International journal of neuropharmacology最新文献

It is suggested that intertrial activity, which is highly correlated with escape/avoidance conditionability, may be enhanced or reduced by central and autonomic nervous system drugs. Furthermore, it is claimed that these drugs produce their effects in entirely different ways.

By employing animals which differed constitutionally in their levels of reactivity, and drugs which were assumed to act differentially upon the mechanisms underlying fear and activation, a systematic examination of these views has been possible. It is shown that a complex interaction exists between the level of emotionality, drugs, and dosage. Some of the parameters of this interaction are outlined and discussed.

The effects of 6-azauridine, a cancerostatic agent, on striated muscle and on neuromuscular transmission, were studied in the isolated phrenic nerve hemidiaphragm preparation of the rat. In the directly stimulated and curarized preparation, 6-azauridine in a concentration of 2 × 10⁻⁶ to 2 × 10⁻⁴ g/ml caused a late increase in contractions. Higher concentrations (2 × 10⁻³ to 2 × 10⁻²) resulted in an initial increase in muscle contractions followed by inhibition of the contractions which developed gradually. The concentration of 6 × 10⁻² led to a decrease in muscle contractions only. In the indirectly stimulated preparation, low concentrations of the drug (2 × 10⁻⁶ to 8 × 10⁻⁵) led to a slight increase in muscle contractions. The concentration from 8 × 10⁻⁴ up to 6 × 10⁻² caused an inhibition or blockade of muscle contractions. It was possible to overcome this inhibition temporarily with physostigmine (1 × 10⁻⁵) or tetanic stimulation. The effects of 6-azauridine on the contractile mechanism of striated muscle correspond to the action on smooth muscle described previously, both being biphasic, depending on the dose. The action of 6-azauridine on neuromuscular transmission was inhibitory in the concentrations having an opposite effect on directly stimulated muscle. It is concluded that this curare-like action of 6-azauridine is non-depolarizing.

The activities of 6-azauridine, 6-azauracil, some of 5-alkyl derivatives of 6-azauracil and 1-phenyl derivatives of 6-azauracil in producing a neurological impairment (estimated by dropping off a reversed wire mesh) and behavioural changes (measured on the intensity of exploratory activity) were compared in mice.

The substitution by an alkyl group on C-5 of 6-azauracil, which decrease the antimetabolite activity, increases the intensity and the rapidity of dropping off the mesh parallel to the prolongation of the alkyl chain. On the other hand there was no intensification in depression of exploratory activity with prolongation of alkyl chain. Effective inhibitors of orotidylic acid decar☐ylase—6-azauridine and 6-azauracil—produced depression of exploratory activity in doses ten times lower than those producing dropping off the mesh. Compounds lacking antimetabolite activities—5-alkyl derivatives of 6-azauracil and 1-phenyl derivatives of 6-azauracil—caused the depression of exploratory activity only in doses inducing falling off the mesh suggesting an unspecific character of this effect. In 6-azauridine and 6-azauracil the peak of the falling off the mesh was attained 1 hr after the injection of both substances, while the maximal depression of exploratory activity occurred after 4–5 hr, i.e. at the time when the former effect has already disappeared.

On the basis of this findings it is supposed that the central effects of 6-azauridine and 6-azauracil may be induced both by direct action of their substituted asym-triazine structure (the neurological disturbances) as well as by their specific antimetabolite action (behavioural changes).

The effect of a series of phenylethylamine and related compounds has been investigated on the activity of specific neurones from the isolated brain of the snail,Helix aspersa. Dopamine and Epinine were the most potent of the compounds tested. Both compounds inhibited the spontaneous activity of the neurones and hyperpolarized the cell membrane potential. (−)-Noradrenaline and (−)-adrenaline were respectively twenty-five and ninety-two times less potent than dopamine. Isoprenaline had no effect on neurone activity.

Evidence is presented for a dopamine receptor as distinct from an action of dopamine on either an α or β adrenaline receptor. There are two specific requirements for this dopamine receptor: (a) two hydroxyl groups on the 3 and 4 position of the benzene ring; (b) the presence of a terminal nitrogen either unsubstituted or with one methyl group. The presence of an ethyl or an isopropyl group on the terminal nitrogen of dopamine reduces activity. Ethyldopamine and isopropyldopamine are respectively 106 and 193 times less potent than dopamine. The presence of a hydroxyl group β to the terminal nitrogen reduces dopamine-like activity.

