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.
Biogenic amines and related compounds, and certain amino acids were applied by microelectrophoresis onto single red nucleus neurons. The cats were either lightly anesthetized or specially prepared in the unanesthetized state.l-Glutamic anddl-homoeysteic acids were potent excitants while gamma-aminobutyric acid was a strong depressant of neuronal activity. Acetylcholine and carbamylcholine, 5-hydroxytryptamine and lysergic acid diethylamide, noradrenaline and dopamine and other phenylethylamines stopped brachio-rubral synaptic transmission, reduced “spontaneous” firing and amino-acid evoked firing of RN neurons. Parenterally administered drugs which disturb motor coordination, such as lysergic acid diethylamide, bufotenine and mephenesin depress directly or indirectly rubral neuronal activity. 4-Methoxyphenylethylamine when applied locally did depress rubral neurons. However, when applied intravenously 4-methoxyphenylethylamine caused a hypokinetic rigid syndrome to develop; parallel to the increases in muscle tension and electromyogram activity were increases in rubral neuronal firing. The evidence presented and from a Preliminary Note (H. McLennan) indicates that the transmitter released from the brachium fibers to excite rubral neurons is not acetylcholine. The rubro-cerebellar fibers may be cholinergic.
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.
Rats pretrained in ago-nogo avoidance discrimination were treated daily with 1mgkg of scopolamine HBr s.c. 40 min before testing sessions. EEG records were taken twice a week, before and after sessions. The drug caused initially a disruption in performance and EEG synchronization. Upon repeated exposure the behavioural deficit was progressively compensated for, while the EEG alteration persisted. The administration of physostigmine (1mgkg s.c.) to desensitized scopolamine-treated animals provoked a disruption in the performance and an EEG desynchronization. Repeated exposure to scopolamine and physostigmine led to a rapid behavioural desensitization to the combined treatment.
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.
Microinjections ofd-tubocurarine chloride (d-Tc) were made into the hypothalamus of cats through a stereotaxically implanted cannula-electrode to reproduce the effects of intraventricular doses (100–200 μg/kg) ofd-Tc. Single intrahypothalamic injections of 3–6 μg caused rise of blood pressure, stimulation of respiration and enhancement of knee jerk and produced tremor and jerks in most of the experiments. After a delay of 10–15 min the electrical activity of the injected site changed with the appearance of high voltage waves and spikes which were found to spread to other areas recorded. The effects of similarly low intraventricular doses were comparatively much less in incidence and intensity. Thus the hypothalamus appeared to be the site of origin ofd-Tc-induced autonomic and motor effects, and abnormal electrical activity. The effects of intrahypothalamic doses ofd-Tc were poorly counteracted by Prostigmin.
The effect of stereotaxic administration of tremorine and oxotremorine into four brain areas has been investigated using rats. Tremorine produced tremor significantly higher than control after administration into the globus pallidus, caudate nucleus, and substantia nigra. Oxotremorine produced tremor significantly higher than control only after injection into the substantia nigra. Dyflos injected into the caudate nucleus produced tremor. No change in the tremorgenic action of tremorine was observed after the simultaneous intracaudate injections of atropine and tremorine, and dyflos and tremorine. Intraperitoneal atropine reduced the tremorgenic action of an intracaudate injection of tremorine.
The centrally mediated cardiovascular effects of prostaglandin E1 (PGE1) were investigated using cross-circulation procedures. PGE1 was injected into the arterial inflow (IA-R) of vascularly isolated, ncurally intact heads of anesthetized recipient dogs. Following the administration of 5 and 10 μg/kg of PGE1 (IA-R) consistent depressor responses occurred in the donor dogs and in the recipient's isolated trunk. The administration of 5 and 10 μg/kg of PGE1 (IA-R) to debuffered recipients (carotid sinus-body areas bilaterally denervated) elicited centrally mediated pressor responses in the recipient's trunk paralleled by depressor effects in the donor and a decline in the recipient's perfusion pressure. Centrally mediated pressor responses of angiotensin II were inhibited by PGE1 only in the non-debuffered recipients. Pressor responses to PGE1 in debuffcrcd recipients were blocked by the ganglionic blocking agent, hexamethonium. These data plus results from the intra-artcrial administration of PGE1 into the carotid sinus area before and after denervation suggest that the carotid sinusbody structures, most likely the baroreceptors, are primarily implicated in the hypotensive response to PGE1 in the non-debuffered recipient's trunk. On the other hand, the central nervous systemper se appears to be involved in mediation of the central pressor responses obtained in the debuffered preparations. This study provides evidence for the involvement of the carotid sinus-body structures and the central nervous system as additional loci for the cardiovascular effects of PGE1.
