Modification of drug-induced tremor by systemic administration of kainic acid and quisqualic acid in mice.

The effects of excitatory amino acids, kainic acid and quisqualic acid, on the tremorine- and harmaline-induced tremor were quantitatively examined in mice using the power spectral analyzing method. The severity of the tremor was determined quantitatively in terms of the cumulative sum of the mean square value of the data. Kainic acid enhanced the tremor induced by tremorine but depressed the tremor induced by harmaline. Quisqualic acid depressed the tremor induced by both tremorine and harmaline in a dose-dependent manner. Kainic acid shifted the frequency of each component of the tremor induced by tremorine to the high frequency side, but quisqualic acid did not affect the frequency of tremor of the tremor induced by tremorine. The frequency of tremor of the tremor induced by harmaline was shifted by both excitatory amino acids to the low frequency side, and another component of tremor in the power spectral densities developed, of which the mean square values were very small. The present results suggest that, at least in part, the glutamatergic system can take a role on the modification of drug-induced tremor.

Effect of lesioning dopamine, noradrenaline and 5-hydroxytryptamine pathways on tremorine-induced tremor and rigidity.

The effects of lesioning monoamine pathways in the rat brain on tremorine-induced hind-limb tremor and rigidity were studied. Nigro-striatal and mesolimbic dopamine (DA) neurones were lesioned unilaterally by injecting 6-hydroxydopamine (6-OHDA) into the median forebrain bundle. Tremor was reduced in the contralateral leg and rigidity was prevented in the ipsilateral leg. Injection of 6-OHDA into the nucleus accumbens affected tremor but not rigidity. In general, nigral DA neurones may influence rigidity whilst mesolimbic DA neurones affect tremor. A unilateral locus coeruleus electrolesion which destroys noradrenaline (NA) fibres reduced both tremor and rigidity. A median raphe electrolytic lesion affecting 5-hydroxytryptamine (5-HT) neurones had no effect on tremor and rigidity, whereas lesioning the dorsal raphe electrolytically or by injecting 5,6-dihydroxytryptamine prevented rigidity without affecting tremor. Electrical stimulation of the dorsal raphe increased transiently the hindlimb tone of normal rats. The findings demonstrate that the monoamines, especially 5-HT, are differently involved in the mechanisms of tremor and rigidity produced by tremorine.

Parasympatholytic (anticholinergic) esters of the isomeric 2-tropanols. 1. Glycolates.

The 38 esters in Table I were prepared from the four isomeric 2-tropanols and a variety of racemic glycolic acids and their optical isomers. Anticholinergic activity in mice was measured in the peripheral nervous system (mydriasis) and in the central nervous system (anti-tremorine) and compared with that of atropine, scopolamine, and racemic 2-quinuclidinyl benzilate. The results (Table III) showed that several esters (such as 8, 12, 14, and 21) had significantly greater activity in both the peripheral and central nervous systems than did the reference compounds. Esters of (+)-2alpha-tropanol were more potent than those of either its epimer (-)-2beta-tropanol or its optical isomer(-)-2alpha-tropanol. Esters derived from (-)-glycolic acids were uniformly more potent than those from the (+)-glycolic acids. Esters of (+)-2alpha-notropanol and five of its N-substituted derivatives had markedly decreased activity. Peripheral/central activity ratios and time-activity profiles for five active compounds are discussed and compared with those of the reference compounds.

Parasympatholytic (anticholinergic) esters of the isomeric 2-tropanols. 2. Non-glycolates.

The 19 esters in Table I were prepared from (+)-2 alpha-tropanol, (-)-2 beta-tropanol, (+/-)-3-quinuclidinol, and a variety of non-glycolic acids in order to compare their central and peripheral activities with those of the glycolates reported in the previous paper. The results (Table II) showed that esters 6 and 17 were approximately equivalent to one another and to atropine, that 8 was equal in both central and peripheral activity to reference glycolates, that 9 and 19 were less active than 8 but 9 had a substantially reduced central activity, and that 10 and 11 were more active than the methoxy analogue reported earlier.

