Oxotremorine In Mice Research Articles

Effects of AIT-082, a Purine Derivative, on Tremor Induced by Arecoline or Oxotremorine in Mice

The effects of AIT-082, a hypoxanthine derivative, on tremor in mice were investigated. The mice received intragastric administration of AIT-082 for consecutive 60 days at doses of 150, 300 and 600 mg·kg^–1. The results showed that AIT-082 not only effectively inhibited the tremor induced by arecoline or oxotremorine, but also alleviated the tremor intensity and significantly shortened the tremor durations. The inhibition of tremor was perhaps associated with the central cholinergic nerve depressant effects as well as the stimulation of proliferation and differentiation of nerve cells.

Ryanodine receptors are involved in muscarinic antinociception in mice

The role of ryanodine receptors (RyRs) in the induction of muscarinic antinociception was investigated in a condition of acute thermal pain by means of the mouse hot-plate test. I.c.v. administration of non-hyperalgesic doses of ryanodine (0.001–0.06 nmol per mouse i.c.v.), an antagonist of ryanodine receptors (RyRs), dose-dependently prevented the antinociception induced by both physostigmine (100–150 μg kg −1 s.c.) and oxotremorine (40–70 μg kg −1 s.c.). A shift to the right of the dose–response curve of both cholinomimetic compounds was observed. Pretreatment with non-analgesic doses of 4-chloro- m-cresol (4-Cmc; 0.003–0.3 nmol per mouse i.c.v.), an agonist of RyRs, reversed in a dose-dependent manner the antagonistic effect produced by ryanodine of muscarinic antinociception. The pharmacological treatments employed neither modified the animals’ gross behavior nor produced any behavioral impairment of mice as revealed by the rota-rod and hole-board tests. These results indicate that a variation of intracellular calcium contents at the central nervous system level is involved in muscarinic antinociception. In particular, the stimulation of RyRs appears to play an important role in the increase of the pain threshold produced by physostigmine and oxotremorine in mice.

The interaction of tetrahydroisoquinoline derivatives with antinociceptive action of morphine and oxotremorine in mice.

To extend our earlier data on synergistic action of tetrahydroisoquinolines and morphine, we have investigated the analgesic effects of 1,2,3,4-tetrahydroisoquinoline (TIQ) and its 1-methyl-(1-MeTIQ) and N-methyl (N-MeTIQ) analogs on analgesia induced by morphine and oxotremorine. 1-MeTIQ and N-MeTIQ induced a moderate, delayed and prolonged analgesic action measured in the tail-flick test in CD-1 mice; 1-MeTIQ and TIQ prolonged the opiate (morphine, 2.5 mg/kg i.p.) analgesia while TIQ and N-TIQ potentiated cholinergic (oxotremorine, 0.02 mg/kg i.p.) analgesia. The involvement of the opioid and noradrenergic systems in this effect is discussed.

Effects of Ropinirole on Various Parkinsonian Models in Mice, Rats, and Cynomolgus Monkeys

Ropinirole (4-[2-(dipropylamino)ethyl]-2-indolinone monohydrochloride) a nonergoline dopamine receptor agonist with high affinity for native dopamine D 2-like receptors in human caudate tissue, was tested with respect to the stimulation of postsynaptic brain dopamine receptors in standard preclinical models of Parkinson's disease. Additionally, in these animal models the antiparkinsonian activity of ropinirole was compared to that of bromocriptine. The ED 50s (95% confidence limits) of ropinirole and bromocriptine on the turning behavior in 6-OHDA–lesioned rats were 20.17 mg/kg (14.27–26.88 mg/kg) and 11.99 mg/kg (9.37–14.17 mg/kg), respectively. The ED 50s (95% confidence limits) of ropinirole and bromocriptine on the catalepsy induced by reserpine were 18.55 mg/kg (15.29–22.99 mg/kg) and 12.56 mg/kg (10.25–14.64 mg/kg), respectively. Ropinirole and bromocriptine had no effect on the tremors induced by oxotremorine in mice, whereas atropine markedly suppressed the tremors. The ED 50s (95% confidence limits) of ropinirole and bromocriptine on the tremors in VMT-lesioned monkeys were 0.18 mg/kg (0.12–0.29 mg/kg) and 2.63 mg/kg (1.06–6.45 mg/kg), respectively. In rodent parkinsonian models, bromocriptine was more potent than ropinirole; however, in the nonhuman primate parkinsonian model, ropinirole was a more potent inhibitor of parkinsonian activity than bromocriptine. This study suggests that ropinirole is a dopamine D 2-like receptor agonistic drug of potential use in the treatment of Parkinson's disease.

