[The effect of desmethylimipramine and other "anti-tremorine" drugs on the metabolism of tremorine and oxotremorine in rats and mice].
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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.
5-Hydroxytryptophan↗
Effects of lesions in some basal ganglia nuclei and efferent projections on tremorine-induced limb rigidity in rats.
A mechanical apparatus was used to measure in rats the effects of some unilateral basal ganglia lesions on the hind-limb rigidity produced by the cholinomimetic compound, tremorine. A globus pallidus lesion reduced the resting tone and greatly increased rigidity in the contralateral leg. Lesions in the entopeduncular, subthalamic, and accumbens nuclei had no effects on rigidity, although the entopeduncular nucleus lesion reduced resting limb tone. The role of the globus pallidus in rigidity is significant in relation to work in which striatal lesions abolished tremorine-induced rigidity. Some brain regions that receive basal ganglia efferent fibers received a lesion unilaterally. Lesions in the substantia nigra, red nucleus, or pedunculopontine nucleus had no effect on tremorine-induced rigidity. A habenular lesion significantly reduced rigidity in both hind legs. Very pronounced reductions in rigidity occurred after midbrain lesions involving the central periaqueductal grey region and the superior colliculus. The basal ganglia output pathways that may mediate tremorine rigidity are discussed, together with the possibility that the superior colliculus, which has many muscarinic receptors, may be influenced directly by tremorine.
Animals↗
Spectral analysis of tremorine and cold tremor electromyograms in animal species of different size.
In 14 mice (36.2 +/- 5.4 g), 17 rats (425 +/- 46.4 g), and 11 rabbits (3,200 +/- 340 g) a comparative electromyographic analysis of tremorine tremor and cold tremor was performed in gastrocnemius and tibialis anterior muscles using spectral analysis. The mean frequency of cold tremor decreased with increasing body weight (mice: 40.2 +/- 4.5 Hz; rats: 31.3 +/- 4.9 Hz; rabbits: 16.4 +/- 3.2 Hz). With tremorine tremor no such allometric correlation was found for tremor frequency and body weight (mice: 17.7 +/- 3.6 Hz; rats: 19.6 +/- 5.1 Hz; rabbits: 15.9 +/- 2.1 Hz). Cross spectral analysis revealed that during cold tremor the flexor muscle (tibialis anterior) and the extensor muscle (gastrocnemius) of rabbits are activated alternately. The mean phase shift between the activation of flexor and extensor muscle was -155.5 degrees. Stronger activation was observed in the flexor muscle. Tremorine tremor was characterized by synchronous activation of flexor and extensor muscles with a mean phase angle of 3.0 degrees and a predominance of the extensor muscle. The results suggest that the nervous mechanisms for the generation of tremorine tremor and cold tremor are different.
Animals↗
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.
Animals↗
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.
Animals↗
Antagonism by naloxone of anti-tremorine effect of bromocriptine in mice.
Effects of the opioid antagonist naloxone (10 mg/kg) and its interaction with anticholinergic (scopolamine) and dopaminergic (bromocriptine) agents against tremorine-induced tremors was studied. Naloxone (10 mg/kg) per se gave significant protection and significantly potentiated the protective effect of scopolamine against tremorine-induced tremors at 5 min only. When naloxone and subeffective dose of bromocriptine (2 mg/kg) were administered simultaneously, instead of protection, an enhancement of tremorogenic activity was seen. Although the exact mechanism of this drug interaction is far from clear, a multireceptor involvement (i.e. opioid, dopaminergic and cholinergic type) in the modulation of tremorine-induced tremors in mice has been speculated.
Animals↗
Ultrasonic analysis of tremorine and cold tremor activity in unanesthetized rats.
In order to quantify the tremorine and cold tremor activity in unanesthetized rats, a new ultrasonic motion transducer method was used. Both kinds of activity are reported as vibratory body motion that occurred between 18-32 Hz as determined by spectral analysis. The recorded signal was analyzed and its power spectrum was obtained through a fast Fourier transform operation. It was found that a negative linear relation occurs between shiver amplitude and ambient temperature (r = 0.999). A negative linear relation also occurs between metabolic rate and ambient temperature (r = 0.997). In addition, a positive linear relation between metabolic rate and cold shiver exists (r = 0.999). Both tremorine (30 mg/kg, i.p.) and cold tremor (Ta = 2-22 degrees C) activity monitored by the ultrasonic method were completely abolished by premedication with 1 mg/kg atropine. Thus, it appears that the advantages of this tremor detection method are that is non-invasive and non-contact. Therefore, the ultrasonic method provides a good choice for quantifying tremorine and cold tremor activity in unanesthetized animals during studies of thermoregulatory physiology or motor disorders.
Animals↗
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.
Animals↗
Antiparkinsonian-like effects of Plumbago scandens on tremorine-induced tremors methodology.