The relationship between tremor and change in brain acetylcholine concentration produced by injection of tremorine or oxotremorine in the rat.

1. The relationship between tremor and change in brain acetylcholine concentration after the injection of tremorine or oxotremorine has been investigated in rats.2. Tremorine produced a significant increase in whole brain acetylcholine and in tremor 5 min after injection. After this time tremor subsided but brain acetylcholine continued to increase.3. Oxotremorine produced tremor within 30 sec. This became maximal within 5 min of injection and then declined rapidly. The brain acetylcholine concentration showed a significant increase 5 min after injection and continued to increase until 30 min afterwards.

The effects of atropine and dyflos on tremor and increase in whole brain acetylcholine produced by injection of oxotremorine in the rat.

1. Injection of oxotremorine in the rat results in tremor and an increase in brain acetylcholine. The effects of atropine and dyflos have been investigated on both these actions.2. Atropine decreased brain acetylcholine concentration and inhibited oxotremorine-tremor. It did this in doses which did not prevent the oxotremorine-induced increase in whole brain acetylcholine.3. Dyflos increased brain acetylcholine concentration, but it was without effect on oxotremorine tremor. Some mutual antagonism was observed between the actions of oxotremorine and dyflos on rat brain acetylcholine concentration.4. These results do not support a causal relationship between the increase in whole brain acetylcholine and the tremor produced by oxotremorine.

Effects of drugs on tremor and increase in brain acetylcholine produced by oxotremorine in the rat.

1. In rats the effect of drugs on oxotremorine tremor and oxotremorine-induced increase in brain acetylcholine has been investigated.2. Reserpine, (+/-)-alpha-methylmetatyrosine and diethyldithio-carbamic acid, drugs which have in common the ability to decrease tissue noradrenaline concentration, inhibited oxotremorine tremor without preventing the oxotremorine-induced increase in brain acetylcholine.3. (+/-)-p-chlorophenylalanine, a depletor of tissue 5-hydroxytryptamine, did not inhibit oxotremorine tremor.4. Phenoxybenzamine and propranolol inhibited oxotremorine tremor, and propranolol was without effect on oxotremorine-induced increase in brain acetylcholine.5. The toxicity of oxotremorine was increased by reserpine and phenoxybenzamine.6. The significance of these findings is discussed with regard to the mode of action of oxotremorine.

The pharmacology of ambenoxan (2-(3',6'-dioxaheptyl)-aminomethyl-1:4-benzodioxane), a centrally acting muscle relaxant.

1. The intravenous, subcutaneous and oral toxicity of ambenoxan in mice is reported.2. Ambenoxan is a centrally acting skeletal muscle relaxant shown to be effective in mice, rats, rabbits, dogs and monkeys without loss of the righting reflex.3. It had no peripheral neuromuscular blocking properties.4. Decerebrate rigidity was depressed or abolished in the rabbit.5. The effects of strychnine, leptazol, or tremorine were not antagonized.6. In common with other depressants of the central nervous system, ambenoxan prolonged the sleeping time of hexobarbitone.7. Ambenoxan had no local anaesthetic properties.8. In the anaesthetized cat the drug lowered the blood pressure and reduced the pressor response to adrenaline but not to noradrenaline.

Comparison of the antinociceptive activities of physostigmine, oxotremorine and morphine in the mouse.

1. Morphine, oxotremorine and physostigmine showed antinociceptive activity in mice using the hot plate reaction time test.2. The action of morphine, but not that of oxotremorine, was antagonized by naloxone and by nalorphine, whereas the effect of physostigmine was unaffected by naloxone and increased by nalorphine.3. The antinociceptive effects of morphine and of physostigmine were increased by procedures reported to increase the ratio of 5-hydroxytryptamine to dopamine in the brain. It was decreased by procedures reported to cause a fall in brain 5-hydroxytryptamine or a rise in dopamine relative to 5-hydroxytryptamine.4. The antinociceptive effect of oxotremorine was potentiated by procedures reported to decrease brain noradrenaline and was unaffected by procedures altering brain 5-hydroxytryptamine.5. The results suggest differences in the mode of action of morphine and physostigmine on the one hand and of oxotremorine on the other.

