International journal of neuropharmacology最新文献

The interaction between phenylalkylamines and reserpine was studied on rats and cats be examination of the pressor and basal metabolic rate enhancing action of amphetamine, the psychostimulant and basal metabolic rate enhancing actions of ortho-bromo-methyl-amphetamine (V-104), and the pressor, psychotomimetic, basal metabolic rate enhancing and EEG-actions of para-bromo-methylamphetamine (V-111) and para-chloro-methylamphetamine(S-33). In all measurements of the effects of the compounds it was observed that if 0·5 mg/kg of reserpine was administered subcutaneously after the end of the phenylalkylamine effects, all central and peripheral effects reappeared with the equal intensity to that which could be expected from a repeated dose of the particular phenylalkylamine derivative. This phenomenon is thoughy to be due to the inactive bonding of the major part of the phenylalkylamine molecules on the receptor area from where they are released by reserpine into the active state. No such phenomenon may be observed after chronic reserpine pretreatment. Thus, it is suggested that chronic reserpine treatment enhances the sensitivity of the central nervous system to phenylalkylamines.

The interactions of chlorpromazine (5 mg/kg), chlorpromazine sulfoxide (5 mg/kg) or imipramine (0·5 mg/kg), agents which have both adrenergic-blocking and adrenergic-potentiating properties, with amphetamine (2 mg/kg) or methoxamine (0·88 mg/kg), indirectly and directly acting sympathetic amines, were studied on the flexor reflex of the chronic spinal dog. Both methoxamine andd-amphetaminefacilitate the flexor reflex. Chlorpromazine completely antagonized the facilitatory effects of both methoxamine andd-amphetamine. Chlorpromazine sulfoxide and imipramine partially antagonized the facilitatory action of methoxamine; however, the antagonism was surmounted. Neither chlorpromazine sulfoxide nor imipramine antagonized the facilitatory effect of amphetamine; in fact, it was somewhat enhanced by chlorpromazine sulfoxide. It has been concluded that the central adrenergic-blocking property of chlorpromazine predominates, whereas, the adrenergic-blocking and adrenergic-potentiating effects of chlorpromazine sulfoxide and imipramine counterbalance each other.

The sites of action of ketamine (CI-581; 2-(0-chlorophenyl)-2-methylamino cyclohexamine HCl) were determined in the central nervous system using electrophysiological techniques in both acute and chronic cat experiments. It was demonstrated in chronic preparations that the cataleptic anesthetic state induced by ketamine is accompanied by an alternating pattern of hypersynchronous delta wave bursts and low voltage, fast wave activity in the neocortex and thalamus. The delta wave bursts had a distribution in the neocortex similar to that of spindles produced by low doses of barbiturates or natural sleep. Subcortically, the delta wave bursts were observed prominently in the thalamus and in the caudate nucleus. The EEG patterns of the diffusely projecting thalamic nuclei were closely related phasically to the delta waves of the neocortex. EEG changes in the midbrain reticular formation and hypothalamus were not as prominent. Paradoxically, the hippocampus showed theta “arousal” waves during thedelta wave burst period of the thalamo-neocortical system. This functional dissociation between the thalamo-neocortical and limbic system was one of the EEG characteristics of ketamine.

Ketamine, in contrast to the barbiturates, depressed the recruiting response at a time when neocortical EEG activation was minimally affected. Somatosensory potentials evoked from stimulation of the median nerve were depressed primarily in the nonspecific thalamic nuclei, midbrain reticular formation, somatosensory cortex and sensory relay nuclei, respectively, with minimal anesthetic doses. Multiple neuronal unit activity showed clear grouping in the thalamus. The closest relationship of multiple unit activity to the delta waves in the neocortex was observed in the diffusely projecting thalamic nuclei. After ketamine the reticular formation showed neither grouping nor suppression of multiple unit activity during the neocortical delta bursts. Based upon these observations, the site of action of ketamine in minimal anesthetic doses appears to be in the non-specific thalamo-neocortical system. This system seems to be a primary factor in producing the hypersynchronous delta wave burst pattern in the EEG.

Previous studies have shown certain striking similarities between the behavioral effects produced by some anticholinergic drugs and the effects produced by hippocampal destruction. To investigate this parallel more thoroughly, scopolamine hydrobromide was administered to rats in one-way and two-way active avoidance learning situations. The drugged animals showed improved learning of the two-way problem, reaching criterion in one-half the number of trials and making one-third as many errors as the saline injected controls. In the one-way task the drugged subjects performed slightly worse than control animals. These data correspond very closely to those from similar experiments using hippocampectomized subjects.

• 1.

  ACh-excited granule layer neurones and Purkinje cells have been found in several areas of the cerebellar cortex. The proportion of responsive cells was greatest in the depths of the cortex.

• 2.

  This action of ACh was potentiated by cholinesterase inhibitors and depressed by ‘nicotinic’ type antagonists. Dihydro-β-erythroidine was the most potent antagonist.

