7-Nitroindazole enhances amphetamine-evoked dopamine release in rat striatum. an in vivo microdialysis and voltammetric study.

The intracellular second messenger nitric oxide (NO) is implicated in a variety of physiological functions, including release and uptake of dopamine (DA). In the described study, in vivo microdialysis and differential pulse voltammetric techniques were used to determine the involvement of NO in release of DA and its metabolites (dihydroxyphenylalanine, DOPAC; homovanillic acid, HVA) in neostriatum of freely moving rats. While the NO donor molsidomine (30.0 mg/kg; MOLS) and neuronal NO synthase- (nNOS-) inhbitor 7-nitroindazole (10.0 mg/kg; 7-NI) had no effect on the basal in vivo microdialysate level of DA, 7-NI specifically enhanced D,L-amphetamine-(1.0 mg/kg i.p.; AMPH) evoked release of DA. Basal or AMPH effects on DOPAC and HVA levels were not influenced by MOLS or 7-NI. Findings indicate that nitrergic systems have an important role in mediating effects of AMPH on dopaminergic systems.

Basic pharmacological properties of a novel antiinflammatory drug tryptamide.

In rats and mice the basic pharmacological properties of tryptamide (TRP), a novel antiinflammatory substance were studied. The LD50 doses were for male rats 1260 mg/kg ip or 8.5 g/kg po, for male mice: 1980 mg/kg ip or 9.3 g/kg po. TRP produced evident antiinflammatory effects of potency comparable with those of phenylbutazone when studied by means of carrageenin-induced rat paw oedema and prostaglandin synthetase activity in vitro. TRP reversed pyrogen-induced hyperthermia in rats, elicited analgesic effects in rats, but not in mice, prolonged the time of hexobarbital sleep in rats and inhibited locomotor activity in rats and mice. TRP has not elicited side effects on the circulatory system of rats and cats. It is concluded that TRP may undergo clinical trials as a potential antiinflammatory drug. During these trials the attention should be paid to possible central side effects the drug.

Modulation of striatal dopamine metabolism by the activity of dorsal raphe serotonergic afferences.

Serotonin (5-HT)-dopamine (DA) interaction was studied in the caudate nucleus after electrical stimulation of the dorsal raphe (DR), an area containing 5-HT cell bodies and sending afferences to nigrostriatal dopaminergic neurons. The DR was stimulated by means of a bipolar stainless steel electrode for 16 min (10 Hz, 0.6 ms, 200 microA). 5-HT and DA metabolism were monitored before, during and after stimulation by in vivo differential pulse voltammetry. This electrochemical technique uses carbon fiber electrodes implanted in brain areas to record oxidation peaks corresponding to extracellular 5-hydroxyindolacetic acid (5-HIAA) and dihydroxyphenylacetic acid (DOPAC). Changes in the concentrations of the metabolites were recorded every 2 min in freely moving rats. Both 5-HIAA and DOPAC increased in the first minutes after the beginning of stimulation, the rise lasting 30 min after the end. That DR was closely involved was borne out by the fact that stimulation in the surrounding areas had no effect on either metabolite. Classical biochemical determinations in tissue samples were also used to study the effect on DA release: 3-methoxytyramine (3-MT) levels, measured in basal conditions and after blockade of its degradation by pargyline, were not changed, indicating that DR stimulation, though increasing DA metabolism, does not affect release. However, modulation of DA transmission by 5-HT afferences seems possible in certain circumstances. This 5-HT-DA interaction appears to be presynaptic (on dopaminergic terminals or cell bodies) since it is not prevented by kainic acid degeneration of striatal neurons.

Functional meaning of tryptophan-induced increase of 5-HT metabolism as clarified by in vivo voltammetry.

Differential pulse voltammetry with carbon fiber electrodes was used to study serotonin (5-HT) metabolism in freely moving rats. The electrodes implanted in the striatum recorded the extracellular 5-hydroxyindoleacetic acid (5-HIAA) oxidation peak after oral tryptophan (150 mg/kg). This 5-HT precursor did not modify the 5-HIAA peak in any rat tested, but it raised 5-HIAA levels determined in total tissue by a classical biochemical method (HPLC). The administration of 5-hydroxytryptophan (5-HTP) (25 mg/kg i.p.) induced an increase of 5-HIAA detectable both in the extracellular medium by voltammetry and in tissue samples. As previously shown, dorsal raphe electrical stimulation raises extracellular 5-HIAA in the striatum and this effect is enhanced by pretreatment with tryptophan. The results suggest that tryptophan in 'normal' conditions enhances 5-HT metabolism without affecting 5-HT release unless such release is stimulated. 5-HTP increases 5-HT metabolism and release.