1-Hydroxy-3-amino-pyrrolidone-2(HA-966): a new GABA-like compound, with potential use in extrapyramidal diseases.

1. The drug HA-966 (1-hydroxy-3-amino-pyrrolidone-2), which chemically resembles the cyclic form of GABA, has been studied for neuro-pharmacological properties and for effects on the catecholamine content of the corpus striatum.2. The acute effects on spontaneous behaviour of rodents included flaccid catalepsy and reversible tranquillization in doses which were 5% or less of the lethal dose. Long lasting depression of the CNS, followed by complete recovery, was produced in the cat and the dog. In the monkey HA-966 caused periodical sleeping episodes.3. The exploratory behaviour and the amphetamine-induced motor activity in mice were blocked by HA-966. The toxicity of amphetamine in aggregated mice was only moderately reduced, suggesting that HA-966 differs from neuroleptics.4. Tremors induced by chemical agents (nicotine, zinc and tremorine) were markedly inhibited by HA-966. The muscarinic effects of tremorine were not reduced by HA-966, indicating a selective central antitremor effect.5. HA-966 elevated the threshold to strychnine convulsions and abolished the ipsilateral flexor reflex, while not having motor endplate blocking properties. It is suggested that HA-966 depresses central internuncial neurones.6. In rats and rabbits HA-966 produced synchronous EEG and inhibited the sensory arousal in doses not causing sedation. In the monkey the drug caused a periodical dissociation between ;sleep-EEG' and behaviour.7. In rat brain, HA-966 selectively elevated the dopamine content in the corpus striatum, while no changes in noradrenaline and 5-hydroxytryptamine contents could be demonstrated. The effect was still present when dopa synthesis was inhibited with alpha-methyl-p-tyrosine.8. Several effects of intravenously administered HA-966 became manifest after an appreciable delay and in hepatectomized mice the effects were much reduced. It is postulated that HA-966 is converted to a pharmacologically active metabolite.9. The results are discussed in the light of current views on drug therapy in extrapyramidal conditions and a GABA-related hypothesis as to the mode of action of HA-966 is presented.

Possible involvement of 5-hydroxytryptamine and cyclic-AMP in tolerance to tremorine analgesia in mice.

The phenomenon of tolerance to the analgesic action of tremorine in mice was studied by the hot-plate and tail-clip methods. Reduction in 5-HT levels in brain by parachlorophenylalamine pretreatment decreased the ED50 of tremorine analgesia in tremorine tolerant mice. 5-Hydroxyptophan, L-Dopa or alpha-methyl-para-tyrosine did not influence the analgesic response to tremorine in tremorine tolerant animals. However, theophylline was found to enhance the tolerance to tremorine analgesia. Brain 5-HT and cAMP are probably involved in tremorine tolerance, whereas neither noradrenaline nor dopamine is involved in the phenomenon.

Quantitative analysis of drug-induced tremor in mice.

A method of analyzing tremor in mice was developed using a power spectral analysis of the random current induced by the movement of a magnet attached to a mouse, on a wire coil. The power spectral density function defined the frequency composition of the tremor, and the mean square value of the data in any frequency range of concern was determined. It was possible to determine qualitative differences in the tremor caused by various tremorgenic agents, and to differentiate the drug-induced tremor from spontaneous motor activity. The power spectral densities of the tremorine- and oxotremorine-induced tremors were tentatively expressed as the sum of 3 main components (Cauchy distribution) with different peak frequencies, consisting of the spontaneous motor activity component and two tremor components. On the other hand, the power spectral densities of the harmaline-induced tremor were expressed as the sum of two components with two peak frequencies, and the plots of the power spectral densities versus frequency, consisting of the spontaneous motor activity component and a tremor component. The frequency of the peak spectral density was almost independent of the dose of tremorgenic agents, but changed slightly with the lapse of time after their injection. The severity of the tremor was determined quantitatively in terms of the sum of the mean square value. The sum of the mean square value for a period of 45 min after the injection of tremorine, changed in a dose-dependent manner. The severity of the tremor was different for each of the mouse strains. The method studied in the present paper is expected to be utilized for the quantitative examination of the fine motor movement of the experimental animal, particularly, for the screening test of new anti-tremor drugs.

