[Role of 5-HT(2A) receptor in increase in respiratory-related rhythmic discharge activity by nikethamide in neonatal rat transverse medullary slices].

To investigate the effects of nikethamide on the generation and modulation of rhythmic respiration of neonatal rats and the role of 5-HT(2A) receptor in this course, experiments were performed on the transverse medullary slices of neonatal rats (both sexes, 1-3 d) in vitro. The slices containing the medial region of the nucleus retrofacialis (mNRF) with the hypoglossal nerve rootlets were prepared in which the respiratory-related rhythmic discharge activity (RRDA) was recorded from the hypoglossal nerve rootlets by suction electrode. The possible role of nikethamide on RRDA was investigated by administration of an agonist of 5-HT(2A) receptor, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), and an antagonist of 5-HT(2A) receptor, ketanserine, dissolved in modified Krebos solution (MKS). Thirty slices were randomly divided into five groups: Group 1: the slices were perfused with different concentrations of nikethamide (0.5, 1, 3, 5, 7, 10 µg/mL), and the most effective concentration was selected; Group 2: the slices were perfused with DOI (40 µmol/L); Group 3: the slices were perfused with ketanserine (40 µmol/L); Group 4: the slices were perfused with ketanserine + DOI; Group 5: the slices were perfused with nikethamide, then perfused with nikethamide + ketanserine after washout of nikethamide. Nikethamide increased RRDA in transverse medullary slices at 0.5-7 µg/mL, and 5 µg/mL was the most effective concentration. DOI increased RRDA with prolonged inspiratory time (TI), increased integral amplitude (IA), and shortened respiratory cycle (RC). Ketanserine decreased RRDA with shortened TI, decreased IA and prolonged RC. Ketanserine + DOI had no significant effects on RRDA. The effects of nikethamide on RC and IA were totally and partially reversed by additional application of ketanserine, but the effect of nikethamide on TI was not influenced by ketanserine. It is proposed that nikethamide increases RRDA partly via 5-HT(2A) receptors.

The effect of central stimulant drugs on acetylcholine release from rat cerebral cortex.

1. The effects of central stimulant drugs injected intraperitoneally were examined on the release of acetylcholine (ACh) from the cerebral cortex of the anaesthetized rat. The effects of the drugs in increasing ACh release were approximately parallel to the increases produced in the electrical activity of the brain.2. Leptazol in a dose of 150 mg/kg increased the release of ACh by 2.9 times the resting release and in a dose of 300 mg/kg by 7.5 times; on the e.e.g. the injection produced a large increase in the electrical activity.3. Picrotoxin in a dose of 12 mg/kg increased the release of ACh by 7.5 times and on the e.e.g. caused a large increase in activity.4. Strychnine in doses of 8 mg/kg and 12 mg/kg increased the release of ACh by 2.0 and 2.4 times and produced a small increase in the activity of the e.e.g.5. Dexamphetamine in a dose of 100 mg/kg increased the release of ACh by 1.9 times and had no appreciable effect on the e.e.g.6. Nikethamide in a dose of 2 g/kg increased the release of ACh by 2.3 times and produced no appreciable change in the e.e.g.7. Caffeine in a dose of 100 mg/kg produced no significant effect on the release of ACh.

Effects of general stimulant drugs on the electrical responses of isolated slabs of cat's cerebral cortex.

1. In the neuronally isolated cortex of the cat, local application of bemegride, picrotoxin, nikethamide, caffeine and strychnine facilitated the surface positive response of the isolated cortex and lowered the stimulus threshold for this response. Excepting nikethamide, they all produced convulsive discharge in the isolated cortex unrelated to the applied stimulus.2. Local application of glutamate to the cortex produced spreading depression, which was sometimes preceded by spontaneous positive bursting.3. In contrast to the "general depressants" which produce a relatively consistent pattern of effects on the electrical responses of isolated cortex, the "general stimulants", although they all have excitatory effects on isolated cortex, each produced a greatly different type of electrical response in the isolated cortex, suggesting that several different mechanisms of action are responsible for their effects.