Tremorine-induced tremors model is used to evaluate antiparkinsonian drugs because rest tremor is a sign that distinguishes Parkinson's disease (PD) from other diseases. The effects of crude ethanolic extract (CEE) and total acetate fraction (TAF) of Plumbago scandens were investigated at several doses. These extracts at doses of 125 and 250 mg/kg i.p. failed to reduce tremors in tremorine-treated mice. TAF showed significant effects only at a dose of 500 mg/kg. Both CEE and TAF at doses of 1000 and 2000 mg/kg i.p. suppressed the tremors in a dose-dependent fashion for 60 min. Biperiden, an anticholinergic drug, was used as standard at a dose of 3 mg/kg i.p. This study suggests that P. scandens is a plant with possible therapeutic value for PD.
Animals↗
Relationship between anti-acetylcholine and anti-Tremorine activity in anti-parkinsonian and related drugs.
The anti-acetylcholine potency of a number of anti-Parkinsonism drugs and related phenothiazine compounds was determined using the isolated guinea-pig ileum. The antagonism was assessed by the difference between the pA(2) and pA(10) values and by log concentration-response curves for acetylcholine in presence and absence of the antagonists. All compounds except chlorpromazine showed some evidence of competitive antagonism to acetylcholine. The anti-tremor potency of the compounds was assessed from suppression of Tremorine-induced tremors in mice. There was a relation between anti-acetylcholine and anti-Tremorine potency among the anti-Parkinsonism drugs, but not among the phenothiazine compounds. Some implications of the findings are discussed in relation to the mode of action of anti-Parkinsonism drugs.
Acetylcholine↗
TREMORINE: ITS EFFECT ON AMINES OF THE CENTRAL NERVOUS SYSTEM.
The administration of tremogenidine doses of Tremorine, 1,4-dipyrrolidino-2 butyne, is followed by a significant decrease in the concentration of norepinephrine in the brain stem of three common laboratory species. The change in the concentration proceeds at a rate which coincides with the occurrence of the tremor in each of these species. In the rat, the change in norepinephrine is followed by a progressive increase in the concentration of 5-hydroxytryptamine in the brain stem. Bilateral adrenalectomy in the rat enhances the Tremorine-induced changes in the concentration of norepinephrine and antagonizes the increase in the concentration of S-hydroxytryptamine.
Amines↗
TREMORINE: ITS PERIPHERAL ACTION ON STRIATED MUSCLE.
Tremorine, injected intraperitoneally into rats, induces the same kind of calcium release in the motor end-plates as that induced by acetylcholine-like agents. Since the same effect results even if the appropriate motor nerve has previously been transected, it is concluded that this myoneural action of Tremorine is not due to a e entral excitation but rather to a peripheral stimulatory property of the drug.
Acetylcholine↗
The role of adrenergic mechanism in tremorine-induced tremors in rats: antitremor effect of beta-adrenoceptor antagonists.
Tranylcypromine (TCP) pretreatment was found to accelerate the tremorogenic activity of tremorine in rats. Conversely, reserpinization delayed the onset of induction of tremors, and a significant diminution in their intensity was observed in these rats. A comparative study of the antitremor activity of beta-adrenoceptor antagonists against this tremor-model showed that butoxamine (beta 2-antagonist) and propranolol (nonselective antagonist) were able to afford a rapid and powerful protection, whereas a weaker and delayed effect was observed in rats treated with the beta 1-antagonist, acebutolol. Furthermore, the antitremor activity of butoxamine and propranolol but not that of acebutolol was found to be potentiated and diminished in rats pretreated with reserpine and TCP, respectively. It was inferred that beta 2-receptor modulated the tremorogenic activity of tremorine, and that inhibition by propranolol or butoxamine of this subtype beta-adrenoceptor resulted in rapid and powerful suppression of tremors, and that the antiadrenergic activity of acebutolol was unlikely to have a role in its antitremor effect.
Adrenergic beta-Antagonists↗
GABAergic, dopaminergic and cholinergic interaction in tremorine-induced tremors in mice.
Antitremor effects of systemically administered GABA agonists (GABA and sodium valproate) and GABA antagonists (bicuculline and picrotoxin) were studied in mice against tremorine-induced tremors. None of the GABA agonists were found to possess any antitremor effect, whereas GABA antagonists were found to possess protective effect against tremorine-induced tremors. Simultaneous administration of GABA agonists with sub-effective doses of anticholinergic agent (scopolamine) did not potentiate antitremor effect of scopolamine, whereas GABA antagonists and effective doses of scopolamine when administered simultaneously resulted in antagonism of protective effect of scopolamine. Similarly, when GABA agonists and sub-effective doses of dopaminergic agent, bromocriptine, were administered simultaneously, the protective effect of bromocriptine was potentiated. When GABA antagonists and effective doses of bromocriptine were administered simultaneously, the protective effect of bromocriptine was antagonized. The modification of the protective effect of anticholinergic and dopaminergic agents by GABAergic agents has been explained on the basis of neurotransmitter interaction.
Animals↗
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.
Acetylcholine↗
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.
Animals↗
Antagonism of the effects of tremorine by tropine derivatives.
Methods of testing new drugs for anti-Parkinson activity are briefly reviewed. The production in animals of Parkinson-like effects by Tremorine (1,4-dipyrrolidin-1'-ylbut-2-yne), and the inhibition of these effects in mice by a number of tropine derivatives, are described. No correlation was found between the activity against tremor and the anticholinergic, antihistaminic or local anaesthetic properties of the compounds.
Animals↗