Neuropharmacological evaluation of RX 77368--a stabilised analogue of thyrotropin-releasing hormone (TRH).

L-Pyroglutamyl-L-histidyl-L-2,3-dimethylprolineamide (Pyr-His-Dmp . NH2; RX 77368) a stabilised analogue of thyrotropin-releasing hormone (TRH) has been examined for neuropharmacological effects in animal tests. The compound was more potent than either TRH or clinically established drugs in four animal tests of antidepressant potential (reserpine reversal, clonidine antagonism, tremorine reversal and learned immobility). RX 77368 also antagonised barbiturate sleeping time. Given by itself to rats the peptide produced arousal as characterised by EEG and EMG measurements and delayed the onset of sleep. The arousal induced was not accompanied by increases in locomotor activity. The profile of pharmacological activity for RX 77368 did not correspond to the profiles of tricyclic antidepressants, psychic-stimulants or analeptic drugs. The possible clinical uses for such a molecule are discussed.

Genetical differences in sensitivity to tremorine and oxotremorine in mice.

Male mice from 14 strains were injected i.p. with tremorine (3.0 mg/kg) or oxotremorine (0.15 or 0.1 mg/kg). Large inter-strain differences in the degree and duration of the subsequent hypothermia were noted. 2 strains, BALB/c and Simpson, were particularly sensitive to the hypothermic effect of oxotremorine. The offspring from a cross between BALB/c and Simpson were less sensitive than the parental strains, suggesting genetic complementation. A set of 7 recombinant inbred (RI) lines derived from strains C57BL and BALB/c were tested with oxotremorine. 5 RI lines resembled strain C57BL in their response and 2 RI lines resembled strain BALB/c. It was concluded that strains C57BL and BALB/c differ at a gene which has a major effect on the response to oxotremorine.

Direct or indirect action of histamine on dopamine metabolism in the rat striatum?

Intraventricular administration of 500 microgram of 2-pyridylethylamine, an agonist of the histamine (Hi) H1-receptor, produced a 20% increase of striatal HVA in the rat while the Hi H2-receptor agonist 4-methylhistamine had no influence on HVA and DOPAC levels. L-Histidine (1.5 g/kg) or amodiaquine (60 mg/kg) given i.p. increased HVA and DOPAC levels to the same extent as did pyridylethylamine. Histidine combined with tremorine had an additive effect with respect to the increase of DA acidic metabolites while mepyramine slightly attenuated the tremorine-induced rise of HVA.

Effects of striatal and pallidal lesions and intrapallidal GABA and opiate drugs on tremorine-induced rigidity in the rat.

Tremorine-induced hindlimb rigidity was prevented by the neurotoxin kainic acid in one neostriatum. A unilateral globus pallidus (GP) electrolesion reduced the tone of the contralateral leg (CL) and differentially modified tremorine rigidity. The ipsilateral leg rigidity was reduced and the CL rigidity was increased. Resting tone and tremorine-induced rigidity were measured in CL after injection in one GP of drugs that modify pallidal GABA function. The GABA drugs tested in GP had no consistent effects on resting limb tone. By contrast, baclofen and muscimol, agonists for GABA receptors, both prevented tremorine rigidity, whereas the antagonists bicuculline and picrotoxin increased rigidity. Opiate receptor agonists in GP did not effect tone of rigidity but naltrexone prevented rigidity in CL leg. The findings suggest a close involvement of GP in mediating cholinergic limb rigidity.

Pimprinine, an extracellular alkaloid produced by Streptomyces CDRIL-312: fermentation, isolation and pharmacological activity.

