Oxotremorine-induced Tremors In Mice Research Articles

A selective potentiation by naloxone of L-dopa but not atropine suppression of oxotremorine-induced tremor in mice.

Oxotremorine-induced tremor activity in mice was suppressed by pretreatment with either L-dopa or atropine. Additional pretreatment with the opiate receptor blocker naloxone significantly potentiated the antitremor effect of L-dopa but not that of atropine. These findings indicate a selectivity of drug interaction between naloxone and L-dopa.

Ninjin-yoei-to (Ren-Shen-Yang-Rong-Tang) and Polygalae radix improves scopolamine-induced impairment of passive avoidance response in mice.

We investigated the effect of Ninjin-yoei-to (Ren-Shen-Yang-Rong-Tang), a Japanese herbal medicine, and found that 1000 mg/kg p.o. improved the scopolamine-induced impairment of passive avoidance response in mice. Further, the same dose of Ninjin-yoei-to enhanced oxotremorine-induced tremors in mice. The water extract of Polygalae radix, one of the constituent herbs of Ninjin-yoei-to, at a dose of 100 mg/kg significantly improved the scopolamine-induced impairment of passive avoidance response and enhanced oxotremorine-induced tremors in mice. Moreover, the enhancement of oxotremorine-induced tremors by Ninjin-yoei-to (1000 mg/kg) and Polygalae radix (100 mg/kg) was completely antagonized by pretreatment of scopolamine hydrobromide (0.5 mg/kg). These results suggest that Ninjin-yoei-to may improve the scopolamine-induced impairment of passive avoidance response by enhancing the cholinergic system and that Polygalae radix may be involved in the action of Ninjin-yoei-to.

Evidence for the involvement of the muscarinic cholinergic system in the central actions of pentoxifylline.

This study shows that pentoxifylline (ptx), a xanthine derivative, significantly attenuates scopolamine-induced memory impairment in rats, as demonstrated in a passive avoidance task (50 mg/kg intraperitoneally [i.p.]) and in an elevated T-maze (10 and 50 mg/kg i.p.). Ptx (25, 50 and 100 mg/kg i.p.) also potentiates oxotremorine-induced tremors in mice, in a dose-dependent manner, and this effect was completely prevented by atropine. In addition, ptx (50 and 100 mg/kg i.p.) increased the number of animals developing pilocarpine-induced seizures, and potentiated the latency to the first pilocarpine-induced convulsion. Hippocampus homogenates from rats treated with ptx (100 mg/kg) for 1 week and sacrificed 15 min after the last injection showed a significant decrease in the muscarinic receptor numbers, indicative of a downregulation phenomenon. Similar effects were observed when assays were performed 24 h after the last ptx injection (10 and 50 mg/kg i.p.), but not after 72 h. Additionally, in vitro assays showed that ptx inhibits acetylcholinesterase activity in a dose-dependent manner when incubated with homogenates from rat hippocampus. Our data suggest that the muscarinic agonist effect of ptx could possibly depend on factors such as endogenous cholinergic activity.

Synthesis and Biological Evaluation of Phenylacetyl Derivatives Having Low Central Nervous System Permeability as Potent and Selective M2 Muscarinic Receptor Antagonists.

A series of phenylacetyl derivatives containing the 5,10-dihydro-11H-dibenzo[b,e,][1,4]diazepin-11-one or 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one skeleton was prepared and evaluated for their binding affinities to muscarinic receptors in vitro and for antagonism of bradycardia, salivation and tremor in vivo. Among them, compounds 56 and 66 had high affinity for M2 muscarinic receptors in the heart (pKi = 8.7 and 8.9, respectively) with low affinity for M3 muscarinic receptors in the submandibular gland. A structure-activity relationship (SAR) study suggested that the high M2 selectivity over the M3 muscarinic receptors of 56 may be attributed to the direction of the carboxamide carbonyl group. In in vivo studies, 56 and 66 antagonized oxotremorine-induced bradycardia in rats on both intravenous and oral administration, and their heart rate increasing effect in dogs with nocturnal bradycardia was about 3-fold greater than that of AF-DX 116. Furthermore, they had almost no influence on oxotremorine-induced tremor in mice, presenting no evidence of central transfer.

