International journal of neuropharmacology最新文献

DMPP administered intrarterially in doses of 1–2 μg produced a short biphasic ganglionic demarcation potential consisting of an initial period of depolarization with a subsequent phase of hyperpolarization. During depolarization, ganglionic action potentials were increased whereas during hyperpolarization the amplitude of the action potentials rapidly diminshed.

DMPP administered in the 5–20 μg doses evoked a biphasic blockade of transmission in the superior cervical ganglion of the cat. The first period of blockade was associated with the ganglionic depolarization and its magnitude and duration were dose-dependent. During the falling phase of depolarization, a partial recovery of ganglionic transmission occured, but after larger doses of DMPP (20–100 μg) this effect was not observed. The second period of blockade coincided with ganglionic hyperpolarization. This period was characterized by a strong increase of the negative after potentials while the spikes and positive after potentials were completely or partially blocked.

After 5–20 μg i.a. DMPP, asynchronous postganglionic firing of high amplitude was observed. Repetitive preganglionic stimulation markedly increased the postganglionic firing produced by DMPP, while hexamethonium (2 mg) and Ecolid (0·5 mg) abolished it almost completely.

Ganglionic depolarization evoked by ACh administered 15–60 min after DMPP was slightly diminished, whereas the postganglionic firing produced by ACh was strongly enhanced.

It is concluded that DMPP is a potent ganglionic stimulating agent actiing on the “nicotinic cholinoceptive sites” in the superior cervical ganglion of the cat.

The effects of a variety of neurotropic drugs on excitability and action potential form of the giant nerve fibers of the earthworm ventral cord were studied with external electrodes.

Earthworm giant fibers were like frog sciatic myelinated fibers in the types of changes induced by most drugs tested, the worm fibers being generally more sensitive. Many centrally active drugs, such as chlordiazepoxide, LSD and methamphetamine, resembled local anesthetics in causing conduction block by increased threshold; unlike procaine, the threshold elevation caused by the above drugs could not be restored transiently toward normal by repetitive maximal stimulation. With most imipraminics, phenothiazines and related agents the mechanism of conduction block did not seem to depend on threshold increase.

Earthworm fibers differed from frog sciatic in several respects: they were not made hyper-excitable by calcium depletion; they showed repetitive firing with high concentration of calcium (the repetitive firing could be antagonized by barbital and trimethadione, not by bromide or diphenylhydantoin); they showed transient lowering of threshold by cholinesterase inhibitors; catelectrotonic repetitive firing could be blocked byd-tubocurarine. Some of the above findings suggest that N-cholinergic receptors may function in earthworm but not in frog myelinated fibers.

The following relationships held true over a wide range of variation of nerve properties by drugs and physiological maneuvers. The ratio of spike voltage when at maximum rate of activation to the maximum spike voltage itself remained relatively constant (0·7 approximately): spike amplitude was modifiable independently of threshold or maximum rate of activation; usually there was an inverse relation between threshold and maximum rate of activation, the only notable exception being initial threshold-lowering action of typical depolarizing monovalent cations (K, Rb, Cs).

Effects of indole, indican, 1-methylindole, 1-methylindican, indoxylo-acetate, adrenochrome, adrenolutin, adrenochrome methyl ether, and 5,66-dihydroxy-1-methylindole were examined on activity of rats doing a variable-interval, positive-reinforcement task (bar pressing for food reward). All of the 3-hydroxylated indoles with the exception of indican were active. When the 3-hydroxyl group was blocked or removed, as in adrenochrome methyl ether or 5, 6-dihydroxyl1-methylindole, activity was lost completely. 1-Methylindole was also active, but a study of its metabolism showed it to be converted to 1-methylindican, which is probably the active agent. A side observation was that ethanol exhibited a synergistic effect to indoxylo-acetate.

The effect of atropine and curarine on the time course of the end-plate potential was studied in the presence and absence of anticholinesterases.

Methods consisted of measuring the voltage-current relation of the muscle membrane, using microelectrophoretic application of acetylcholine to the end-plate region, and measuring end-plate current with a voltage-clamp technique.

Atropine (10⁻⁴Eq/1) decreased the amplitude and shortened the time course of the end-plate potential in curarized muscle. The underlying end-plate current was decreased on the average by about 20%, and its time course was shortened by 30–40%. These effects of atropine became more pronounced during treatment of the muscle with anticholinesterases prostigmine (3 × 10⁻⁶M), diisopropylfluorophosphate (10⁻⁴ M) and tetraethylpyrophosphate (10⁻⁴ M).

