Abstract-Effectsof central depressants-chlorpromazine, diazepam, pentobarbital and ethanol-on rota-rod and traction performances in mice were investigated. The walking technique of the animals on the rotating rod (3 cm in diameter, 24 r. p. m.) was established after about 15 trials, and was well maintained for one week thereafter. No training was required for the traction.Both the rota-rod and traction performances were inhibited by chlorpromazine, diazepam, pentobarbital and ethanol in fairly good parallel with the dosages. However, the sensitivities to one same drug markedly differed between the two performances.Chlorpromazine more than diazepam inhibited the rota-rod, while in the traction performance the inhibition with diazepam was greater than that with chlorpromazine.Pentobarbital and ethanol inhibited the two perfor mances to nearly the same degree. On the basis of the present results, the rota-rod test is considered to be suitable for the estimation of the positive adaptability to forced motor activity, and the traction for that of muscle relaxation.By comparing the dose effect relationships in the two performances, it may be possible to elucidate the character istics of various central depressants, and to apply these procedures for the screening test in drug evaluations.When a mouse is repeatedly placed on a rod or cylinder which is rotating at a constant speed, the animal gradually learns to walk on it, adapting itself to the rotation speed. After ingestion of a central depressant, however, the animal easily falls from the rod. This procedure is called 'rota-rod test' and was first introduced by Dunham and Miya (1) for assaying the drug effects on the motor activity. Since then, the effects of various central depressants, investigated by this test have been reported (2-4). There is, however, no established interpretation of the results obtained by this test, for many factors, e.g. lowered general activity, ataxia, muscle relaxation, fatigue, etc, are considered to inhibit the rota-rod performance (RR performance).On the other hand, when a mouse hangs from a thin bar by means of its forelimbs, the animal can maintain this posture for a certain time without falling. This traction behavior (TR performance) or grasping reflex is also sharply altered by central depressants.We studied the effects of various central depressants on these two performances, and found that the sensitivities differed depending on the drug. MATERIALS AND METHODSAdult, male ddG strain mice were obtained from the breeding room of Gunma Univer sity, Medical School. A solid diet MF (Oriental Yeast Co., Tokyo) and tap water were
Abstract-Acquisition processes of discrete lever-press (L-type) and shuttle (Stype) avoidance responses as well as effects of psychoactive drugs thereon were investigated in dd strain mice. The mice showed a more rapid acquisition of S-type avoidance than L-type. However, the mean avoidance rates and occurrences of good-performing mice (showing an avoidance rate of higher than 75%) were almost the same in both types when the training was carried out for more than 15 sessions of 1 hr each. The response rate of L-type avoidance was 2.5-3 times as high as that of S-type avoidance. Methamphetamine and cocaine increased the response rate in almost the same grade in both types of avoidance. Chlorpromazine, haloperidol, pilocarpine and physostigmine suppressed both L-type and S-type avoidance responses. However, the L-type showed a higher sensitivity than the S-type to the avoidance-suppressing effect of these drugs. Atropine, scopolamine and morphine suppressed L-type avoidance response, while they facilitated S-type avoidance. The drug-induced changes in the response rate of the S-type were well correlated with those in the ambulatory activity. The changes in the response rate of the L-type were also consistent with those in the ambulatory activity after administration of methamphetamine, cocaine, chlorpromazine, haloperidol, pilocar pine and physostigmine, but inconsistent after atropine, scopolamine and morphine. The present results suggest that L-type and S-type avoidance responses in mice sometimes show a different change after administration of psychoactive drugs.