• 3.

  Evidence for the release of ACh by some mossy afferent fibres arising in the mesencephalon and pons is presented.

• 4.

  In conjunction with associated studies on cerebellar ACh and acetylcholinesterase, the findings presented in this paper support the concept of cholinergic synaptic transmission in the cerebellar granule cell layer.

Sodium barbitone was given to rats in increasing doses over a period of 5 weeks. The effects of a convulsant barbiturate, leptazol, and electroshock were determined at weekly intervals throughout the period of barbitone administration and at 2, 7 and 14 days following the withdrawal of the barbiturate.

There was a marked decrease in the seizure susceptibility of the experimental rats during the period of barbiturate administration. On withdrawal of the barbiturate all the experimental rats were hyperexcitable and some developed spontaneous convulsions. However, the seizure susceptibility to electroshock and to the convulsant barbiturate was no greater than that observed in the untreated animals. After the withdrawn animals had been challenged with leptazol however, the severity of the convulsions was considerably increased compared with that in the untreated animals. The seizure susceptibility of the experimental rats was the same as that of the untreated animals 14 days after the barbiturate had been withdrawn.

Facilitatory and depolarizing drugs both produce facilitation of the cat skeletal muscle, and antidromic firing in the motor nerve following an orthodromic stimulus. Drugs were administered i.v. or close-arterially to the anterior tibialis muscle of the cat, and gross motor nerve potentials were recorded from the ventral root. Antidromic firing following an orthodromic stimulus was asychronous in the presence of facilitatory drugs and a mixture of synchronous and asynchronous firing in the presence of depolarizing drugs. The depolarizing drugs and the facilitatory drugs, neostigmine, edrophonium and ambenonium, also produced antidromic firing in the absence of nerve stimulation. Methoxyambenonium augmented the antidromic firing of the depolarizing drugs following an orthodromic stimulus but prevented it in the absence of nerve stimulation. Hemicholinium and triethylcholine prevented the antidromic firing produced by both facilitatory and depolarizing drugs. Tubocurarine also prevented the antidromic firing by both types of drug. The results are explained on the basis of two cholinoceptive sites on the motor nerve terminal, one at the first node and the other on the unmyelinated terminal.

Intraventricular injections of triethylcholine made in conscious rats produced catatonia preceded in a number of animals by a seizure. Hemicholinium-3 also produced a brief period of catatonia but any seizures which occurred did so only after an interval of about 1 hr. Both compounds reduced the total amount of brain acetylcholine and this effect was prevented when choline was administered at the same time. A small intraventricular dose of triethylcholine, which was not sufficient to affect the total amount of brain acetylcholine, did reduce the amount of free acetylcholine. A larger dose decreased both the free and bound components. An intraperitoneal injection of triethylcholine had no effect on brain acetylcholine. The catatonia and seizures produced by triethylcholine and hemicholinium-3 cannot be related to any apparent changes in either brain acetylcholine content or acetylcholinesterase activity.

The intravenous administration of 6-azauridine, an antimetabolite of pyrimidine nucleotides, causes no apparent changes in the EEG of the conscious rabbit and the catence´phale isole´ preparation. Its administration into the lateral cerebral ventricle in theence´phale isole´ cat caused an initial shift of the record to higher frequencies followed by a period of EEG synchrony. Similar changes were also seen after the intraventricular administration of 6-azauracil and the antimetabolically inactive 5-ethyl-6-azauracil. Excitability of the hippocampus, measured as the threshold for afterdischarges, was decreased after intravenous administration of higher doses of 6-azauridine in the rabbit and after intraventricular administration in the catence´phale isole´ preparation. Also, the threshold for cortical desynchronization elicited by electrical stimulation of the midbrain reticular formation was higher and its duration shortened after intraventricular administration of 6-azauridine in the cat. The duration of cortical desynchronization elicited by intravenous administration of nicotine was shortened after intravenous and intraventricular injection of 6-azauridine in the same preparation; the higher doses given intraventricularly blocking the reaction completely. Cortical desynchronization elicited by acetylcholine was influenced to the same degree but that elicited by arecoline only slightly affected. From this interaction with cholinergic agents it is concluded that 6-azauridine has an anticholinergic component in its central action, which is more antinicotinic than antimuscarinic. 6-Azauracil and cancerostatically ineffective 5-ethyl-6-azauracil failed to show any antinicotinic action. The relation between antimetabolic activity and the central nervous system effects is discussed. The initial EEG changes observed after intraventricular administration of these three derivatives are not related to antimetabolic activity and are probably due to the direct action of the compoundsper se. The anticholinergic component, on the other hand, was seen only after antimetabolically active 6-azauridine. It is suggested that the central anticholinergic and cancerostatic activities might be based on the same biochemical mechanism—the inhibition of orotidylic acid decarboxylase.