International journal of neuropharmacology最新文献

It has been observed that (1) in chloralosed cats, centrally pretreated with either reserpine, imipramine or chlorpromazine, injection of phentolamine (3mg) or pronethalol (2mg) into the lateral cerebral ventricle, significantly reduces noradrenaline-induced pressor responses and heart rate increases, respectively; (2) equal intravenous doses of phentolamine or pronethalol lead to a less marked blockade of the cardiovascular effects of intraventricular noradrenaline in cats centrally pretreated with imipramine. These findings would suggest that sympathetic receptor mechanisms showing responses like those of “alpha” and “beta” types, as postulated at peripheral adrenergic sites, might also be involved in the central nervous system regulation of cardiovascular manifestations.

EEG analyses of amphetamine and its psychotomimetic methodoxy derivatives have been made in order to find their sites for evoking EEG alerting in rabbit brain. Four groups of animals were studied: controls with intact brain and others with transections of the brain at one of three different levels: above the midbrain, below the midbrain and through the first cervical segment.

Both d-amphetamine and methamphetamine induced EEG alerting at the midbrain level. In contrast, relatively potent psychotomimetic congeners paramethoxyamphetamine, 2,4,5-trimethoxyamphetamine and 2,5-dimethoxy-4-methylamphetamine provoked EEG alerting caudal to the midbrain and cephalad to the first cervical segment at the medullary level. A weak psychotomimetic congener 3,4-dimethoxyamphetamine possessed both sites, midbrain and medullary regions, for evoking EEG alerting.

l-Epinephrine administered via the lateral cerebral ventricle was found to decrease exploratory locomotor activity and potentiate hexobarbital sleeping time in rats. Both effects were dose-dependent and occurred with microgram quantities (3·3–125 μg) of epinephrine. Additional signs of a central depressant effect were noted in gross behavior. Although subcutaneous injections of l-epinephrine (0·025 and 1·0 mg/kg) also depressed locomotor activity, intraventricular injections proved much more effective. Lethality of l-epinephrine was enhanced by the intraventricular route, but the observed depressant effects occurred at doses well below the ld₅₀ and were observed to be completely reversible. The importance of the catechol moiety for the central depressant effects of epinephrine was emphasized by the results obtained from studying the effect on locomotor activity of a series of sympathomimetic amines. The parent compound, phenylethylamine, which is devoid of hydroxyl groups on the benzene ring and aliphatic side chain, was found to be excitant rather than depressant. Rank order of potency studies indicated that the depressant effect of catecholamines on locomotor activity might be mediated through central adrenergic receptors of the β-type. Studies with adrenergic blocking agents did not support this idea, however, and suggested that the central receptors involved are not identical to either the classical α or β adrenergic receptor.

The evoked and spontaneous activity of Renshaw cells in unanesthetized spinal cats was studied with metal microelectrodes before and after pentylenetetrazol (40 mg/kg). The drug did not prolong the discharge of Renshaw cells following dorsal root or ventral root stimulation. In addition, several cells were examined for the effects of the drug on spontaneous activity. Pentylenetrazol did not produce consistent changes in the rate of discharge.

Microinjections of histamine, norepinephrine or several cholinergic substances into the posterior hypothalamus of rats resulted in various effects on arterial blood pressure. Centrally injected histamine and norepinephrine produced an immediate rise in blood pressure. Carbachol usually produced a hypotensive response but on occasion a delayed rise in blood pressure or an immediate fall followed by a rise was observed. Pronounced changes in respiratory rate accompanied the rise in arterial blood pressure. The hypotensive response, which was also produced by acetylcholine and oxotremorine (a muscarinic agent) but not by nicotine, was mediated both centrally and peripherally by muscarinic mechanisms. Eserine, which produces a rise in blood pressure following systemic administration, caused a similar effect upon injection into the hypothalamus.

Serotonin, l-epinephrine, histamine and other neurotropic drugs increase spike amplitude in toad sciatics. The biogenic amines, pentolinium, nicotine and arecoline antagonized nerve block induced by cocaine, procaine, chlorpromazine, imipramine, strychnine, LSD, etc. Reversal of conduction block (without removal of blocker) showed that the antagonism did not result from interference with penetration. The action of the biogenic amines seems related to interactions with specific receptors rather than to general ionic effects since (a) they antagonized both Na-dependent threshold raisers (cocaine) and Na-independent blockers (chlorpromazine); (b) specific competitive-like antagonisms were observed (serotonin vs. imipramine block; antihistaminics vs. histamine protection against cocaine). The presence of scattered synaptic-like receptors on the axonal membrane is discussed.

Nicotine, in low doses of 20–40 μg/kg i.v., blocked the monosynaptic reflex without influencing spindle afferent activity. In contrast, succinylcholine depressed the monosynaptic reflex only when it enhanced spindle discharge. Abolition of the spindle excitatory effect of succinylcholine by gallamine or deafferentation eliminated the monosynaptic reflex depressant action of succinylcholine but did not affect that of nicotine. Mecamylamine, on the other hand, which blocks the nicotinic synapse at the Renshaw cell, abolished the monosynaptic reflex blocking effect of nicotine but not that of succinylcholine. These results emphasize the basically different mechanisms underlying the blockade of the monosynaptic reflex by nicotine and succinylcholine.

At intermediate doses of nicotine (40–80 μg/kg i.v.) spindle afferent activity was affected through changes in fusinotor activity consisting of a brief increase followed by prolonged depression. In still higher i.v. doses of nicotine, a direct excitatory effect on the spindle organ was observed. Depression of the monosynaptic reflex through this peripheral effect was revealed when the central action of nicotine was blocked by mecamylamine. Like the action of succinylcholine, it could be blocked by gallamine. Excitation of skin receptors and motor nerve terminals was excluded as a contributory cause of the monosynaptic reflex depression induced by nicotine in the dose range used.

Noradrenaline, isoprenaline, 5-hydroxytryptamine, acetylcholine, glutamate and gaba have been applied iontophoretically onto spontaneously active cortical neurones in cats under different anaesthetic conditions. Neurones were predominantly excited by monoamines in halothane anaesthetised cats and encéphale isolé preparations, and excitation was still seen when careful controls for current, pH and anion effects were made.

Noradrenaline excitations were blocked selectively by α-adrenergic antagonists (dibenamine, thymoxamine and phentolamine) and β-adrenergic antagonists (propranolol, d-INPEA and sotalol) when responses to acetylcholine, 5-hydroxytryptamine and glutamate were unaffected. However, noradrenaline depressions were relatively resistant to these antagonists. Cells tested with both noradrenaline and isoprenaline invariably responded in the same direction, in contrast to cells tested with either noradrenaline and 5-hydroxytryptamine, or noradrenaline and acetylcholine.

The time-course of noradrenaline, isoprenaline and 5-hydroxytryptamine excitation was similar, though slower than that seen with acetylcholine. The time-course of depression was identical for all four substances. The latency of onset of noradrenaline and 5-hydroxytryptamine excitation, but not depression, was inversely related to the spontaneous neuronal discharge rate. Since most neurones discharged at a low rate, there was usually a long latency for monoamine excitation.