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Biomedical subjects

M R Dzoljic

Publications and source records attributed to M R Dzoljic.

At least 19 recordsLinked to original sources
PubMed1997

Vigilance and EEG power in rats: effects of potent inhibitors of the neuronal nitric oxide synthase.

We examined the effects of potent neuronal nitric oxide synthase inhibitors, 3-bromo-7-nitro indazole (3-Br-7-NI) and S-methyl-L-thiocitrulline (S-Me-TC) on general behaviour, vigilance stages and electroencephalographic (EEG) power spectra in rats. In addition, we studied the effect of 7-nitro indazole (7-NI) on EEG power spectra in rats during dark and light periods. 3-Br-7-NI induced ptosis and decrease of slow wave sleep and rapid eye movement sleep in the rat. 7-NI and 3-Br-7-NI reduced the EEG power density in all frequency bands in the rat, suggesting a depression of central neuronal activity. This effect of 7-NI was more prominent during the day than during the night, indicating a circadian variation in the nitric oxide synthase (NOS) response to NOS inhibitor. EEG power was the most reduced in the 7-9 Hz range of the rhythmic slow activity (theta rhythm), which is in accordance with decreased locomotion observed following administration of NOS inhibitors. Although S-Me-TC is the most potent NOS inhibitor in vitro experiments, it had less effect on vigilance and EEG power in the rat than other NOS inhibitors used in this study, probably due to its short lasting and blood pressure raising effect. The present results indicate that nitric oxide exerts an excitatory and circadian dependent effect in the central neuronal structures involved in the regulation of vigilance.

Animals↗
PubMed1997

Anticonvulsant activity of new and potent inhibitors of nitric oxide synthase.

The effects of new and potent NOS inhibitors, S-methyl-L-thiocitrulline (S-Me-TC), 3-bromo 7-nitro indazole (3-Br-7-NI), and 1-(2-trifluoromethylphenyl) imidazole (TRIM), were examined on the pilocarpine-induced seizures in mice. 3-Br-7-NI and TRIM decreased the frequency of status epilepticus and mortality, while TRIM. In addition, significantly reduced the incidence of seizures. The latencies to onsets of seizures, status epilepticus, and mortality were significantly prolonged by all three NOS inhibitors, while duration of seizures was reduced by 3-Br-7-NI and TRIM. These data suggest an excitatory effect of NO in the neuronal structure involved in the pilocarpine-induced seizures.

Animals↗
PubMed1996

Sleep and nitric oxide: effects of 7-nitro indazole, inhibitor of brain nitric oxide synthase.

We examined the effect of 7-nitro indazole (7-NI, 2.5-50 mg/kg, i.p.), an inhibitor of central nitric oxide (NO) synthesis, on general behaviour and sleep. The results show that 7-NI induces ptosis, a loss of the righting reflex and decrease of the EEG amplitudes. Furthermore, a duration of slow wave sleep (SWS) and REM sleep decreased, while the latencies of SWS and REM sleep increased. The effects of 7-NI on general behaviour and sleep were partially antagonized by intraventricular administration of the NO precursor, L-arginine (600 micrograms). These findings indicate that 7-NI induces a state of prominent central depression associated with motor deficit and decrease in sleep stages and wakefulness. It further suggests that NO exerts a significant excitatory effect on the neuronal structure involved in the regulation of locomotion and vigilance.

Animals↗
PubMed1996

Visual evoked potentials and nitrous oxide-induced neuronal depression: role for benzodiazepine receptors.

We have examined the role of benzodiazepine receptors in nitrous oxide-induced neuronal depression in rats. The changes in neuronal excitability induced by nitrous oxide and the benzodiazepine inverse agonist, Ro15-4513, were monitored by measurement of visual evoked potentials (VEP). Administration of Ro15-4513 10 mg kg-1 i.p., in rats breathing air, did not affect the amplitude or latency of VEP. However, the same concentrations of Ro15-4513 antagonized nitrous oxide-induced depression of VEP amplitudes. We conclude that antagonism of nitrous oxide-induced depression by Ro15-4513 indicates that at least part of the decreased neuronal excitability caused by nitrous oxide could be ascribed to interactions with the GABAA receptor complex.

