Biomedical subjects

T Tonohiro

Publications and source records attributed to T Tonohiro.

12 recordsLinked to original sources

PubMed2000

The allocentric place discrimination task is selectively and highly dependent on the central muscarinic system in rats.

The allocentric place discrimination task (APDT) is useful in evaluating working memory separately from and simultaneously with motivation, motor and sensory ability. Muscarinic acetylcholine receptor antagonist scopolamine has been shown to selectively impair the accuracy of APDT without changing swimming speed, distance, and still time. For further evaluation of other neurotransmitters' roles in the APDT, pharmacological manipulations were performed. Neither diazepam 3.0 mg/kg, mecamylamine 10 mg/kg, haloperidol 0.5 mg/kg, nor 8-OH DPAT 1.0 mg/kg affected accuracy of place discrimination. Two kinds of responses were observed following the administration of MK-801 0.3 mg/kg: the accuracy of rats for longer swimming distance tended to decrease, and the accuracy of rats for normal swimming distance did not change. Therefore, NM-801 did not seem to affect the working memory selectively. In addition, neither flumazenil 10 mg/kg, ondansetron 0.3 mg/kg nor R(-)-alpha-metylhistamine 10 mg/kg attenuated the scopolamine-induced deficits. These results suggest that the central muscarinic receptors are selectively and highly important in the APDT.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2000

Activation of cerebral function by CS-932, a functionally selective M1 partial agonist: neurochemical characterization and pharmacological studies.

A newly synthesized agonist for muscarinic acetylcholine (ACh) receptors CS-932, (R)-3-(3-iso-xazoloxy)-1-azabicyclo-[2.2.2]octane hydrochloride, showed a relatively higher affinity for M1 than M2 receptors expressed in Chinese hamster ovary (CHO)-cells in comparison with ACh. CS-932 elevated the intracellular Ca2+ level only in M1-CHO cells, although ACh increased the level in both M1- and M3-CHO cells. CS-932 and ACh reduced forskolin-stimulated accumulation of cAMP in M2-CHO cells by 20% and 80%, respectively. This neurochemical profile of CS-932 indicates that the compound can activate M1-receptor-mediated functions selectively. CS-932 increased firing of cholinoceptive neurons in rat hippocampal slices, and this excitation was antagonized by pirenzepine, but not by AF-DX 116. CS-932 increased awake and decreased slow wave sleep episodes of daytime EEG in free-moving rats. It counteracted scopolamine-induced slow waves in rat cortical EEG. CS-932 also increased the power of alpha- and beta-waves, but decreased delta-wave of the cortical EEG in anesthetized monkeys. It ameliorated scopolamine-induced impairment of working memory in rats. Orally administered CS-932 had the best penetration into the brain among the muscarinic agonists tested and caused the least salivary secretion among the cholinomimetics examined. These results indicate that CS-932 has potential as a cognitive enhancer with fewer side effects in therapy for Alzheimer disease.

Animals↗

PubMed1999

Stereoselective pharmacokinetics of RS-8359, a selective and reversible inhibitor of A-type monoamine oxidase, in rats, mice, dogs, and monkeys.

RS-8359, (+/-)-4-(4-cyanoanilino)-5,6-dihydro-7-hydroxy-7H-cyclopenta[d]-py rimidine, inhibits, selectively and reversely, A-type monoamine oxidase (MAO-A). In order to clarify the stereoselective metabolism of this drug, plasma concentrations of the [R] and [S]-enantiomers of RS-8359 were determined by chiral column HPLC after oral administration of each enantiomer to rats, mice, dogs, and monkeys. After administration of the [R]-enantiomer, high levels were retained in all animal species studied. On the other hand, when the [S]-enantiomer was administered, plasma concentrations decreased rapidly in rats and mice, and extremely rapidly in dogs, while in monkeys, only a trace amount was detected immediately after dosing. Thus, it was found, as a common phenomenon in rats, mice, dogs, and monkeys, that plasma concentrations of the [S]-enantiomer were markedly lower than those of the [R]-enantiomer. Secondly, the [R]-enantiomer was observed in plasma after administration of the [S]-enantiomer, and the [S] to [R] chiral inversion rate was estimated from AUC([R] after [S])/AUC([R] after [R]). The percentage was 45.8% in rats, 3.8% in mice, 0.8% in dogs, and 4.2% in monkeys. Further, the [S]-enantiomer was detected in plasma of SD rats dosed with the [R]-enantiomer, suggesting [R] to [S] chiral inversion in rats. These results show marked species differences in the chiral inversion of the cyclopentanol group of RS-8359. A mechanism of chiral inversion is discussed based on experiments using isolated rat hepatocytes.

Animals↗

PubMed1999

Simultaneous evaluation of spatial working memory and motivation by the allocentric place discrimination task in the water maze in rats.