Curarine decreased the amplitude but did not affect the time course of the end-plate potential and end-plate current. During treatment of the muscle with prostigmine (3 × 10⁻⁶M) ,however, a similar increase in the concentration of curarine shortened the time course on the average by 5–10%.

It is possible that in presence of atropine and curarine a late component of transmitter action (e.g. on more distant receptors) is suppressed.

A series of pharmacological trials conducted on AF 1161 are described. AF 1161 explicates, at doses much lower than toxic ones, certain effects on behaviour characterized by a picture of sedation and diminished reactivity to external stimuli. Even at very high doses, the drug does not provoke catatonia, paralysis, or a true hypnotic state. Death is preceded by a state of prostration, overtaken by clonic convulsion. The conditioned avoidance reflex in rats and reactions to different types of painful stimuli are inhibited at doses that scarcely influence general behaviour. Duration of sleep induced by hexobarbital is increased immediately after AF 1161 administration, but returns to normal after 24 hr. No significant hypothermic effect in normal animals was noted. Toxicity of amphetamine in grouped mice is inhibited. A depressant action on the linguomandibular reflex and, no a slight extent, on the knee jerk has been observed. AF 1161 possesses a very slight anti-histamine action, a moderate adrenolytic action and a powerful anti-serotonin action. Convulsions due to pentetrazol, electroshock and strychnine are not inhibited. A local anesthetic effect was also observed.

These results are discussed, and possible therapeutic use in man of AF 1161 is postulated.

The actions of imipramine on the inhibitory effects of the catecholamines norepinephrine, epinephrine and dopamine on transmission in the superior cervical ganglion of the cat were studied, in order to observe its influence on adrenergic sites at the synaptic level. Lower doses of imipramine potentiated only the inhibitory effects of norepinephrine, although with higher doses the potentiation of epinephrine action was also noted. The effects of dopamine were not changed significantly. Imipramine was found to depress ganglionic transmission, and it is suggested that it increases the amount of free norepinephrine acting on neurones involved in cholinergic transmission.

The effects of amphetamine, methylphenidate and caffeine were investigated on the locomotor activity of rats in a novel Y-maze situation. Parallel studies were made using locomotor wheels. Neither amphetamine nor caffeine increased Y-maze activity at doses which increased locomotor wheel activity. In contrast methylphenidate greatly increased activity in the Y-maze indicating a qualitative difference in the effects of this drug.

The effects of reserpine were determined on eleven measures of drug action at 2, 26, and 50 hr following an acute injection. All measures were almost equally affected at 2 hr after injection and estimates of ED-50 from the log dose-effect curves ranged from 1·20 to 2·12 mg/kg. There were large differences, however, between the various indices in the time required for recovery from reserpine action. Five separate patterns of recovery would be distinguished. (1) Complete recovery within 26 hr; tremor and conditioned escape. (2) Partial recovery at 26 hr and complete recovery by 50 hr; muscle tone and hunched posture. (3) Little or no recovery at 26 hr but complete recovery by 50 hr; ptosis, exploratory behavior and lever pressing on variable interval schedules. (4) No recovery at 26 hr and only partial recovery by 50 hr; spontaneous locomotor activity and lever pressing on a continuous reinforcement schedule. (5) No recovery at 26 or 50 hr; the conditioned avoidance response. These differences in the duration of reserpine action are discussed with respect to differences in duration of neurochemical effects of the drug on monoamine in the brain.

The changes in body temperature resulting from the handling, saline and amphetamine treatments of two inbred strains of mice, C3H/HeLac and BALB/c/Lac, have been recorded. The effects of strain, sex and aggregation on the response were studied at two environmental temperatures. The difference between the sexes for the effect of aggregation on the temperature response to handling 20 min after treatment was significant for both strains at room temperature. For BALB mice the effect was greater for females than males, and for C3H mice the effect was greater for males, thus showing a strong genetic influence. Because the response to saline was correlated with that to handling, and in order to minimize both the effects of handling and the injection of fluid, the response to saline was used as control when studying the response to amphetamine. The effects of strain and sex as previously found for amphetamine were confirmed. Whereas other workers always found an increase in the response when the mice were aggregated, we found that at room temperature 20 min after treatment, aggregation reduced the response for C3H mice particularly when compared with the control. The difference evident between the strains again emphasizes the genetic influence.