The relative effectiveness of N,N-dimethyltryptamine derivatives and amphetamine derivatives was evaluated in seven squirrel monkeys, trained to discriminate between two black discs of different sizes. After the animals learned the task, they were injected intraperitoneally with the test compounds and then retested. The dose-response curves showed that debilitating effects of the compounds were a function of dose. The median effective doses (ED₅₀) that disrupted their performance were calculated according to the graphic logarithmic probit method. The descending rank order of effectiveness of the compounds, according to theED₅₀ was: 2,5-dimethoxy-4-ethyl-amphetamine; 2,5-dimethoxy-4-methyl-amphetamine; psilocybin; 4-methoxy-N,N-dimethyltryptamine; N,N-dimethyltryptamine; and 6-hydroxy-N,N-dimethyltryptamine.

The action on ganglionic transmission of 6-azauridine, an antimetabolite of pyrimidine nucleotides, was studied in the sympathetic superior cervical ganglion of the cat. The action potential evoked by preganglionic stimulation and asynchronous discharge caused by close intra-arterial injections of acetylcholine were recorded from postganglionic fibers. The administration of low doses of 6-azauridine (50–70 μg) resulted in an increase in action potential amplitude and in prolongation of the asynchronous discharge. Medium doses (200–500 μg), caused an initial decrease in amplitude of both the action potential and asynchronous discharge, followed by a delayed increase in action potential amplitude and prolongation of the asynchronous discharge. After the administration of higher doses (1–5 mg) preganglionic stimulation or acetylcholine administration failed for several hours to evoke any response. After administration of low and medium doses of 6-azauridine, hexamethonium (0·5–2·0 mg) ord-tubocurarine(0·4 mg) completely blocked the prolonged asynchronous discharge. However, atropine (1–2 μg) caused the disappearance of the prolongation of asynchronous discharge alone. Tetanic stimulation and physostigmine administration were not capable of restoring the responses blocked by high doses of 6-azauridine. It is suggested that the facilitatory action of 6-azauridine might be due to an unmasking of muscarinic cholinergic receptors in the ganglion. The inhibitory effects might be due to the blocking of nicotinic receptors alone after administration of medium doses, and to the blocking of both nicotinic and muscarinic receptors after the administration of high doses of 6-azauridine.

Pooled plasma or serum from psychotic children was administered subcutaneously to mice prior to an intraperitoneal challenge with pentylenetetrazol. Experiments ranging over a wide interval between injection of blood fluid and convulsant failed to reveal an optimum time at which seizure behaviour was effectively altered. No significant difference was observed in the proportion of animals convulsing or dying in comparison with a control solution of either saline or plasma or serum from normal children. In addition the mean time of onset of either clonic or tonic seizures and the mean time of death were not appreciably altered.

Two modifications in experimental design, whereby (a) individual plasma samples were injected into individual mice, and (b) samples giving rise to death of the animal were pooled and administered to a further group, produced no change in any of the varibles measured. The results do not support the reported evidence for a pentylenetetrazol synergist in the serum of psychotic children.

In normal cats, 1, 1-diphenyl-2-aminoethanol (DPAE) caused ataxia, intentional tremors, and convulsions whereas lidocaine caused ataxia and convulsions but no tremors. In decerebrate cats, DPAE markedly inhibited cerebellar disfacilitation of spinal monosynaptic reflexes, slightly depressed reticular inhibition and had no effect on direct inhibition. The unconditioned monosynaptic reflex was facilitated by low doses and depressed by high doses of DPAE. DPAE did not affect reticular facilitation indicating that DPAE did not block cerebellar disfacilitation by depressing the facilitatory input to lower motoneurones. Lidocaine markedly reduced cerebellar disfacilitation and also reduced reticular and presynaptic inhibition as well as pressor and facilitatory responses.

It is concluded that the tremors and ataxia of DPAE are manifestations of the preferential blockade of cerebellar disfacilitation, and that this action of DPAE may take place at the inhibitory synapses of cerebellar Purkinje cells on neuronal systems responsible for the tonic excitatory input to lower motoneurones.

The effects of picrotoxin, strychnine, and pentobarbital on cuneate transmission were investigated in the cat. The positive wave, recordable at the surface of the cuneate nucleus and indicative of depolarization of cuneate afferent terminals, was reduced by picrotoxin. Picrotoxin also blocked the increase in excitability of cuneate presynaptic terminals produced by conditioning cortical or cutaneous volleys (applied 10–150 msec before the test volley). It reduced the inhibition of the lemniscal discharge by conditioning cutaneous sources. Pentobarbitone showed opposite effects and antagonized those of picrotoxin. Strychnine enhanced the increase in excitability of the cuneate terminals and increased the size of the test lemniscal response, but it further increased inhibition of that response by conditioning volleys applied 10–150 msec before the test volleys. The results give pharmacological evidence for the presence of presynaptic and postsynaptic inhibition in an important sensory nucleus.