Sakutaro Tadokoro

Correlation between antiavoidance activities of antipsychotic drugs in rats and daily clinical doses.

Effects of oral antipsychotic drugs, 12 phenothiazines, 3 thioxanthenes, 5 butyrophenones and 8 other derivatives on Sidman and discriminated avoidance responses in rats were investigated and compared to their clinical doses routinely used PO. Almost all drugs except sulpiride and clozapine suppressed the avoidance responses with a dose-dependent decrease in the response rate (lever-pressing) and increase in the shock rate in the Sidman avoidance performance or a decrease in both the response and avoidance rates in the discriminated one. Sulpiride (80-640 mg/kg) produced no marked change in the avoidance responses. Clozapine (2.5-10 mg/kg) increased the shock rate or decreased the avoidance rate without eliciting any change in the response rate. The avoidance-suppressing activities of the antipsychotic drugs were well correlated with their clinical daily doses. However, the avoidance-suppressing effects of carpipramine, clocapramine, thiothixene and sulpiride were relatively less potent, while that of clotiapine was more potent than in the clinical activities. The potencies of the avoidance-suppressing effects of each drug on the Sidman and the discriminated avoidance responses were almost identical except for triflupromazine, pimozide, thioridazine, spiclomazine and propericiazine. The former two drugs suppressed the Sidman avoidance response more than the discriminated avoidance response. However, the latter three drugs suppressed the discriminated avoidance response more markedly than the Sidman avoidance response. The present results suggest that the avoidance response in rats is applicable in evaluating the clinical efficacies of antipsychotic drugs.

Comparison of Sensitization to Ambulation-increasing Effects of Cocaine and Methamphetamine after Repeated Administration in Mice

Abstract— The effects of repeated (5 times) subcutaneous administration of cocaine (10, 20 or 40 mg kg−1) and methamphetamine (1, 2 or 4 mg kg−1) at 3–4 day intervals have been compared in mice placed individually into tilting activity cages. A progressive enhancement of the ambulation‐increasing effect was noted for 3–4 h after each administration, indicating that sensitization occurred. This occurrence and the existence of an optimal dose producing sensitization were similar for both drugs. However, enhancement of the effect after cocaine progressed rapidly and maximum sensitization was observed earlier than after methamphetamine administration. Moreover, the higher doses of cocaine (40 mg kg−1) caused stereotypies concurrent with preconvulsive signs of short duration that were enhanced by serial administration. In contrast, methamphetamine caused a more progressive enhancement, but stereotypies with no preconvulsive signs were produced by the higher dose (4 mg kg−1). The respective, effective doses for the development of enhancement suggested that cocaine was less potent than methamphetamine in producing sensitization. Cross‐sensitization occurred between both drugs. Thus, sensitization to cocaine was distinct from that to methamphetamine due to differences in its rapidity, intensity, and the presence or absence of preconvulsive changes.

Automatic measurement of drinking in rats: effects of hypophysectomy.

A new apparatus for the continuous measurement of drinking in the rats was assembled. The principle of the device is as follows: a cartridge which makes water drops (0.05 ml) is inserted between a water tank and a drinking spout. When a rat drinks, water falls into the cartridge drop by drop and the number of drops is electrically counted. The total count of drops per day, as well as counts at definite intervals, can be atuomatically printed out. To test apparatus reliability and applicability, drinking behavior in hypophysectomized rats was investigated in the light and dark phases, alternating every 12 hr. Activity and feeding in these phases were also observed. In the sham-operated rats, the total daily water intake was 30-40 ml, which corresponded to 10-15% of the body weight, and 85-95% of the total daily drinking counts were recorded in the dark phase. In the hypophysectomized rats, a large amount of water was drunk immediately after the operation. However, the high rate of drinking rapidly returned to near the normal level within a few days. Drinking in the dark phase decreased to about 75% of the total daily, but synchronization with the light-dark cycle was still maintained. The daily patterns of activity and eating ran nearly parallel with the drinking behavior. These results indicate that our drinkometer could have extensive applications within many fields of research.