The Post-training Memory Enhancement Induced by Physostigmine and Oxotremorine in Mice Is Not State-Dependent

Immediate post-training subcutaneous administration of either the centrally acting anticholinesterase physostigmine (35, 70, or 150 μg/kg) or the centrally acting muscarinic cholinergic agonist oxotremorine (OTM; 25, 50, or 100 μg/kg) significantly enhanced retention of male Swiss mice tested 48 h after training in a one-trial step-through inhibitory avoidance task (0.8 mA, 50 Hz, 1 s footshock). Neither physostigmine nor OTM affected latencies to step through in mice not given the footshock on the training trial, suggesting that the effects of both cholinomimetics on retention performance were not due to nonspecific actions on response test latencies. The peripherally acting anticholinesterase neostigmine (35, 70, or 150 μg/kg) did not significantly influence retention latencies of either shocked or unshocked mice. The influences of physostigmine (150 μg/kg) and OTM (100 μg/kg) on retention were time-dependent, which suggests that the drugs facilitated memory storage. Administration of physostigmine (150 μg/kg) or OTM (100 μg/kg) 30 min prior to the retention test did not affect the retention performance of mice given post-training injections of either saline, physostigmine (150 μg/kg), or OTM (100 μg/kg). Considered together, these findings indicate that the memory-enhancing effects of post-training administration of physostigmine or OTM are not state-dependent and are consistent with the view that the behavioral effects of the cholinomimetics drugs are mediated through an interaction with the neural processes underlying the storage of acquired information.

Anticonvulsant activity of 3-oxo-5-substituted benzylidene-6-methyl-(4H)-2-pyridazinylacetamides and 2-pyridazinylacetylhydrazides.

A series of 3-oxo-5-substituted-benzylidene-6-methyl-(4H)-2- pyridazinylacetamides and 2-pyridazinylacetylhydrazides were synthesized and evaluated for anticonvulsant activity against electrically and chemically induced seizures. In the maximal electroshock-induced seizures test, most of the derivatives showed an anticonvulsant effect better than that of sodium valproate, a commonly used anticonvulsant drug. At 100 mg/kg orally, compounds 5a and 5b respectively protected 50 and 60% of the mice against pentylentetrazole-induced seizures. In addition, these two derivatives showed significant anticonvulsant properties at doses that did not produce ataxia or sedation. The title compounds were also tested for their ability to antagonize convulsions induced by bicuculline and strychnine. Their effect on tremors induced by oxotremorine in mice was also evaluated.

Power Spectral Analysis of Tremor Induced by TRH and Oxotremorine in Mice

Power Spectral Analysis of Tremor Induced by TRH and Oxotremorine in Mice

Power Spectral Analysis of Tremor Induced by TRH and Oxotremorine in Mice

Power Spectral Analysis of Tremor Induced by TRH and Oxotremorine in Mice

Potentiation by naloxone of the anti-oxotremorine effect of L-DOPA

Pretreatment with the catecholamine precursor L-DOPA but not the narcotic antagonist naloxone suppresed the tremorigenic effect of oxotremorine in mice. However, when animals were pretreated with both L-DOPA and several different doses of naloxone, there was a dose-related potentiation of the antitremor effect of L-DOPA. Naloxone also produced dose-dependent protentiation of the antitremor activity of lower doses of L-DOPA in the presence of the peripheral decarboxylase inhibitor carbidopa. These findings suggest a possible therapeutic application ofr naloxone in treatmen of dopamine dysfunction disorders.

Possible cholinergic-dopaminergic link in memory facilitation induced by oxotremorine in mice.