Anesthetics, Inhalation↗
PubMed1995

7-Nitro indazole, an inhibitor of neuronal nitric oxide synthase, attenuates pilocarpine-induced seizures.

7-Nitro indazole (25-100 mg/kg i.p.), an inhibitor of neuronal nitric oxide (NO) synthase, attenuated the severity of pilocarpine (300 mg/kg i.p.)-induced seizures in mice. This indicates that the decreased neuroexcitability of the central nervous system (CNS) following administration of 7-nitro indazole may be due to inhibition of neuronal NO synthase, implying that NO acts as an excitatory and proconvulsant factor in the CNS.

Animals↗
PubMed1995

Comparative study of normotensive and hypertensive nitric oxide synthase inhibitors on morphine withdrawal syndrome in rats.

The effects of the normotensive, mainly centrally active nitric oxide synthase (NOS) inhibitor 7-nitro indazole and the hypertensive drug NG-nitro-L-arginine, which blocks both the endothelial and the central NOS, have been examined on naloxone-precipitated withdrawal in morphine-dependent rats. Both drugs attenuated the same withdrawal signs (teeth-chattering, penile licking, diarrhoea, chewing, wet-dog shakes, grooming), while other signs remained unaffected (rearing, jumping, ptosis, rhinorrhoea, irritability on touch). These findings indicate that mainly central (but not endothelial) nitric oxide is involved in the expression of some opioid withdrawal symptoms.

Amino Acid Oxidoreductases↗
PubMed1994

The inhibitory effect of norharman on morphine withdrawal syndrome in rats: comparison with ibogaine.

Norharman (20 mg/kg, i.p.) and ibogaine (40 mg/kg, i.p.) significantly attenuated naloxone (4 mg/kg, i.p.)-precipitated withdrawal syndrome in morphine-dependent rats. Several withdrawal signs, such as teeth-chattering, chewing, penile licking and diarrhoea, were decreased by both norharman and ibogaine. In addition, norharman reduced also the withdrawal grooming and rearing. It is concluded that both norharman and ibogaine are inhibitors of withdrawal syndrome in morphine-dependent rats.

Animals↗
PubMed1994

Nitric oxide synthase inhibition reduces wakefulness.

The effect of NG-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide (NO) synthase and L-arginine, a precursor of NO, was examined on the sleep-waking pattern in rats. L-NMMA (3.75-15 mg/kg, i.p.) reduced wakefulness with a corresponding increase of slow wave sleep and rapid eye movement sleep. The effect of L-NMMA on vigilance was limited to the first hour following drug administration. The effect of L-NMMA was abolished by intracerebroventricular administration of L-arginine (600 micrograms). This indicates that the inhibitory effect of L-NMMA on wakefulness is mediated by decreased NO synthesis and that central NO exerts an excitatory role in vigilance. It further implicates that factors facilitating a release and/or synthesis of NO might lead to increased wakefulness and sleep disturbances.

Amino Acid Oxidoreductases↗
PubMed1994

Behavioral and electrophysiological aspects of nitrous oxide dependence.

We examined the effect of 70% nitrous oxide (N2O) on locomotion and visual-evoked potentials (VEP) in rats. The animals exposed to N2O showed an initial decrease of locomotion, followed by development of tolerance and unaltered motor activity during N2O withdrawal. Similarly, an initial decrease of VEP amplitudes was followed by tolerance to N2O. In addition, some amplitudes (N2-P3, P3-N3, and N3-P4) exceeded the control values, indicating an increase of neuronal excitability of the visual system during a long lasting exposure to N2O. The increase of VEP amplitudes was further potentiated by cessation of this gas. The VEP latencies after initial increase, returned to normal and remained unaltered during N2O withdrawal suggesting that the speed of neurotransmission is not essentially changed during chronic exposure to N2O. However, a significant increase of neuronal excitability during chronic N2O exposure, which further increased by cessation of N2O, could be of clinical importance. Therefore, monitoring of VEP, particularly the amplitude values, may significantly improve a detection of altered neuronal excitability during anaesthesia and drug withdrawal.

