drugs, however, alpidem was inactive against shock-induced fighting and shock-suppressed exploration. In rats, alpidem exerted anticonflict activity in the punished drinking test, but failed to antagonize punishment-induced inhibition of operant behavior. Moreover, in rats trained to discriminate chlordiazepoxide from saline, alpidem did not produce a benzodiazepine-like interoceptive stimulus. Alpidem also produced anticonvulsant effects in a variety of tests sensitive to benzodiazepines. However, the order of potencies against convulsions induced by different convulsive agents was different from that of the benzodiazepines. Alpidem decreased motor performance in the rotarod test and only produced a deficit in muscle strength at doses which were more than 20 times higher than the doses active in anxiolytic tests. Moreover, alpidem did not interfere with the acquisition of conditioned fear, except at very high doses, indicating a weak potential to impair memory. The effects of alpidem were antagonized by flumazenil, indicating that central omega receptors are involved in the action of this drug. The weak sedative effects of alpidem may be attributed to its low intrinsic activity, as demonstrated by its low efficacy in increasing latency to isoniazid-induced convulsions.

Animals↗
PubMed1990

Ifenprodil and SL 82.0715 as cerebral antiischemic agents. III. Evidence for antagonistic effects at the polyamine modulatory site within the N-methyl-D-aspartate receptor complex.

Ifenprodil and SL 82.0715 are noncompetitive N-methyl-D-aspartate (NMDA) antagonists whose inhibitory actions are not explained by antagonistic effects at any of the three commonly recognized sites within the NMDA receptor complex (recognition, channel and modulatory glycine sites). We presently show that ifenprodil and SL 82.0715 antagonize the effects of NMDA via a selective action at the recently described polyamine modulatory site. Spermine and spermidine (0.5-100 microM) increase the binding of [3H]1-[1-(2-thienyl)cyclohexyl] piperidine to washed rat forebrain membranes in the presence of glutamate (10 microM). This effect is antagonized by ifenprodil and SL 82.0715 (0.1-10 microM) at concentrations which do not displace [3H]1-(2-thienyl)cyclohexyl] piperidine in the absence of added polyamine. Spermine and spermidine (up to 100 microM) do not significantly alter the binding of [3H]glycine but increase the binding of the NMDA recognition site ligand [3H](+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid. Ifenprodil and SL 82.0715 (0.1-10 microM) antagonize this effect; ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-10-imine maleate) or 7-chlorokynurenate (100 microM) are ineffective. In immature rat cerebellar slices, spermine and spermidine (10-1000 microM) potentiate the maximal effects of NMDA (80-160 microM) on cyclic GMP production. Spermine (100-1000 microM) reverses the antagonistic effects of ifenprodil (0.15-50 microM) but not of ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-10-imine acid or kynurenate on the NMDA receptor-mediated increase in cyclic GMP levels. Ifenprodil (0.01-1 microM) potently but only partially antagonizes the depolarizing effects of NMDA (10 microM) on the immature rat spinal cord.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1989

Metalloendopeptidase (EC 3.4.24.11) but not angiotensin converting enzyme is involved in the inactivation of substance P by synaptic membranes of the rat substantia nigra.

Substance P is a neuropeptide released in vivo from the substantia nigra, the principal substance P nerve terminal region in the rat brain. Its inactivation was investigated in a purified nigral synaptic membrane preparation. The membrane-bound enzyme shares many features with the endopeptidase 24-11 (EC 3.4.24.11): 1) hydrolysis of peptide bonds Gln6-Phe7, Phe7-Phe8 and Gly9-Leu10, 2) sensitivity to the inhibition by phosphoramidon and 3) relative affinity for substance P. Bestatine and captopril inhibit only the hydrolysis of the metabolites. These results suggest that substance P is inactivated in substantia nigra by endopeptidase 24-11 and that a bestatin-sensitive aminopeptidase and angiotensin converting enzyme may play a role in subsequent degradation of the substance P metabolites.

Animals↗
PubMed1989

The gabaergic hypothesis of depression.

