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.

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.

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.

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.

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.

Tremorine-oxotremorine-induced tremor, hypothermia and analgesia, and physostigmine toxicity, in mice after pretreatment with beta-adrenoceptor antagonists.

The beta-adrenoceptor blockers propranolol, PhQA33 and LB-46 exhibited appreciable activity against tremorine-(TMN) and oxotremorine-(OTMN) induced tremor, whereas pronethalol, (+)-H56/28, (-)-H56/28, Kö-592 and L(+)-INPEA possessed weak action. The two beta-blockers, namely D,L(+/-)-INPEA and D(-)-INPEA acted as weak tremorgens. None of the above compounds suppressed the induced peripheral cholinergic phenomena; or possessed any central anticholinergic activity, as they were unable to afford protection against physostigmine-induced death. Propranolol, PhQA33 and LB-46 antagonized TMN-induced hypothermia and analgesia, but were inactive against OTMN-induced changes. A correlation of the beta-blocking and anti-tremor activity of these agents is unlikely.

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.

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.