Pimprinine, an extracellular alkaloid has been isolated from the culture filtrate of Streptomyces CDRIL-312. Pimprinine was subsequently purified using silica gel column chromatography and also by preparatory thin layer chromatography. Some physicochemical properties, antimicrobial activities (in-vitro) and pharmacological activities of pimprinine were studied. Pimprinine showed promising anticonvulsant activity in both minimum and maximum electric seizure threshold test in mice. Its anticonvulsant activity is very much comparable to that of phenyl hydantion sodium. Pimprinine also inhibited effectively tremorine-induced tremors and analgesia in mice.

Effects of lesioning basal ganglia nuclei and output pathways on tremorine-induced tremor in rats.

The tremor produced by muscarinic cholinomimetics is believed to originate in the neostriatum but the efferent pathways are unknown. The intensity and frequency of tremor induced by tremorine was measured in the hindlegs of rats with unilateral basal ganglia lesions. A kainic acid lesion of one neostriatum reduced tremor intensity in the contralateral leg (CL). Unilateral electrolesions of the globus pallidus and nucleus accumbens had no effects on tremor. Both entopeduncular and subthalamic nuclei lesions reduced the frequency and intensity of tremorine tremor in the CL leg. The subthalamic lesion also increased tremor intensity and frequency in the ipsilateral leg. Lesions were made in some brain areas that receive basal ganglia efferent projections. Peak tremor intensity and frequency in both legs was greatly reduced by unilateral decortication. Unilateral lesions of the habenula, red nucleus and pedunculopontine nucleus had no effects on tremor intensity but reduced peak tremor frequency. Lesions of the substantia nigra and periaqueductal gray area had no effects on tremor. Unilateral removal of the superior colliculus reduced tremor intensity in both legs. The findings suggest that intensity and frequency of tremor are influenced by different basal ganglia efferent pathways; intensity involves strio-entopeduncular-cortical projections and frequency is determined by projections to midbrain and brainstem. The superior colliculus, with many muscarinic receptors, may be a direct target area for tremorine.

Biochemorphology of cyclobutanecarbonylureas.

Ten urea derivatives of cyclobutanecarboxylic acid were synthesized and examined for general CNS depressant properties, barbiturate potentiation, and myorelaxant, antitremorine, and anticonvulsant potencies. Although water solubility plays an important role in the activity of these compounds, other factors also appear to be involved. 1-Cyclobutanecarbonyl-3,3-dimethylurea appears to be the most active CNS depressant, whereas 1-cyclobutanecarbonyl-3-(alpha-naphthyl)thiourea is the most active barbiturate potentiator. 1-Cyclobutanecarbonyl-3,3-dimethylurea, 1-cyclobutanecarbonyl-3-phenylurea, and 1-cyclobutanecarbonyl-3-tert-butylurea, 1-cyclobutanecarbonyl-3-allylurea, and 1-cyclobutanecarbonyl-3-phenylurea apparently are the most active against pentylenetetrazol-induced convulsions. 1-Cyclobutanecarbonyl-3-tert-butylurea, 1-cyclobutanecarbonyl-3,3-dimethylurea, and 1-cyclobutanecarbonyl-3-phenylurea are also slightly active tremorine antagonists.

Pharmacology of Quercus infectoria.

The galls of Quercus infectoria (Fagaceae), a commonly available plant in Iran, were studied pharmacologically. Two fractions were employed, a dried acetone-treated methanol extract dissolved in water (Fraction A) and a subfraction prepared by chloroform-methanol extraction (Fraction B). Fraction A was active as an analgesic in rats and significantly reduced blood sugar levels in rabbits. Fraction B had CNS depressant activity. Data obtained with a treadmill indicated a decreased activity ratio by Fraction B, suggesting a possible interference in motor coordination. It potentiated the barbiturate sleeping time significantly without changing the onset time or the loss of the righting reflex. In addition, Fraction B exhibited a moderate antitremorine activity by causing a delay in the onset and a decrease in the severity of tremorine-induced tremors. The local anesthetic action of Fraction B was evident due to the complete blockade of the isolated frog sciatic nerve conduction.