Effects of drugs acting alone and in combination on the motor activity of intact mice.

1. When administered to intact white mice, the central depressants-diphenhydramine, promethazine, chlorpromazine, gammahydroxybutyrate, gammabutyrolactone, hyoscine, and pethidine-produced sedation in small doses, but excitement and convulsions in higher doses. When given to mice pretreated with subanaesthetic doses of phenobarbitone these drugs abolished the righting reflex both in convulsant doses (hyoscine excepted) and in non-convulsant doses. These effects are similar to the effects previously observed with local anaesthetics.2. Meprobamate, diazepam and chlorpromazine produced a loss of righting reflex both when given alone and following phenobarbitone. When given alone in higher doses, chlorpromazine induced convulsions.3. The central stimulants bemegride and picrotoxin antagonized the loss of righting reflex produced by phenobarbitone, but nikethamide, caffeine and strychnine did not alter the depressant effects of phenobarbitone.4. On the basis of these and previous studies with intact white mice a tentative classification of drugs having generalized depressant and stimulant effects on the central nervous system was proposed and discussed.

The effect of solvent polarity upon rotational barriers in nikethamide.

In summary, dynamic nuclear magnetic resonance techniques were used to study the hindered internal rotation of the amide bond of the analeptic nikethamide. The rotatory motion of this bond was studied in a series of solvents of increasing polarity: CDCl3, CH3(CH2)3OD, CH3CH2OD, CH3OD and D2O. Motion about the amide bond was increasingly hindered in direct proportion to solvent polarity, correlating with enhanced hydrogen bond formation between nikethamide and the more polar solvent molecules. Diethylamide group motion would be expected to affect binding of the carbonyl oxygen to cholinergic receptor sites. The degree to which association to a receptor site can be affected by this rotatory motion may vary from 0 to 4 kcal/mole, the variability being entirely dependent upon the polarity of the binding site. An increase in rotamer lifetime, corresponding to a more polar environment, would be expected to enhance the kinetics of nikethamide association to the receptor site.

Enhancement of excitant amino acid release from rat brain slices by the convulsant 3-mercaptopropionic acid.

The convulsant, 3-mercaptopropionic acid (100-1000 microM) enhanced potassium-evoked release of exogenous D-aspartate from slices of rat cerebral cortex and cerebellum, but not that from slices of hippocampus. Elevation of excitant amino acid release may contribute to the convulsant action of 3-mercaptopropionic acid. Unlike the convulsant barbiturate CHEB, 3-mercaptopropionic acid did not influence protoveratrine-stimulated release of D-aspartate and its action on potassium-evoked release appeared to be not dependent on calcium ion fluxes. Several other convulsants, including bemegride (200 microM), benzodiazepine Ro-5-3663 (100 M), nikethamide (500 microM), pentylenetetrazole (500 microM), and 4,6,6-trimethylcaprolactam (100 and 500 microM), and the glutamate decarboxylase inhibitor isoniazid (500 microM) failed to influence potassium-evoked release of D-aspartate.

Potentiation of cathinone by caffeine and nikethamide.

The drug discrimination paradigm was employed to evaluate the effect of coadministration of both caffeine and nikethamide upon the discrimination of a low dose of cathinone. In rats trained to discriminate between 0.8 mg/kg l-cathinone and its vehicle in a two-lever food-motivated operant task, 0.2 mg/kg cathinone produced 29.2% of responses on the cathinone-appropriate lever. This lever was chosen in 0 and 50% of trials with 25 mg/kg nikethamide and 20 mg/kg caffeine, respectively. Coadministration of caffeine, nikethamide, or caffeine plus nikethamide with low-dose cathinone produced strong cathinone-like discriminative performance. This potentiattion of cathinone by caffeine and nikethamide is reflective of noncontrolled drugs of abuse containing similar combinations especially for that of antiadipositum X-112, a drug containing all three agents and widely abused in Europe.