Male rats were subjected to environmental stresses consisting of flashing lights, audiogenic stimulation and oscillation for 20 weeks on a randomized schedule. The mean systolic blood pressure in the stressed animals rose to 150mm Hg±1.01 by week 8 and ranged between 150 and 160 mm Hg for the remaining 12 weeks, whereas the mean systolic pressure of the non-stressed animals fluctuated between 110 and 120mm Hg throughout this same period of time. Serum corticosterone level in the stressed animals were approximately 3 times higher than controls for the first 4 weeks of exposure; however, by the end of week 5. serum corticosterone declined dramatically in the stressed group and was significantly lower than controls, after which serum corticosterone levels exhibited a cyclic pattern at approximately 6-week intervals. No significant alterations were observed in brain NE and DA and serum FFA throughout the 20-week stress exposure. In a second study, rats received 100 mg kg p.o. ofL-α-methyltyrosine. At the end of weeks 2 and 4, brain NE was depleted by more than 80° in the stressed treated group, whereas brain NE in the non-stressed treated animals was depleted by approximately 45°. indicating a significant increase in the turnover of brain NE The elevated turnover of brain NE returned to control values by the end of the 6th week. In addition, a-MT prevented the stress-induced elevation in systolic blood pressure. These data indicate a close temporal relationship between brain NE synthesis rate and adrenocortical steroid secretion as well as demonstrating that a-MT is an effective antihypertensive agent in stress-induced hypertension.
When ACh or carbachol was directly applied to the isolated amphibian spinal cord, a slow depolarization which originated at or near the dorsal root nerve terminals could be recorded by means of the sucrose-gap method. This depolarization was a transient phenomenon. A marked and transient decrease in the amplitude of the DR-DRP was observed during the development of the ACh depolarization. With relatively small concentrations of ACh, the reduced amplitude of the DR-DRP was gradually restored to an almost normal value within 30–40 min. The depolarization of the dorsal root nerve terminals as well as the reduction in the size of the DR-DRP, caused by ACh or carbachol, were enhanced by anti-AChE's and prevented by atropine, DHE, d-TC or nicotine. These pharmacological properties were similar to those of the VR-DRP. On the basis of the experimental observations, the possible location of the cholinoceptive receptor sites in the amphibian spinal cord was discussed.
The amino acids tryptophan and methionine are known to be involved in behavioral alterations and their metabolites have been implicated in mental illness. To learn more about the metabolic interrelationships of these two amino acids, rats were placed on amino acid diets deficient in nicotinic acid and nicotinamide and pair-fed with and without intestinal-antibiotics. Excess methionine (4%) added to such diets resulted in rats showing a decrease in body weight and urinary N1-methylnicotinamide (MNA) and an increase in urinary xanthurenic acid (XA) and total indoleacetic acid (TIAA) in comparison with controls. Urinary creatinine (CR) was relatively unchanged. Intestinal-antibiotics did not affect the overall methionine effect. The overall results demonstrate that excess-dietary methionine alters the tissue metabolism of tryptophan, and gives rise to urinary excretion patterns of tryptophan metabolites claimed to occur in mental illness. The observed data point to a metabolic alteration involving vitamin B6. A natural competition may exist between methionine and tryptophan for vitamin B6 which is utilized in the metabolic pathways of both amino acids. Our work suggests that tolerance load tests of methionine and tryptophan in behavioral alteration studies must take into account the metabolic competition between these two amino acids for vitamin B6, as well as the formation of psychotogenic metabolites by N-methylation and O-methylation reactions.
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.
The results of earlier investigations pointed to a connection between a raised striatal excitability and the catatogenic effect of neuroleptic drugs. This paper describes experiments in which the caudate function in catatonic rats was blocked by means of local application of KCl solution.