The immediate post-trial injection of the centrally active muscarinic agonist oxotremorine (0.025, 0.050 and 0.100 mg/kg, IP) can facilitate the retention of a passive-avoidance response in mice, as indicated by performance on a retention test 24 h later. Injections given 10 min after training also significantly facilitated retention, but given 120 min after training did not affect retention. These findings suggest an action of oxotremorine on memory mechanisms. The enhanced retention was neither the result of a punishing effect of oxotremorine nor of a nonspecific proactive pharmacological action of the drug. The memory facilitation produced by oxotremorine (0.050 mg/kg, IP) was not antagonized by pretreatment with phentolamine (10 mg/kg, 30 min, IP), phenoxybenzamine (10 mg/kg, 120 min, IP) or piperoxane (20 mg/kg, 30 min, IP). The alpha-noradrenergic blocking agents had no effect by themselves. On the other hand, the immediate post-trial injection of oxotremorine (0.050 mg/kg, IP) did not enhance retention when mice were pretreated with haloperidol (0.5 mg/kg, 120 min, IP). Haloperidol injected either before training or before the retention test did not alter performance during the retention test. This suggests that haloperidol impairs neither acquisition of the avoidance response nor its retrieval. Thus, it is probable that haloperidol pretreatment impaired oxotremorine-induced memory facilitation. We suggest a possible participation of brain catecholamines in memory facilitation induced by oxotremorine in mice.

The effect of 6-hydroxydopamine on the antinociceptive action of oxotremorine

Mice received intraventricular 6-hydroxydopamine (6-OHDA) to deplete brain noradrenaline (NA) and dopamine (DA). 6-OHDA reduced the reaction time of mice to nociceptive stimulus (hot plate) and attenuated the antinociceptive action of oxotremorine. The administration of 6-OHDA to desipramine treated mice prevented both the loss of cerebral NA and the antagonism of oxotremorine's antinociceptive action. The administration of 6-OHDA to pargyline-treated mice increased the depletion of cerebral DA, but the antagonism of oxotremorine's antinociceptive action persisted. Catecholamines were measured in mouse brain at intervals from 1 h to 3 days after administration of 6-OHDA. DA levels failed to correlate with either the reduction in the hot plate reaction time or the antagonism of oxotremorine analgesia, whereas these effects were usually accompanied by a loss of brain NA. Centrally acting DA agonists failed to restore oxotremorine's antinociceptive action in 6-OHDA-treated mice. Intraventricular administration of the acetylcholine synthesis inhibitor triethylcholine to mice did not effect the antinociceptive action of oxotremorine. It is concluded that the antinociceptive action of oxotremorine in mice is initiated by stimulation of muscarinic receptors and involves noradrenergic neurones.

Brain catecholamines modifications. The effects on memory facilitation induced by oxotremorine in mice.

the immediate posttrial injection of oxotremorine (0.250 mu Mol/kg, IP) can facilitate the retention of a passive-avoidance response in mice. After the administration of alfa-methyl-p-tyrosine methylester (alpha-MPT) by intracerebroventricular injection at doses that had no effect on retention (100 microgram, 10 microliter, 60 min before trial), the immediate posttrial injection of oxotremorine did not enhance retention. The employed dose of alpha-MPT reduced brain levels of norepinephrine by about 40% and those of dopamine by about 25%. Pretreatment with nialamide (30 mg/kg, 20h IP), which prevents the catecholamine depletion induced by alpha-MPT, counteracted the effects depletion induced by alpha-MPT, counteracted the effects of alpha-MPT on the actions of oxotremorine on retention. These results suggest a participation of brain catecholamines on the actions of oxotremorine on retention and a possible interaction of cholinergic neurons with catecholaminergic system in memory processes.

Central cholinergic receptor supersensitivity after long-term atropine administration.

Rats were treated with a single dose of atropine (AT) at 5 mg/kg, or every day for 14 or 31 days with the same dose of AT, 3 h after the single dose and 24 h after the last dose of chronically administered AT, 10 micrograms of ACh was injected intracerebroventricularly, and two tests were used to examine the behavior of the animals. The tremorigenic effect of oxotremorine was also measured in mice treated with 10 mg/kg of AT for 1 month. It was shown that a single dose of AT antagonized ACh-induced behavior. The long-term treatment with AT enhanced the depressive-behavior of ACh in rats and the tremorigenic effect of oxotremorine in mice. The results suggest that long-term blockade of central cholinergic receptors induces their hypersensitivity.