Effect of neuroleptic drugs on prostaglandin synthetase activity.

The effects of neuroleptic drugs (chlorpromazine, trifluperazine, fluphenazine, benperidol, bromperidol, flupentixol, clozapine, reserpine, RO-4-1284) on the activity of prostaglandin synthetase were studied in the microsomes of the seminal vesicles of the bull. The activity of prostaglandin synthetase was determined in the microsomes of bull brain (cortex, striatum, hippocampus, thalamus, hypothalamus) and the effect of the neuroleptic drugs was determine on the activity of prostaglandin synthetase in the thalamus, where the activity of this enzyme was highest. It was found that the experimental model of seminal vesicles was unsuitable for evaluating the effects of neuroleptic drugs on the central nervous system. It was demonstrated that prostaglandin synthetase activity differed in different parts of the brain and this activity was highest in the thalamus. The obtained results indicate that inhibition of prostaglandin synthetase activity seems to have no significant importance in the mechanism of the neuroleptic action of these drugs.

Effect of prostaglandin synthesis inhibition on the central activity of noradrenaline in rats.

The effects of paracetamol and indomethacin on the action of centrally administered noradrenaline (NA) on the blood pressure, heart rate and rectal body temperature were studied in rats. It was demonstrated that both these substances increased NA effect on the arterial blood pressure and heart rate but caused no changes in NA effect on body temperature. These results suggest a modulating action of prostaglandins in the central nervous system on the functions of the centres regulating cardiovascular functions.

The influence of antidepressive drugs on the level of acetylcholine and on the acetylcholinesterase activity in the brain of rats.

Rats were treated ip with MAO inhibitos (MAO-I): nialamid (NL), pivalylbenzylhydrazine, tranylcypromine, pheniprazine (Ph) or pargyline, and the leve of total, free and bound acetylcholine (Ach) as well as the acetylcholinesterase (Ach-E) activity were estimated in four parts of rats brain 2 or 16 hr after the treatment. These parameters were estimated also after the treatment with tricyclic antidepressants: desmethylimipramine (DMI), amitriptyline, or protriptiline, and in the conditions of the reversal of reserpine-like syndrom. MAO-I, 2 hr after their application and the reversal of reserpine like-syndrom have not changed the level of measured fractions of Ach in parts of the brain. DMI increased the level of all Ach fractions in the striatum. NL caused the decrease of bound Ach level in all parts of the brain with no changes of free Ach level, 16 hr after the treatment. Ph, 16 hr after the treatment, decrease both fractions of ACh only in the cortex. All studied drugs affected evidently ACh-E activity in various parts of brain. It is concluded that:1) Cholinergic mechanisms in the rat brain are involved in the central action of DMI and of some MAO-I., 3) Cholinergic function of the brain may be modulated by the adrenergic activity, 2) Individual parts of the brain have different susceptibility to the influence of different MAO-I on the ACh-E activity.

Acute toxicity and the influence of some undecane, cyclopentylpentane and pyridine alpha- and beta-carboxylic acid derivatives on the increased hyperlipemia in rats.

Acute toxicity and hypolipaemic properties of 17 new compounds were studied in the tyloxapol test. Out of these, sodium salts of 1-chloro-2,6,10-trimethylundecane-1-carboxylic acid (I-2) and of 2-hydroxy-2-methyl-5 (2(2),2(2),3(2)-trimethylcyclopenten-3(2)yl)-pent-3-en-1-carboxylic acid (V) have hypolipemic activity.

Changes of certain pharmacological and biochemical indices in acute methylglyoxal poisoning.

Methylglyoxal in doses over 25 mg/kg injected intravenously in cats and rabbits produces distinct changes in the cardiovascular and respiratory systems, but has no effect on respiration or circulation when injected intraperitoneally even in doses up to 1 g/kg. The effect of MG on blood pressure depends on the species of the animal. The effects of MG are dose-related and dependent on the route of its administration. Biochemical studies showed a significant rise in serum activities of creatine kinase (EC 2-7-3-2), lactate dehydrogenase (EC 1-1-1-27) and aspartate aminotransferase (EC 2-6-1-1-) after intraperitoneal injection of MG in the dose of 200 mg/kg in rabbits and 500 mg/kg in rats. The observed changes probably indicate damage of muscle tissue by MG, presumably as a result of low content of one of the glyoxalases in the muscles of the experimental animals. Elevation of glucose levels by MG was probably an adrenergic effect. These biochemical changes can serve to evaluate toxicity of MG preparations, which exhibit variations probably owing to varying degree of polymerization.