ABSTRACT-Characteristics of the ambulation-increasing effect of MK-801, a non competitive NMDA antagonist, were assessed through the coadministration of MK 801 with various central-acting drugs in mice. The MK-801 (0.3 mg/kg, i.p.)-induced ambulation-increment with a slight ataxia was maximum at around 50 min, and ambulation returned to the control level at about 3 hr after the administration. At 1 mg/kg, the mouse's activity transiently increased, followed by a decrease due to a marked ataxia, which was due to neither stereotypy nor convulsion, for 20-50 min, and then increased again; the ambulation-increment continued even at 4 hr after the administration. Coadministration of MK-801 (0.3 mg/kg, i.p.) with either methampheta mine (2 mg/kg, s.c.), cocaine (20 mg/kg, s.c.), GBR-12909 (10 mg/kg, i.p.), scopol amine (0.5 mg/kg, s.c.), caffeine (10 mg/kg, s.c.) or morphine (10 mg/kg, s.c.) pro duced a significant enhancement of the effect. However, 0.1 mg/kg of MK-801 had no effect on the interaction with these drugs. On the other hand, the ambulation-increas ing effect of MK-801 (0.3 mg/kg) was significantly reduced by haloperidol (0.03 and 0.1 mg/kg, s.c.), ceruletide (0.01 and 0.1 mg/kg, i.p.), reserpine (0.05 and 2 mg/kg, s.c., pretreatment 4 hr before) and nimodipine (1 and 3 mg/kg, i.p.), but it was scarcely modified by a-methyl-p-tyrosine (100 and 200 mg/kg, i.p., pretreatment 24 hr and 4 hr before), imipramine (20 mg/kg, i.p.), 6R-L-erythro-5,6,7,8-tetrahydro-bio pterin (100 mg/kg, i.p.), pilocarpine (1 and 4 mg/kg, s.c.), N6-(L-2-phenylisopropyl) adenosine (0.03 and 0.1 mg/kg, s.c.) and naloxone (1 and 5 mg/kg, s.c.). These re sults indicate the MR-801 increases the mouse's ambulatory activity through stimula tion of the dopaminergic system which is strongly affected by a calcium-dependent mechanism.The noncompetitive NMDA antagonist MK 801, (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine (1), has been re ceiving much attention in behavioral pharma cology as a tool for assessing the role of the central neurotransmission systems of the NMDA-component.It has been reported that MK-801 shows anticonvulsant action (2), neuroprotective ac tion (3), an antiparkinson property (4), and anticonflict action (5, 6). Furthermore, Clineschmidt et al. (7) demonstrated that MK
The noncompetitive NMDA receptor antagonist MK-801, (+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine , increased ambulatory activity in the mouse at doses over 0.1 mg/kg (IP). The effect was enhanced when 0.3 mg/kg MK-801 was repeatedly administered at intervals of 3-4 days. In contrast, a reduction of the effect was induced with repeated doses of 0.1 and 1 mg/kg. The mice that had repeatedly experienced 1 mg/kg MK-801 exhibited a decrease in the sensitivity to methamphetamine (2 mg/kg SC). In addition, the repeated co-administration of 1 mg/kg MK-801 with methamphetamine induced a decrease in the sensitivity to methamphetamine. No modification of methamphetamine sensitivity was elicited by 0.1 and 0.3 mg/kg MK-801 in both the single and co-administration schedules. On the other hand, established sensitization to methamphetamine was hardly affected by repeated treatment with 0.1-1 mg/kg MK-801. These results indicate that the mechanism of the inhibitory action of MK-801 on the development of methamphetamine sensitization is different from that of dopamine D2 antagonists, which may act to decrease the effective unit dose of methamphetamine and reduce ambulation-increasing effect of methamphetamine.
We have observed the acute effects of streptozotocin (STZ) on ambulatory activity by employing the automatic apparatus for continuous and direct measurement of drinking and ambulation. Ambulatory activity (counts) in the control periods was 298.2 +/- 20.1 in the dark, 35.6 +/- 9.4 in the light, and 343.9 +/- 24.1 over 24 h. After administration of STZ (60 mg/kg, ip), the ambulatory activity gradually decreased [at 3 days: 165.0 +/- 12.3 in the dark (P less than 0.001), 34.0 +/- 10.5 in the light (P = NS), and 199.0 +/- 10.5 over 24 h (P less than 0.001). For determination of statistical significance, values were compared with those at the same time in the control groups. We observed decreased ambulatory activity in STZ-induced diabetic rats during the dark, but not the light, cycle. Moreover, ambulatory activity in STZ-induced diabetic rats gradually decreased, while the blood glucose level rose. Ambulatory activity correlated inversely with blood glucose level (r = -0.76; P less than 0.05). We measured the ratio of dopamine (DA) to 3,4-dihydroxyphenylacetic acid (nanograms per g) in the striatum. The turnover rate of DA was significantly lower in the diabetic rats than in the control group [diabetic, 0.102 +/- 0.003; control, 0.112 +/- 0.001 (mean +/- SE); P less than 0.05]. A negative correlation between the 3,4-dihydroxyphenylacetic acid to DA ratio and blood glucose level was observed (r = -0.693; P less than 0.01). The present study suggests that there are metabolic abnormalities in the striatum dopaminergic neurons of STZ-induced diabetic rats associated with decreased ambulatory activity.
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