Abolition of oxotremorine effects by l-DOPA pretreatment

The effects of oxotremorine in mice were prevented by l-DOPA pretreatment. When l-DOPA was given with carbidopa it abolished oxotremorine-induced catalepsy and tremor but not diarrhoea and lachrymation. When l-DOPA was given with fusaric acid it had a similar effect to l-DOPA given with carbidopa. Noradrenaline and dopamine, on the other hand, antagonized only diarrhoea and lachrymation. 5-Hydroxytryptophan was ineffective against oxotremorine. It is concluded that l-DOPA pretreatment abolished catalepsy and tremor induced by oxotremorine through a central action, whereas diarrhoea and lachrymation are prevented by noradrenaline to which l-DOPA is converted.

Genetical differences in sensitivity to tremorine and oxotremorine in mice

Male mice from 14 straind were injected i.p. with tremorine (3.0 mg/kg) or oxotremorine (0.15 pr 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 the 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.

On the interaction of drugs with the cholinergic nervous system—IV: Tolerance to oxotremorine in mice: In vivo and in vitro studies

A new procedure was used to follow continuously and simultaneously four systemic effects induced by oxotremorine in mice: salivation, tremor, hypothermia and those measured in the rotarod test. Using an equipotent dose of methoxotremorine, it was found that apart from salivation, the other systemic effects are centrally originated. By comparing the complete dose-response curves for these systemic effects in naive and tolerant mice, it was found that: (1) Salivation is the most sensitive effect in naive mice; (2) All curves shift in parallel to the right on continuous exposure to oxotremorine, in a manner that seems to be dose-dependent; (3) the tolerance to oxotremorine is reversible. Since oxotremorine-tolerant mice were found to be cross-tolerant to various tertiary anti-cholinesterase agents and cholinergic agonists, the involvement of the muscarinic receptor in the tolerance to oxotremorine was investigated, using two different approaches. (1) Continuous blockade of the receptor by scopolamine in vivo prevented tolerance development to oxotremorine; this effect was found to depend on the time of scopolamine administration relative to oxotremorine injection, and on the systemic effect measured. (2) The amount of receptor and its affinity towards a specific ligand were determined in vitro; no significant differences were found between naive and oxotremorine-tolerant animals. The significance of these results in the elucidation of possible tolerance mechanisms is discussed.

Effect of 6-hydroxydopamine on some actions of tremorine and oxotremorine

The effect of 6-hydroxydopamine on the tremorogenic, hypothermic and antinociceptive activities of tremorine and oxotremorine was investigated in rats and mice. Neither tremor nor hypothermia was affected by 6-hydroxydopamine administered intraventricularly to rats in order to deplete brain noradrenaline. The hypothermia, but not the tremor, was prevented by pretreating the rats with pargyline prior to 6-hydroxydopamine in order to deplete dopamine as well as noradrenaline. Mice given 6-hydroxydopamine were found to respond more quickly in the host plate reaction time test than normal mice. The usual powerful antinociceptive action of oxotremorine in mice was abolished with pretreatment with intraventricular 6-hydroxydopamine. It is concluded that the tremorogenic action of tremorine is probably not mediated by brain monoamines but the hypothermia could be caused by the release of brain dopamine. Brain monoamines appear to be implicated in the antinociceptive actionof oxotremorine in the mouse.

Studies on the potentiation of the antinociceptive effect of oxotremorine by tetrabenazine in mice

The antinociceptive effect of Oxotremorine in mice was increased by tetrabenazine in the hot plate test. This effect of tetrabenazine was antagonized by desmethylimipramine and amphetamine, and enhanced by 5-hydroxytryptophan.

Duration of effect of atropine sulphate against the toxicity of oxotremorine in mice.

Duration of effect of atropine sulphate against the toxicity of oxotremorine in mice.

Drug-induced changes in brain levels of oxotremorine in mice

Drug-induced changes in brain levels of oxotremorine in mice