Enhancement of serotonergic neural activity contributes to cyclosporine-induced tremors in mice

A single cyclosporine injection (50 mg/kg, i.p.) significantly enhanced harmine- but not oxotremorine-induced tremors in mice. This potentiation became more apparent when cyclosporine (50 mg/kg, i.p.) was administered once a day for seven days. These findings suggest an involvement of monoaminergic mechanisms in cyclosporine-induced tremors. The effects of cyclosporine were examined on the dynamics of noradrenaline, dopamine and serotonin in the mouse brain. Both single and repeated treatment with cyclosporine significantly facilitated the serotonin turnover as estimated from the probenecid-induced accumulation of 5-hydroxyindoleacetic acid, but either mode of treatment failed to change the contents of monoamines and their metabolites or the turnover of noradrenaline and dopamine. Therefore, the cyclosporine-enhanced activity of serotonin neurons may be interpreted as producing adverse central effects, including tremors.

Rolipram and Its Optical Isomers, Phosphodiesterase 4 Inhibitors, Attenuated the Scopolamine-Induced Impairments of Learning and Memory in Rats

We investigated the effects of (±)-rolipram, a phosphodiesterase (PDE) 4 inhibitor, and its isomers on scopolamine-induced deficits of learning and memory in rats using an 8-arm radial maze task and a passive avoidance task. 1) In the 8-arm radial maze task, (±)-rolipram (0.02-0.2 mg/kg, p.o.), (—)-rolipram (0.01-0.02 and 0.2-0.5 mg/kg, p.o.) and (+)-rolipram (20-50 mg/kg, p.o.) attenuated the scopolamine-induced deficits of spatial cognition. As for the minimum effective dose of each drug, (—)-rolipram was 2 and 2000 times as potent as (±)-rolipram and (+)-rolipram, respectively. (—)-Rolipram produced a biphasic dose-response and (±)-rolipram produced a broad dose-response. 2) (±)-Rolipram and its isomers also attenuated the scopolamine-induced deficits in the passive avoidance response. Also for the minimum effective dose, (—)-rolipram (0.01-0.02 mg/kg) was 2 and 200 times as potent as (±)-rolipram (0.02-0.1 mg/kg) and (+)-rolipram (2 mg/kg). 3) The behaviorally effective doses of (±)-rolipram and its isomers also enhanced the oxotremorine-induced tremors in mice. Comparing these racemic isomers, (—)- and (±)-rolipram have more potent effects than (+)-rolipram on scopolamine-induced deficits in the 8-arm radial maze task and passive avoidance task. Especially (±)-rolipram has a wide dose range in these behavioral study. These results suggest that the ameliorating effects of rolipram might result from the indirect potentiation of various transmitters including cholinergic and noradrenergic systems by an increase in cAMP with the inhibition of PDE4.

Effect of Nebracetam on the Disruption of Spatial Cognition in Rats

Central cholinergic hypofunction causes the disruption of spatial cognition, while cholinomimetics improve this disruption in rats. Scopolamine (0.5 mg/kg, i.p.) has also been reported to disrupt radial maze performance in rats. Nebracetam (WEB 1881 FU), a new nootropic candidate, was able to correct this scopolamine-induced disruption of spatial cognition at the dose of 10 mg/kg, p.o. Furthermore, nebracetam enhanced oxotremorine-induced tremors in mice. These results indicate that nebracetam has a cholinergic enhancing effect. The scopolamine-induced disruption of spatial cognition has been previously reported to improve not only by cholinomimetics but also by brain noradrenergic drugs such as l-threo-DOPS and amantadine. Nebracetam reversed the change of brain noradrenaline contents in the frontal cortex and hippocampus in which the noradrenaline content decreased by treatment with scopolamine. Nebracetam also decreased the Δ9-tetrahydrocannabinol (6 mg/kg, i.p.)-induced disruption of spatial cognition, which was reported to be related to the lymbic noradrenergic function. These results suggest that the cognitive enhancing effect of nebracetam involves not only cholinergic mechanisms but also involves lymbic and hippocampal noradrenergic mechanisms.