Animals↗
PubMed1993

Inhibitory effect of nitric oxide (NO) synthase inhibitors on naloxone-precipitated withdrawal syndrome in morphine-dependent mice.

The effect of intraperitoneally administered nitric oxide (NO) synthase inhibitors has been examined on the naloxone-precipitated withdrawal syndrome in morphine-dependent mice. L-NAME (30-200 mg/kg) and L-NOARG (7.5-50 mg/kg) induced a significant decrease of naloxone-precipitated withdrawal jumping and diarrhoea. However, L-NMMA (3.5-100 mg/kg), considered as a less potent NO synthase inhibitor, did not significantly affect the withdrawal signs in mice. Although a specificity of NO synthase inhibitors is not fully established, these results indicate that inhibition of NO synthesis in the central nervous system and periphery may significantly affect the morphine withdrawal phenomena. Accordingly, this study suggests an involvement of NO in morphine withdrawal syndrome.

Amino Acid Oxidoreductases↗
PubMed1993

Inhibitory effects of ibogaine on cocaine self-administration in rats.

In order to determine the potential anti-addictive properties of ibogaine, we used the cocaine self-administration model in rats. The results indicate that a single injection of ibogaine (40 mg/kg i.p.) produced a significant decrease of cocaine intake, which remained unaltered for more than 48 h. Since the half-life time of ibogaine is short, this might suggest the involvement of one or several active metabolites of ibogaine in cocaine intake. Repetitive administration of ibogaine on three consecutive days also induced a pronounced decrease of cocaine intake. However, a more prominent inhibitory effect on cocaine intake was observed in animals treated repeatedly with ibogaine (40 mg/kg i.p.), once each week for 3 consecutive weeks. These results indicate that ibogaine or its metabolite(s) is a long-lasting interruptor of cocaine dependence, which supports similar observations from uncontrolled clinical studies.

Analysis of Variance↗
PubMed1993

Excitatory amino acid receptor antagonists and naloxone-precipitated withdrawal syndrome in morphine-dependent mice.

The effects of the excitatory amino acid (EAA) receptor antagonists MK-801 (non-competitive NMDA receptor antagonist), DNQX (competitive non-NMDA receptor antagonist) and 5,7-DCKA (antagonist of glycine site of NMDA receptor) have been examined on the naloxone (4 mg/kg, i.p.)-precipitated withdrawal jumping behaviour in morphine-dependent mice. The results indicate that withdrawal jumping behaviour in morphine-dependent mice was attenuated by all three EAA receptor antagonists, MK-801, DNQX and 5,7-DCKA. However, MK-801, DNQX and 5,7-DCKA inhibited the jumping behaviour in a relatively narrow dose range.

Animals↗
PubMed1992

5-HT1-like receptor agonists enhance wakefulness.

The effects of four 5-HT1-like receptor agonists (8-OH-DPAT, RU 24969, BEA 1654 and 5-carboxamidotryptamine) and some putative 5-HT1-like receptor antagonists on vigilance were examined in an attempt to clarify the role of 5-HT1-like receptors in the sleep-waking pattern of rats. Both 8-OH-DPAT (0.5-2.0 mg/kg, s.c.) and RU 24969 (0.5-2.0 mg/kg, s.c.) increased wakefulness and the latencies of slow wave and rapid eye movement (REM) sleep. The slow wave and REM sleep were correspondingly decreased or completely abolished. The two other 5-HT1-like receptor agonists had either a slight (BEA 1654, 1.0-5.0 mg/kg, s.c.) or no (5-carboxamidotryptamine, 0.5-2.0 mg/kg, s.c.) effect on sleep pattern. The arousal effect of 8-OH-DPAT was further potentiated in rats pretreated with reserpine (2.5 mg/kg, i.p.; 18 hr before 8-OH-DPAT). The non-selective 5-HT1-like and 5-HT2 receptor antagonist, methiothepin (2.0 mg/kg, i.p.) and the beta-adrenoceptor antagonist propranolol (16.0 mg/kg, s.c.), which is a putative antagonist at 5-HT1A and 5-HT1B receptor subtypes, significantly potentiated the arousal effect of RU 24969. The putative 5-HT1A and 5-HT1B receptor antagonist, cyanopinolol (4.0 mg/kg, s.c.), mixed 5-HT1A receptor agonist/antagonist MDL 72832 (1.0 mg/kg, s.c.) and the alpha 1-adrenoceptor antagonist prazosin (2.0 mg/kg) did not affect the vigilance, altered by RU 24969. These results suggest that the arousal effect of 5-HT1-like receptor agonists is probably not mediated by any of the subtypes of 5-HT1-like receptors or by an activation of a noradrenergic system.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1992