Circadian variation in methamphetamine- and apomorphine-induced increase in ambulatory activity in mice

The existence of circadian variation in methamphetamine- and apomorphine-induced change in ambulatory activity in mice was investigated. Adult male mice of dd strain, which had been housed on a 12 hr light-dark schedule (light period; 6:00-18:00) for 4 weeks, received injections of either methamphetamine HCl 1 or 2 mg/kg SC at one of six times of day (3:00, 7:00, 11:00, 15:00, 19:00 and 23:00), or apomorphine HCl 0.5 or 1 mg/kg SC at one of six times of day (3:30, 7:30, 11:30, 15:30, 19:30 and 23:30). The control animals were administered a physiological saline vehicle alone at the corresponding times of day. The ambulatory activity of each mouse was measured by a tilting-type activity cage for 3 hr after methamphetamine, and for 1 hr after apomorphine. A circadian variation in the ambulatory activity was observed after the administration of the saline, methamphetamine and apomorphine. Here, the highest activity counts were found when the saline, methamphetamine and apomorphine were administered during the late dark period (3:00 or 3:30), while the lowest activity counts were found when the saline and apomorphine 1 mg/kg were administered during the mid light period (11:00 or 11:30), and methamphetamine 1 and 2 mg/kg and apomorphine 1 mg/kg were administered during the late light period (15:00 or 15:30). The circadian variation in methamphetamine-induced increase in the activity was abolished by a pretreatment with reserpine 2 mg/kg SC 4 hr before, but that of apomorphine was maintained even by the pretreatment with reserpine. The present results suggest that the methamphetamine- and apomorphine-induced increase in the ambulatory activity in mice is dependent on the time-of-day of the drug administration, and the occurrence is mainly due to a circadian variation in activity of the catecholaminergic systems in the brain.

Effects of repeated MK-801 on ambulation in mice and in sensitization following methamphetamine

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.

Enhancement of avoidance-suppressing effect after repeated administration of haloperidol and serum haloperidol in rats

Adult male rats of the Wistar strain, which were trained under a discriminated lever-press avoidance schedule (intertrial interval; 25 sec. presentation of conditioned stimuli; 5 sec), were given SC 0.025-0.05 mg/kg of haloperidol at fixed intervals of 1, 3-4 and 7 days. The avoidance-suppressing effect of haloperidol was enhanced in parallel to the number of drug administrations until it attained a maximum level. The intensity of the maximum effect tended to be stronger, and the number of administrations necessary to attain it was smaller, when a higher dose was given. When the administration interval exceeded one day, the enhanced effect remained irreversible one month after withdrawal of drug administration. The enhancement of the effect was produced after repeated administrations in an experimental chamber, but not in a home cage. Temporal changes in serum haloperidol concentration were determined 30-90 min after 0.035 mg/kg given SC to the haloperidol-pretreated and saline-pretreated groups. No significant difference in the pharmacokinetic change was detected between the two groups. These results suggest that learning during the drug effect under repeated exposure to a fixed experimental situation influences the enhancing effect.

Circadian variation in susceptibility to methamphetamine after repeated administration in mice.

Since repeated administration of methamphetamine sometimes induces an augmentation in susceptibility, i.e., a reverse tolerance, to the stimulant drug effect in animals, the circadian variation in susceptibility to the ambulation-increasing effect of methamphetamine after repeated administration was investigated in mice. The ambulatory activity of each mouse was measured by a tilting-type round activity cage of 25 cm in diameter. Mice, which had been housed under a 12 hr light-dark schedule (light period; 6:00-18:00) for 5 weeks, were administered methamphetamine 1 or 2 mg/kg SC at one of 6 times of day (3:00, 7:00, 11:00, 15:00, 19:00 and 23:00) for 5 times at intervals of 7 days, and their ambulatory activities were measured for 3 hr after each administration. The repeated administration of methamphetamine induced a reverse tolerance to the ambulation-increasing effect of the drug, and the mean overall ambulatory activity counts on the 5th session were estimated to be 2-4 times as high as the corresponding activity counts on the 1st session. However, the circadian variation in susceptibility, which was at maximum during the late dark period (administration at 3:00) and at minimum during the late light period (administration at 15:00), was well maintained even after the repeated administration. When the time of day of the drug administration were changed by 12 hr on the 6th session, a marked increase in the activity counts was observed in the mice changed from 15:00 to 3:00, while a marked decrease was observed in the mice changed from 3:00 to 15:00.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of psychotropic drugs on avoidance response in rats: Role of baseline performances