Effect of nebracetam on the disruption of spatial cognition in rats.

Central cholinergic hypofunction causes the disruption of spatial cognition, while cholinomimetics improve this disruption in rats. Scopolamine (0.5 mg/kg, i.p.) has also been reported to disrupt radial maze performance in rats. Nebracetam (WEB 1881 FU), a new nootropic candidate, was able to correct this scopolamine-induced disruption of spatial cognition at the dose of 10 mg/kg, p.o. Furthermore, nebracetam enhanced oxotremorine-induced tremors in mice. These results indicate that nebracetam has a cholinergic enhancing effect. The scopolamine-induced disruption of spatial cognition has been previously reported to improve not only by cholinomimetics but also by brain noradrenergic drugs such as L-threo-DOPS and amantadine. Nebracetam reversed the change of brain noradrenaline contents in the frontal cortex and hippocampus in which the noradrenaline content decreased by treatment with scopolamine. Nebracetam also decreased the delta 9-tetrahydrocannabinol (6 mg/kg, i.p.)-induced disruption of spatial cognition, which was reported to be related to the lymbic noradrenergic function. These results suggest that the cognitive enhancing effect of nebracetam involves not only cholinergic mechanisms but also involves lymbic and hippocampal noradrenergic mechanisms.

Dopamine receptor agonists, N, N-dipropyl-2-aminotetralin (TL-68) and 2-di-n-propylamino-4,7-dimethoxyindane (RDS-127) antagonize oxotremorine-induced tremors antimuscarinic action in mice

Central antimuscarinic actions of dopamine receptor agonists: N,N-dipropylaminotetrain (TL-68) and 2-di-n-propylamino-4,7-dimethoxyindane (RDS-127), were evaluated against oxotremorine-induced tremors in mice. Both TL-68 and RDS-127 inhibited the tremor intensity but were less potent than atropine.

Derivatives of the muscarinic agent N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide

A series of tertiary and quaternary analogues (acyclic imides, sulfonimides, N-acetyl sulfonamides, and trifluoroacetamides) of the selective partial muscarinic agonist N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide (BM 5,35) was synthesized. The compounds were found to be muscarinic agonists, partial agonists, or antagonists in the isolated guinea pig ileum. Replacement of the acetyl group or the N-methyl group of 35 and its analogues by a methanesulfonyl group abolished efficacy and decreased affinity at ileal muscarinic receptors. Trifluoroacetamide analogues of 35 also had lower affinity and efficacy than 35. Substitution of an acetyl group for the N-methyl group in compounds related to 35 decreased efficacy, but had no appreciable effect on affinity. Most of the tertiary amines showed central antimuscarinic activity as they antagonized oxotremorine-induced tremors in mice.

Microwave Facilitation of Methylatropine Antagonism of Central Cholinomimetic Drug Effects

Pilocarpine-induced hypothermia and oxotremorine-induced tremors in mice are central cholinomimetic drug effects that are readily blocked by the muscarinic antagonist atropine. However, the quaternary ammonium derivative of atropine, methylatropine, is unable to block these cholinomimetic drug effects by virture of its inability to penetrate the blood-brain barrier (BBB) and blood-cerebral spinal fluid barrier (B-CSFB). Dose-response curves for pilocarpine and oxotremorine effects are not appreciably affected either by pretreatment with methylatropine (1.0 mg/kg) or by exposure to moderate-level microwave irradiation (2.45 GHz, 23.7 W/kg, CW, 10-min exposure). However, in mice receiving both the methylatropine pretreatment and microwave irradiation, the dose-response curves for both pilocarpine and oxotremorine effects were significantly shifted to the right, signifying a central anticholinergic action by methylatropine. These data indicate that a single acute exposure to a thermogenic level of microwave irradiation facilitates methylatropine antagonism of centrally mediated cholinomimetic drug effects. One possible explanation for this observation is that microwave radiation may enhance passage of quaternary ammonium compounds like methylatropine across the BBB and B-CSFB.