In order to evaluate learning and memory deficits separately from and simultaneously with motivational, motor and sensory impairments in identical animals, we developed the allocentric place discrimination task test using a water maze in rats. For this assessment task, two similar, visible platforms, one was fixed and the other was floating, were simultaneously present in a pool, and the working memory of the allocentric place discrimination task was evaluated. After training, the task accuracy was high about 85% correct and animals were used repeatedly. The accuracy decreased significantly when the pool was surrounded with a black curtain. Muscarinic receptor antagonist scopolamine 0.5 mg/kg selectively impaired the accuracy. Muscle relaxant dantrolene 10 mg/kg selectively decreased swimming speed. Under low motivational condition (warm water), still time increased and swimming speed decreased, but the accuracy was not affected. Similar to warm water, opioid receptor agonist morphine 15 mg/kg increased still time and decreased swimming speed. These results suggest that the allocentric place discrimination task is useful in evaluating spatial working memory ability independently of and concurrently with also visual, motor ability and motivation in identical animals.

Analgesics, Opioid↗

PubMed1998

Co-injection of beta-amyloid with ibotenic acid induces synergistic loss of rat hippocampal neurons.

Senile plaques are a pathological hallmark of Alzheimer's disease. The major component of senile plaques is beta-amyloid which consists of approximately 4000 mol. wt of peptide. Accumulating evidence suggests that beta-amyloid may represent the underlying cause of Alzheimer's disease. In vitro, beta-amyloid has been shown either to be directly neurotoxic or to potentiate neurotoxic effects of excitatory amino acids. However, beta-amyloid toxicity in vivo has not always been reproducible. In this study, we injected beta-amyloid fragment 1-40 or 25-35 alone or in combination with a small amount of ibotenic acid, an excitatory amino acid, into rat hippocampus, and examined the histological and immunohistochemical changes two weeks after injection. Although beta-amyloid alone or ibotenic acid alone exerted only minimal degenerating effects on neurons just around the injection site, the co-injection of beta-amyloid 1-40 or beta-amyloid 25-35 with ibotenic acid produced drastic neuronal loss; the haematoxylin-eosin staining revealed that most neurons not only around the injection site but also in distant areas including CA1, CA4 and dentate gyrus were depleted. The neuronal loss occurred in a dose-dependent manner with respect to ibotenic acid. Immunohistochemical analysis showed that beta-amyloid with ibotenic acid induced great depletion of microtubule-associated protein-2 immunoreactivity and infiltration of astrocytes and microglia on neuronal loss. In addition, some apoptotic neuronal death indicated by DNA fragmentation and nucleic condensation was observed. Beta-amyloid depositions detected by two different types of anti-human beta-amyloid antibodies were limited to the injection site. Dizocilpine maleate (MK-801), an antagonist for an excitatory amino acid receptor, completely inhibited the neuronal death in rat hippocampus. These results suggest that the co-injection of beta-amyloid with a small amount of ibotenic acid provides a useful model for investigation of the pathogenetic mechanisms leading to Alzheimer's disease.

Amyloid beta-Peptides↗

PubMed1997

Picolinic acid and indole-2-carboxylic acid: two types of glycinergic compounds modulate motor function differentially.

1. A putative agonist for the strychnine-sensitive glycine receptor picolinic acid was tested for its anticonvulsant activities in mice and muscle-relaxant activities in rats and compared with indole-2-carboxylic acid (I2CA), an antagonist for the strychnine-insensitive glycine receptor. Their effects on segmental reflexes in the cat spinal cord were examined to elucidate their sites of action. 2. Picolinic acid (200 and 400 mg/kg IP) delayed the onsets of strychnine- but not pentylenetetrazole-induced seizures. It delayed the onsets of bicuculline-induced seizures only at the higher dose. I2CA (200 and 400 mg/kg IP) delayed the onsets of these 3 kinds of seizures. Both compounds reduced muscle tone in rat decerebrate rigidity at a dose of 100 mg/kg IV. 3. Picolinate methylester, a picolinate derivative with higher lipophilicity, depressed spinal reflexes in both intact and spinalized cats at cumulative doses of 25 to 200 mg/kg IV. I2CA (50 mg/kg IV) inhibited spinal reflexes only in intact preparations. 4. These results suggest that the anticonvulsant and muscle-relaxant activities of picolinic acid (PA) are due to inhibition of spinal neurons, but that I2CA selectively affects supraspinal structures.

Animals↗

PubMed1993

Sites of action of CS-722, a newly synthesized centrally acting muscle relaxant.

Sites of the muscle relaxant action of CS-722 were investigated in rats. Doses injected intra-4th ventricularly (i.c.v.) or intrathecally (i.t.) were determined according to measurements of CS-722 concentration in the brain stem and the spinal cord after systemic administration. When administered i.c.v. (50 and 100 micrograms) or i.t. (200 and 400 micrograms), CS-722 reduced the radio frequency decerebrate rigidity, although the effect after i.c.v. injection was transient. These results indicate that CS-722 exerts its muscle relaxant action by affecting both the supraspinal structure and the spinal cord. Spinal reflexes were not affected by CS-722 injected i.c.v. It seems that muscle relaxation is not always accompanied by impairment of the spinal reflex.

Animals↗

PubMed1992

The pharmacological properties of CS-722, a newly synthesized centrally acting muscle relaxant.