Abstract Effects of d-amphetamine, chlorpromazine and diazepam on the discriminated avoidance response (intertrial interval = 25 sec; warning duration = 5 sec) in rats were studied with reference to levels of the behavioral baseline. After the administration of d-amphetamine 0.25–2.0 mg/kg SC, the avoidance and response rates increased in all cases dose-dependently. The individual changes of avoidance rates were more marked in the poor performers (initial avoidance rate: 0–33%) with higher baseline response rates than in those with lower response rates. Chlorpromazine 0.5–2.0 mg/kg SC suppressed the avoidance performances in all cases in proportion ith the doses. More marked changes were observed in the good performers (68–100%) than in the poor performers regardless of the baseline response rates. After administration of diazepam 0.5–4.0 mg/kg SC, the response rates decreased in almost all cases, while the avoidance rates varied depending on their baseline levels. Diazepam increased the avoidance rates of the poor performers, but conversely decreased the rates in the good performers in proportion with the doses. Moreover, the improvement of the avoidance rates was more marked in the poor performers with higher baseline response rates than in those with lower rates. The present results suggest that the behavioral effects of psychotropic drugs are a function of the avoidance baseline levels.

Effects of psychotropic drugs on FI responding and adjunctive drinking in rats

Effects of d-amphetamine (AM), chlorpromazine (CPZ) and diazepam (DZ) on schedule controlled responding (lever-pressing) and adjunctive drinking under a fixed interval (FI) 1.5 min schedule of food reinforcement in rats were investigated. The drinking was measured with a drinkometer and a lickometer. AM 0.13--1.0 mg/kg SC increased the total responses, and decreased the total amount of drinking and licking counts dose-dependently. A marked response increase in the early portion (0.30 sec component of the FI) and mid portion (30--60 sec component), and decrease of the drinking in the mid portion and terminal portion (60--90 sec component) occurred. CPZ 0.25--2.0 mg/kg SC decreased responses, drinking and licking in proportion with the doses. After CPZ, a response decrease in the mid and terminal portions was observed, but not in the early portion. Higher doses of CPZ decreased the drinking and licking in the whole range of the interval. A small dose of DZ (0.25 mg/kg SC) produced a significant response increase. Higher doses of DZ also increased responding, but the change was not significant. The drinking and licking were suppressed by DZ. A dose-related response increase in the mid portion was observed after DZ, but not in the early and terminal portions except after 0.25 mg/kg. Higher doses of DZ (more than 0.5 mg/kg) decreased drinking and licking throughout the whole range of the FI. The present results suggest that the interpellet distribution of responding, drinking and licking, as well as their total values, yield important information when assessing drug effects on FI responding and adjunctive drinking in rats.

Conditioned lever-press avoidance response in mice: acquisition processes and effects of diazepam

Acquistion of conditioned lever-press avoidance behavior on a continuous avoidance schedule (response-shock interval=30 s and shock-shock interval=5 s) and on a discrete avoidance schedule (intertrial interval=25 s and duration of the warning presentation=5 s with an escape contingency) in dd mice was investigated. When the behavioral baseline had stabilized, the effects of diazepam on avoidance behaviors were examined. About 60% and 80% of the mice achieved criterion levels of avoidance behavior under continuous avoidance (shock rate being less than 0.5/min) and discrete avoidance (avoidance rate being higher than 75%), respectively. Diazepam (0.5–4 mg/kg SC) dose-dependently impaired avoidance behavior of mice which had a low baseline shock rate and a high baseline avoidance rate under continous and discrete avoidances, respectively. The changes in avoidance behavior in mice after diazepam were almost identical with those previously found in rats.