5-(<I>o</I>-Chlorophenyl)-1-methyl-7-nitro-1, 3-dihydro-2H-1, 4-benzodiazepin-2-one (ID-690)の薬理学的研究 ―特に運動系に対する作用―

Effects of ID-690 on motor systems were compared with those of clonazepam, diazepam and nitrazepam. ID-690 exerted muscle relaxant action in the rotarod method using rats and mice; this action was almost equal in potency to clonazepam and nitrazepam and more potent than diazepam. Pretreatment with ID-690, clonazepam and nitrazepam increased the sleeping time of mice under thiopental anesthesia to the same degree, whereas diazepam produced a lesser effect. ID-690 was almost equal in potency to diazepam and nitrazepam in protecting against oxotremorine-induced tremor in mice, and approximately 10 times as potent as clonazepam. The anticonvulsant action of ID-690 was similar to that of clonazepam. These benzodiazepines effectively augmented the dorsal root reflexes, while showing no effects on the ventral root reflexes. Rigidity in rats due to anemic decerebration was not affected after intraduodenal administration of these drugs, while phasic augmentation of the rigidity by mechanical stimulation of the hind limb was clearly depressed. These drugs had no effects on the neuromuscular junction. From these results, it is concluded that ID-690 has a wider pharmacological spectrum than clonazepam, is almost equal in potency to nitrazepam and is more potent than diazepam.

Antioxotremorine action of propranolol.

1. The influence of propranolol on the neuromuscular, tremor-producing and muscarinic effects of oxotremorine was examined. 2. In the isolated rat phrenic nerve-diaphragm preparation the neuromuscular blocking effect of oxotremorine was inhibited by propranolol in a dose-dependent manner. 3. Propranolol intensified the paralytic effect of tubocurarine in the rat diaphragm and prevented antagonism of tubocurarine paralysis by tetraethylammonium. 4. Propranolol was devoid of any curare-like effect in the isolated rectus abdominis muscle of the frog. 5. Vasodepressor responses to oxotremorine in rats and spasmogenic responses to oxotremorine in guinea-pig ileum were not antagonized by propranolol. 6. A dose-dependent antagonism of oxotremorine-induced tremor in mice was observed after pretreatment with propranolol and it is suggested that this effect is due to an antagonism of a presynaptic effect of oxotremorine at skeletal neuromuscular junctions.

Effect of l-5HTP on Tremorine- or Oxotremorine-Induced Tremor in Mice and Rats

According to the most predominant hypothesis, Parkinsonism, the main symptoms of which are tremor, muscle rigidity and akinesia, seems to result from disturbances in the basal ganglia, especially disturbance of the amine balance between the cholinergic and dopaminergic system in the corpus striatum (1, 2). L-Dopa (L-dihydroxyphenylalanine) has recently been used, as well as anticholinergic agents, antihistamines and phenothiazines. in the treatment of Parkinsonism. Although it is remarkably effective against muscle rigidity and akinesia, L-dopa shows only slight inhibition against tremor both in animal experiments and clinical cases (3). Some authors ascribe Parkinsonism to a decrease in intracerebral 5-HT (5-hydroxytryptamine) level (4) and there are reports about the application of 5-HTP (5-hydroxytryptophan), a metabolic precursor of 5-HT, to the treatment of Parkinsonism (5, 6).

The peripheral and central actions of some anticholinergic substances.

The peripheral and central anticholinergic potencies of six glycollic acid esters were measured and compared with similar results for atropine and hyoscine. There was no correlation between estimates of in vivo peripheral anticholinergic activity as measured by production of mydriasis in mice and by antagonism of oxotremorine-induced salivation in mice. The reason for this lack of correlation is not apparent. A significant correlation was demonstrated between estimates of central activity obtained by measuring antagonism of oxotremorine-induced tremors in mice and elevation of the EEG arousal threshold in cat encéphale isolé preparations. It is concluded that blockade of central cholinergic synapses was responsible for both effects and there is some discussion of the significance of the system involved in EEG arousal. The relationship between chemical structure of the drugs and their pharmacological activity is also discussed.