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B Zivkovic

Publications and source records attributed to B Zivkovic.

68 records · Page 4Linked to original sources
PubMed1976

Cyclic AMP content and regulation of tyrosine-3-mono-oxygenase in rat striatum.

The unilateral transection of nigro striatal dopaminergic axons produced a short lasting (15-30 min) increase in the affinity of striatal tyrosine 3-mono-oxygenase (TH), for a synthetic pteridine cofactor (DMPH4). The kinetic changes of striatal TH were paralleled by an increase of striatal cAMP content. Apomorphine (10 mg/kg i.p.) failed to block the activation of TH by cerebral hemisection. Haloperidol (5 mg/kg i.p.) and reserpine (5 mg/kg i.p.) also elicited a sudden and similar change in striatal TH activity but this response occurred without an increase in the cAMP content and lasted for longer than 2 hrs. If the hemisection of nigrostriatal pathway was performed after haloperidol or reserpine injection the activation of TH produced by these two drugs was reversed rapidly (about 30 minutes). Pretreatment with haloperidol or reserpine prevented the increase of striatal cAMP following cerebral hemisection. Moreover, haloperidol injected 30 min after cerebral hemisection failed to change the TH kinetic properties in the striatum ipsilateral to the lesion but it changed striatal TH in the side contralateral to the lesion. These results suggest that the increase in the affinity of striatal TH for the pteridine cofactor elicited by cerebral hemisection is not related to a lack of stimulation of DA autoreceptors. Moreover these experiments provide an evidence that postsynaptic dopamine receptors play a role in the activation of striatal TH elicited by haloperidol.

Animals↗
PubMed1975

The regulation of striatal tyrosine hydroxylase. Effects of gamma hydroxybutric acid and healperidol.

Gamma-hydroxybutyric acid (GHBA) in doses that increased the striatal dopamine (DA) content of rat brain failed to increase the affinity of striatal tyrosine hydroxylase (TH) for its pterdine cofactor or to change the sensitivity of the enzyme to the inhibition by DA. Haloperidol (1 mg/kg) decreased the apparent Km of striatal TH for the pteridine cofactor. However, when GHBA was injected before haloperidol it prevented the decrease in the apparent Kn of TH, in a dose related manner. In vitro GHBA (10(-4) M) neither changed the stimulation of the striatal adenylyl cyclase by DA nor its inhibition by haloperidol. These results suggest that in striatal dopaminergic terminals the Kn of TH for the pteridine cofactor is regulated by an molecuular mechanism which requires that the impulse flow in the DA neurons is unimpaired.

Adenylyl Cyclases↗
PubMed1975

Effect of thioridazine, clozapine and other antipsychotics on the kinetic state of tyrosine hydroxylase and on the turnover rate of dopamine in striatum and nucleus accumbens.

In rats, a single injection of antipsychotic drugs produced a transitory change in the kinetic state of tyrosine hydroxylase (TH) in striatum and nucleus accumbens. The affinity of TH for 2-amino-4-hydoxy-6,7-dimethyl-5,6,7,8-tetrahydropterine (DMPH4) and the Vmax with respect ot tyrosine were increased. The relative potencies of anti-psychotics to change the kinetics of TH in striatum and nucleus accumbens when injected into rats were measured in the presence of 0.4 mM DMPH4. The doses of methiothepin, pimozide and halopridol which increased the affinity for DMPH4 of striatal TH were lower than those required to produce a similar change in nucleus accumbens. In contrast, thioridazine and clozapine were more effective in nucleus accumbens than in striatum. Chlorpromazine was equally active in these two tissues. Haloperidol increased the turnover rate of dopamine in striatum with doses that are relatively smaller than those required in the nucleus accumbens. Clozapine was more active in increasing turnover rate of dopamine in nucleus accumbens; the activity of chlorpromazine in these two tissues was equal. These results suggest that antipsychotics with high incidence of extrapyramidal side effects affect the nigrostriatal dopaminergic pathway selectively.

Adenylyl Cyclases↗
PubMedDate not supplied

[Contribution of zolpidem in the management of sleep disorders].

Zolpidem is a nonbenzodiazepine hypnotic agent belonging to a new class of psychotropic drugs the imidazopyridines which enhance the GABAA receptor function by interacting with a specific receptor population. Zolpidem binds selectively to the Omega-1 receptor subtype and from a pharmacological point of view differs from benzodiazepines (BZD) by producing a strong sedative and hypnotic profile which predominates over the anticonvulsivant and anxiolytic activity and moreover appears practically devoid of myorelaxant properties. From a pharmacodynamic point of view, these results suggest that zolpidem facilitates more selectively than BZD, GABAA function and produces a selective hypnotic effect. Though if the role played by receptors in tolerance and dependence has not been yet fully elucidated, it could be described as an adaptative process to sustained stimulation of GABA function. Animal data obtained with zolpidem differs substantially from that of the BZD and indicates that repeated zolpidem administration may not lead to phenomena of tolerance and withdrawal syndrome after abrupt drug discontinuation. In human following oral intake, zolpidem is very rapidly (Tmax: 30-40 min) absorbed. The clearance is essentially metabolic and less than 1% is recovered in urine. The apparent plasma half-life is of 2.0-2.5 hours in most adult subjects and metabolites are totally inactive. The hypnotic activity of zolpidem and its effects on sleep architecture have been assessed in polysomnographic studies: 11 studies in 579 healthy volunteers and 12 studies in 202 insomniac patients. From all the patient studies, it emerges clearly that zolpidem at the dose of 10 mg significantly decreases sleep onset latency, the number and the duration of nocturnal awakenings, and concomitantly increases total sleep time. Furthermore, at variance with what observed with reference benzodiazepine hypnotics, zolpidem does not alter patient sleep architecture: it increases only moderately stage 2, it increases, when reduced, stages 3 and 4 (slow wave sleep) and it does not decrease REM sleep. Clinical studies conducted on more than 4,000 insomniac patients have clearly shown that at the dose of 10-20 mg, zolpidem induces from the first night a definite hypnotic effect in all types of insomnia. In elderly subjects an initial dose of 5 mg should be considered. The possible presence of residual effects during the day following administration of zolpidem has been assessed in 535 healthy volunteers and in 133 insomniac patients according to a double blind (versus placebo and/or benzodiazepine) controlled design.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMedDate not supplied

[A specific domain (the omega 1 site) of the GABA(A) receptor may be implicated in the hypnotic effects of zolpidem].

Zolpidem (Stilnox) is a new hypnotic belonging to the imidazopyridine series. In animals, in contrast to the benzodiazepines which alter sleep architecture, zolpidem induces a physiological pattern of deep sleep. Zolpidem also differs from the benzodiazepines by its hypnoselective profile (its sedative effects are seen at doses much lower than those needed for anticonvulsant or myorelaxant effects). In this review, the authors analyze the hypothesis that the hypnoselective profile of zolpidem is linked to its interaction with a specific domain, the omega 1 site, of the GABAA receptor complex. This hypothesis is supported by: 1) the high selectivity of zolpidem for omega 1 as compared to omega 2 sites and its high intrinsic activity, 2) autoradiographic studies of the regional distribution of omega 1 and omega 2 sites in the human and non-human primate brains showing that omega 1 sites are located preferentially in sensorimotor cortical regions whereas omega 2 sites predominate in the limbic system and spinal cord. The selectivity of zolpidem for omega 1 sites could also account for the fact that in contrast to the benzodiazepines, this compound does not alter memory functions at hypnotic doses.

Animals↗