EFFECT OF NIKETHAMIDE AND DIAZEPAM ON THE LEVELS OF BIOGENIC AMINES IN THE DIFFERENT PARTS OF THE POULTRY BRAIN AT THREE AGE GROUPS.

Fifty four female poultry birds of 3, 4 and 5 months age were given nikethamide and diazepam intramuscularly as stimulant and depresent, respectively. The effects of above two drugs on the levels of biogenic amines were measured Fluorometrically in the rostral, middle and caudal portions of poultry brain. Diazepam increased the levels of 5-HT and dopamine in the caudal and middle portion of the brain respectively. The levels of dopamine and non-epinephrine increased with the nikethamide administration and also with increasing age of the birds, but the effect of diazepam was inconsistant. Unlike the levels of dopamine and nor-epinephrine which were maximum in middle protion, the epinephrine concentration was highest in the caudal portion of brain. It was concluded that 5-HT acted as inhibitory particularly in the caudal portion, whereas, catecholamines as excitatory neurotransmitter of the poultry brain. The increased levels of catecholamines in the poultry brain with increasing age speaks of their positive role in sexual maturity and subsequently in reproduction of the birds.

Effects of tranquillising, antidepressant and central nervous system stimulant drugs on the gamma-aminobutyric acid (GABA) level of rat brain.

The level of y-aminobutyric acid (GABA) was determined in the brain of rats 1 hr. after i.p. injection of chlorpromazine, prochlorperazine, diazepam, trimipramine, methamphetamine and nikethamide. Diazepam increased, and, trimipramine and amphetamine decreased the brain GABA level over wide dose ranges. Low doses of chlorpromazine and prochlorperazine increased but high doses of the drugs reduced the GABA level. Low doses of nikethamide reduced whereas high doses increased the level of GABA. The effects of the drugs have been discussed in relation to the brain GABA level.

[The perception of an odogen is proportional to the activity of the autonomous nervous system in man]. / Pertseptsiia odogena proportsional'na aktivnosti avtonomnoi nervnoi sistemy u cheloveka.

Women aged 18-26 characterized according to R. M. Baevskii's cardiointervalometric criteria by the balance between sympathetic and parasympathetic activities ("normotonicity") participated in the experiments. Sniffing subthreshold concentrations of cordiamin solution vapour during 7-9 s was revealed to increase activity of the sympathetic nervous system and heart rate frequency with a decrease of its variability. Normotonic subjects with predominance of the parasympathetic activity were found to have lower thresholds of the odogen detection and to be more cardioreactive to the subthreshold odogen than the "normotonics" with slight predominance of the sympathetic activity.

[Effect of long-term administration of undevit and its combination with cordiamine on hydroxylation, glucuronidation and glutathione conjugation systems and lipid peroxidation in rat liver]. / Vliianie dlitelnogo vvedeniia undevita i ego kombinatsii s kordiaminomna gidroksiliruiushchuiu, gliukuro-, glutationkoníugiruiushchuiu sistemy i perekisnoe okislenie lipidov pecheni intaktnykh krys.

Increase of N-demethylase and antioxidant activities and decrease of amount of hydroperoxides were observed in liver of rats after intragastric administration of Undevit (1/8 dragee/rats/day, 5 times a week during 2 months). Combination of Undevit with Cordiamin (5 mg/rat/day) resulted in augmentation of cytochromes P-450 and b5 content and activities of their reductases, velocity of amidopyrine and ethylmorphine N-demethylation and oxidation of HADPH. Activities of UDP-glucuronyltransferase, glutathionetransferase and hydrophobity of microsomal membranes were also increased. Antioxidant activity was increased and amount of hydroperoxides in liver microsomes and homogenates and in plasma was decreased in greater degree after administration of combination two compounds than after administration of Undevit alone.