UNLABELLED: 1. GABAergic mechanisms have been generally ignored in the study of mood disorders and antidepressant drug (AD) action. Recently data have accumulated indicating that GABAergic mechanisms may be involved in both of these. 2. Mood disorders: GABA levels are reported to be low in the CSF and plasma of depressed patients and are related to mood changes. GABAB receptors are decreased in the frontal cortex in two rodent behavioral models of depression and GABA release is reported diminished in the hippocampus. GABAergic drugs (progabide, fengabine) reverse the behavioral deficits in the rodent models and exert clear therapeutic effects in depressed patients. 3. AD action: In behavioral models imipramine upregulates GABAB receptors only in those animals which respond behaviorally to the AD. In naive rats repeated administration of varied ADs upregulates GABAB receptors in the frontal cortex whereas non-ADs (including amphetamine) do not. Bicuculline inhibits the action of imipramine in the learned helplessness model. GABAA receptor stimulation enhances noradrenaline release in the ventral NA pathway. 4. CONCLUSIONS: GABAergic mechanisms likely play a role in the modulation of mood and increasing GABAergic tone exerts and antidepressant effect. Actions at GABA synapses appear to be a fundamental facet of ADs, perhaps together with beta-adrenoceptor mediated events.

Animals↗
PubMed1988

The interaction between zolpidem and beta-CMC: a clue to the identification of receptor sites involved in the sedative effect of zolpidem.

The interaction of beta-CMC, an amino beta-carboline recently described as a selective antagonist of the sedative effect of diazepam, with zolpidem, an imidazopyridine hypnotic, which like beta-CMC binds preferentially to the omega 1 (BZ-1) site of the GABA benzodiazepine chloride channel receptor complex, was investigated. In mice, beta-CMC antagonized the effect of zolpidem against isoniazid-induced convulsions without affecting its activity against convulsions induced by pentylenetetrazole or electroshock. beta-CMC also antagonized the decrease in locomotor activity and the impairment in muscle strength provoked by zolpidem. In rats trained to discriminate zolpidem, beta-CMC antagonized both the interoceptive stimulus and the decrease in the rate of lever pressing produced by zolpidem. This selective antagonism, inhibition of effects of zolpidem exerted by low doses (locomotor activity and isoniazid-induced convulsions) as well as effects produced by high doses (muscle strength) but not those provoked by intermediate doses (pentylenetetrazole and electroshock-induced convulsions), could not be explained by a receptor occupancy hypothesis. These results suggest that the anticonvulsant and sedative effects of zolpidem do not involve the same receptor subtype and that the hypnoselective properties of zolpidem may be linked to its selectivity for the omega 1 (BZ-1) site of the GABAA receptor.

Animals↗
PubMed1988

Degradation of substance P by membrane peptidases in the rat substantia nigra: effect of selective inhibitors.

The hydrolysis of substance P by membrane peptidases prepared from the rat substantia nigra was studied in the presence of selective inhibitors. Substance P degradation by synaptic and mitochondrial membranes was completely inhibited by 1,10-phenanthroline (1 mM), a non-specific metallopeptidase inhibitor. Captopril and bestatine, selective inhibitors of angiotensin converting enzyme and aminopeptidases respectively, were without effects. However, phosphoramidon (1 microM), a putative 'enkephalinase' inhibitor, selectively inhibited substance P degradation by synaptic membranes. These results suggest that a phosphoramidon-sensitive endopeptidase may be the principal enzyme responsible for substance P degradation in substantia nigra.

Animals↗
PubMed1988

Further behavioural evidence for the selective sedative action of zolpidem.

Small doses of benzodiazepines stimulate behavioural output in experimental animals in a variety of situations. Zolpidem, which displaces benzodiazepines from their binding sites, however, has been shown to exert preferential sedative activity. In order to investigate whether small doses of zolpidem would also have stimulant effects, the actions of zolpidem and chlordiazepoxide were compared in three procedures which are sensitive to the behavioural-facilitating effects of benzodiazepines in rats. A small dose of chlordiazepoxide (3.0 mg/kg) increased locomotion in an open field whereas a large dose (30 mg/kg) suppressed this behaviour. Zolpidem (0.3-3.0 mg/kg) only decreased locomotion. The effects of both chlordiazepoxide and zolpidem were antagonised by flumazenil. Chlordiazepoxide (2.5-10 mg/kg) increased the intake of food in rats habituated to a daily feeding schedule but similar doses of zolpidem neither increased nor decreased the intake of food. Rates of punished operant responding were increased by chlordiazepoxide (3.0-30 mg/kg) but zolpidem (1.0-4.0 mg/kg) produced no such anti-punishment effect and suppressed responding at the large dose. These results show that zolpidem does not increase behavioural output in situations which are sensitive to the stimulant effects of benzodiazepines and further emphasize the selective sedative activity of this drug.

Animals↗