Adrenaline (10–200 μg) and noradrenaline (50 μg) when injected into the lateral cerebral ventricle of pentobarbital-anesthetized rabbits produced a fall in systemic blood pressure, a decrease in spontaneous heart rate and a stimulation of spontaneous respiration. Isoproterenol (50–200 μg) caused a fall in blood pressure and an acceleration of heart rate, whereas phenylephrine (200 μg) caused a slight rise in blood pressure in association with a decrease in heart rate. The hypotension and bradycardia induced by adrenaline were not significantly affected by bilateral vagotomy. Pretreatment of rabbits with intravenous reserpine reversed the adrenaline-induced hypotension to a hypertension and abolished the bradycardia induced, but did not affect the respiratory stimulation. The cardiovascular responses to intraventricular adrenaline were abolished by transection of the spinal cord. In unanesthetized rabbits adrenaline produced presser and cardio-stimulatory effects followed by depressor and cardio-inhibitory effects. These findings would suggest a centrally mediated hypotensive action of adrenaline in anesthetized rabbits but a hypertensive action in unanesthetized rabbits. Furthermore, changes in the cardiac function might be associated with changes in local blood flow, as postulated byKanekoet al. (1960).
A series of antihistamines with widely differing chemical structures and pharmacological profiles have been compared to the standard antidepressants, imipramine and amitriptyline, in four laboratory antidepressant tests. Dexchlorpheniramine and tripelennamine are examples of antihistamines which were effective antagonists of tetrabenazine ptosis in mice, mouse-killing behavior in rats, and reserpine hypothermia in both species. Other antihistamines such as cyproheptadine, pyrilamine and promethazine were ineffective in these tests. The effectiveness of dexchlorpheniramine and tripelennamine in these procedures was equal to or greater than that of imipramine or amitriplyline. Potentiation of methamphetamine-induced excitation differed from other antidepressant tests because amitriplyline was ineffective, whereas promethazine, ineffective in other antidepressant tests, was a potent potentiator of methamphetamine.
Dose-response curves for the prevention of tetrabenazine-induced ptosis in mice by antihistamines such as dexchlorpheniramine, are shifted to the right in parallel fashion by raising the dose of tetrabenazine, whereas the dose-response curves for imipramine-like antidepressants are relatively unaffected. Another difference between dexchlorpheniramine and imipramine is that the antihistamine reverses α-methyl-tyrosine-induced ptosis whereas imipramine is ineffective. In both procedures, methamphetamine produces effects similar to dexchlorpheniramine, suggesting that dexchlorpheniramine has a central sympathomimetic effect. Additional evidence for this hypothesis is that dexchlorpheniramine-indueed lethality is enhanced by aggregation (ten mice per cage vs. five mice per cage) and that this aggregate lethality can be prevented by phenoxybenzamine but not by α-methyl-tyrosine. The central sympathomimetic effect of dexchlorpheniramine may be similar to the direct effect of methamphetamine, which has been demonstrated in the present studies by reversal of both tetrabenazine- and α-methyl-tyrosine-induced ptosis. The present studies have not ruled out the possibility that antihistamines such as dexchlorpheniramine can antagonize ptosis in part by inhibition of norepinephrine uptake.
Effects of 5-hydroxytryptamine (5-HT), lysergic acid diethylamide (LSD) and other psychotomimetics upon the potentials induced in thin sections from the superior colliculus of the guinea pig were studiedin vitro. The postsynaptic field potential (PSR) evoked by optic tract stimulation was suppressed by 5-HT in concentrations of 10−7–10−6M. Single neuron discharges induced by optic tract stimulation were also suppressed by 5-HT but spontaneous cell firings were not affected. By higher concentrations of 5-HT (more than 10−4M) PSR was once suppressed but gradually recovered. LSD, lysergic acid ethylamide (LAE) and other related compounds potentiated the 5-HT suppressing action in relatively low concentrations but blocked it in higher ones. Morphine and 2-bromolysergic acid ethylamide (BOL) did not antagonize the 5-HT action. When two shocks were delivered to the optic tract at short intervals and the time course of suppression of the second PSR was studied, it was found that LSD and related compounds accelerated the recovery of the test PSR. Physiological roles of 5-HT in the superior colliculus are discussed.