The effects of orally active enkephalinase inhibitors on morphine withdrawal syndrome.

Considerable evidence has accumulated to suggest that intracerebroventricular administration of enkephalinase inhibitors, which do not penetrate the blood-brain barrier, significantly attenuates opioid withdrawal syndrome. Therefore, the aim of this study was to examine the effect of intraperitoneal (i.p.) administration of orally active enkephalinase inhibitors, acetorphan (2.5-20 mg kg-1) and SCH 34826 (15-120 mg kg-1). These drugs significantly decreased the severity of the naloxone precipitated withdrawal syndrome in morphine dependent rats and mice. It therefore appears that these orally active enkephalinase inhibitors are promising tools in studying modulation of opioid dependence phenomena.

Administration, Oral↗
PubMed1991

Sleeping with and without norepinephrine: effects of metoclopramide and D,L-threo-3,4-dihydroxyphenylserine on sleep in dopamine beta-hydroxylase deficiency.

Sleep characteristics are presented for two female patients (aged 21 and 31 years) with central and peripheral dopamine beta-hydroxylase (DBH) deficiency. This deficiency results in the absence of norepinephrine, epinephrine, and their metabolites in plasma, urine, and cerebrospinal fluid, while concentrations of dopamine are increased. The sleep pattern of these patients was studied when they were untreated, after blockade of central dopamine receptors with metoclopramide, and after restoring norepinephrine production with D,L-threo-3,4-dihydroxyphenylserine (DOPS). When the patients were untreated sleep duration was normal, with tendencies of a decreased amount of rapid eye movement (REM) sleep, presence of alpha-delta sleep, and an increased amount of slow-wave sleep. The amount of REM sleep varied between 18 and 21% of sleep period time. Administration of metoclopramide resulted in a slight reduction of REM sleep to 16-17%, whereas wakefulness after sleep onset increased. During treatment with DOPS, an increase in the amount of REM sleep was observed in both patients to an average amount of 27%. These data indicate that in patients with DBH deficiency norepinephrine is not essential for the development of a normal sleep/wake pattern but may have a facilitatory role in the generation of REM sleep.

Adult↗
PubMed1991

Decrease of beta-endorphin in the brain of rats following nitrous oxide withdrawal.

beta-Endorphin levels in the whole rat brain were not changed during acute (25 min) or chronic (48 h) exposure of rats to N2O. However, a significant decrease of beta-endorphin was found in the whole brain, brain stem and subcortex during the withdrawal from chronic exposure to N2O. It has been suggested that decrease of beta-endorphin levels during N2O withdrawal could be ascribed to unspecific stress accompanying drug withdrawal. Decrease of central beta-endorphin during N2O withdrawal might have a significant modulatory effect on transmitter balance, neuronal excitability and corresponding withdrawal behaviour. Furthermore, the decrease of beta-endorphin levels in the whole brain during N2O withdrawal might contribute to the postanaesthesia N2O-excitatory syndrome in humans. This might explain the known therapeutic effect of the opioid drug, meperidine on the excitatory N2O withdrawal phenomena during recovery from N2O anaesthesia in man.

Animals↗