The pharmacological properties of (R)-4-chloro-2-(2-hydroxy-3-morpholinopropyl)-5-phenyl-4-isoxaz olin-3-one hydrochloride (CS-722), a newly synthesized, centrally acting muscle relaxant, were studied in rats. The drug CS-722 reduced the radio frequency decerebrate rigidity in a dose-dependent manner (25-100 mg/kg, p.o.); it inhibited the increase in discharges from Ia afferent fibers, gamma-motor activity, which was induced by stimulation of the reticular formation. The compound, however, showed no effect on the basal discharge of Ia afferent fibers. The polysynaptic reflex was depressed by CS-722, with less influence on the monosynaptic reflex in intact and spinal preparations and CS-722 did not prolong thiopental-induced sleeping time. In rats anesthetized with halothane, CS-722 did not affect the electroencephalogram (EEG) arousal response, which was elicited by stimulation of the reticular formation. The results of this study suggest that CS-722 can exert a muscle relaxant action, at a dose range at which depression of the ascending reticular activating system was negligible. The results also suggest that depressions of the gamma-motor system and the polysynaptic reflex may contribute to the muscle relaxant action of CS-722.

Animals↗

PubMed1992

Mechanisms of spinal reflex depressant effects of CS-722, a newly synthesized centrally acting muscle relaxant, in spinal rats.

The mechanisms of the depressant action of (R)-4-chloro-2-(2-hydroxy-3-morpholinopropyl)-5-phenyl-4-isoxaz olin-3-one hydrochloride (CS-722), a newly synthesized centrally acting muscle relaxant, on spinal reflexes were investigated in spinal rats. The drug CS-722 (50 mg/kg, i.v.) depressed the polysynaptic reflex but was less effective on the monosynaptic reflex. Eperisone-HCl (10 mg/kg, i.v.) and baclofen (2 mg/kg, i.v.) markedly decreased the monosynaptic and polysynaptic reflexes, with longer durations than CS-722; CS-722, eperisone and baclofen depressed the dorsal root reflex. The excitability of the motoneurone was reduced by CS-722 and eperisone. Excitability of the primary afferent fibres was reduced by CS-722, while eperisone and baclofen had no effect. Both CS-722 and eperisone did not have a depressant influence on the focal synaptic potential. These results suggest that CS-722 and eperisone but not baclofen, have a common motoneurone-membrane-stabilizing action and that this action may contribute, in part, to the spinal reflex depressant effects of CS-722 and eperisone.

Animals↗

PubMed1990

Is picolinic acid a glycine agonist at strychnine-sensitive receptors?

By means of unit recording and electrophoretic application, the effect of picolinic acid on feline spinal interneurons in situ was studied in comparison with glycine. Picolinic acid inhibited neuronal firing in 60% of neurons and in some cases the inhibitory actions were antagonized by strychnine. Inhibition of firing by glycine, which was also strychnine-sensitive, was reduced in case of concomitant administration of picolinic acid. These results suggest that picolinic acid might act as a glycine agonist at strychnine-sensitive receptors.

Animals↗

PubMed1980

Effects of CS-386 and diazepam upon the gastric contraction and excitation of lumbar gamma-motoneurons following stimulation of the hypothalamus in the cat.

Effects of a new minor tranquilizer, CS-386 and diazepam were studied upon the gastric contraction and excitation of lumbar gamma-motoneurons following stimulation of some of the brain structures as well as upon the spontaneous gastric motility in the cat. CS-386 inhibited the hypothalamus-induced gastric contraction with little changes in spontaneous motility at doses of 5 and 10 mg/kg (i.d.). Diazepam inhibited both the hypothalamus-induced contraction and spontaneous motility at these doses. The vagal nerve-induced gastric contraction was suppressed by diazepam (5 mg/kg, i.d.) but not by the same dose of CS-386. Bemegride (5 mg/kg, i.v.) antagonized almost completely the depression caused by 5 mg/kg of CS-386, but not that by a dose of 10 mg/kg or 5 as well as 10 mg/kg of diazepam. Excitation of the lumbar gamma-motoneuron following stimulation of the posterior hypothalamus or the mesencephalic reticular formation was depressed by CS-386 or diazepam (10 mg/kg, p.o.), but not by lower doses. Based on the these evidences, it was suggested that CS-386 could be effective in stress-induced gastric lesions with lower side effects in digestive organs than diazepam.

Animals↗

PubMedDate not supplied

Age-related working memory deficits in the allocentric place discrimination task: possible involvement in cholinergic dysfunction.

It is well known that learning and memory ability declines with aging. Age-related long-term changes in learning and memory ability in rats were investigated with the place navigation task and the allocentric place discrimination task (APDT) in a water maze using the same animals for each task. In a working memory place navigation task, aged animals could learn the location of the platform as well as when they were young, although strategy shifts were observed. In contrast, accuracy in the APDT significantly declined from 90% to 65% with aging. This impairment was ameliorated by an acetylcholine esterase inhibitor physostigmine at 22-23 months old. No amelioration was, however, detected in the same animals tested when they further aged to 26-27 months old. These results suggest that the APDT performance is sensitive to age-related memory deficits and that this may be due to the cholinergic dysfunction.

Aging↗