Ambulation-increasing Effect Research Articles

Behavioral Effects of Adenosine Agonists: Evaluation by Punishment, Discrete Shuttle Avoidance and Activity Tests in Mice

Behavioral effects of propentofylline and N6-(L-2-phenylisopropyl)-adenosine (PIA) were evaluated by operant behavior under a punishment situation, discrete shuttle avoidance response and ambulatory activity in mice. Propentofylline (3 mg/kg, s.c.) and PIA (0.01 mg/kg, s.c.) significantly decreased the punished response without producing a significant change in the non-punished response. Propentofylline and PIA reduced the increase in the punished response induced by caffeine (30 mg/kg) and diazepam (1 mg/kg). Propentofylline and PIA also reduced the increase of ambulation induced by caffeine. Furthermore, the single administration of propentofylline and PIA decreased the response rate and/or % avoidance in the discrete shuttle avoidance situation. However, the effective doses of propentofylline and PIA to reduce the ambulation-increasing effect of caffeine and to produce a change in the avoidance behavior were much higher than those effective for eliciting a significant change in the punished response. The present results suggest that there is an intimate interaction between central adenosine and benzodiazepine systems with regards to the change of punished response.

Behavioral effects of adenosine agonists: Evaluation by punishment, discrete shuttle avoidance and activity tests in mice.

Behavioral effects of propentofylline and N6-(L-2-phenylisopropyl)-adenosine (PIA) were evaluated by operant behavior under a punishment situation, discrete shuttle avoidance response and ambulatory activity in mice. Propentofylline (3 mg/kg, s.c.) and PIA (0.01 mg/kg, s.c.) significantly decreased the punished response without producing a significant change in the non-punished response. Propentofylline and PIA reduced the increase in the punished response induced by caffeine (30 mg/kg) and diazepam (1 mg/kg). Propentofylline and PIA also reduced the increase of ambulation induced by caffeine. Furthermore, the single administration of propentofylline and PIA decreased the response rate and/or % avoidance in the discrete shuttle avoidance situation. However, the effective doses of propentofylline and PIA to reduce the ambulation-increasing effect of caffeine and to produce a change in the avoidance behavior were much higher than those effective for eliciting a significant change in the punished response. The present results suggest that there is an intimate interaction between central adenosine and benzodiazepine systems with regards to the change of punished response.

Enhancement of ambulation-increasing effect and changes of striatal dopamme levels produced by daily injections of nicotine in rats

Enhancement of ambulation-increasing effect and changes of striatal dopamme levels produced by daily injections of nicotine in rats

Cross Interaction between Methamphetamine and Scopolamine by Means of Ambulatory Activity in Mice

AbstractInteraction between methamphetamine (MAP; 1 and 2 mg/kg, s.c.) and scopolamine (SCP; 0.5 and 2 mg/kg, s.c.) was investigated by means of ambulatory activity in mice of the dd strain. The single administration of MAP and SCP increased the ambulatory activity in a dose-dependent manner. The repeated administration” of SCP, 5 times at intervals of 3–4 days, elicited a tolerance to its ambulation-increasing effect. The SC P-exper fenced mice showed no marked change in their sensitivity to the ambulation-increasing effect of MAP. However, when MAP was additionally administered, these mice showed a reverse tolerance to MAP. Such repeated administration of MAP was effective for attenuating the SCP-tolerance. On the other hand, the repeated MAP administration produced not only reverse tolerance to MAP itself but also cross reverse tolerance to SCP. However, as observed in the drug-naive mice, the MAP-experienced mice also exhibited tolerance to the additionally administered SCP. The repeated SCP administration scarcely modified the acquired MAP-reverse tolerance. The present results suggest that a cross reverse tolerance from MAP to SCP, but not from SCP to MAP, is developed in this mouse strain. It is also suggested that the reverse tolerance to MAP and tolerance to SCP appear regardless of the pretreatment of SCP and MAP, respectively, and that the reverse tolerance to MAP is well-maintained

薬物の反復投与による行動効果の修飾 逆耐性現象を中心に

It has been well-known that a chronic abuse of amphetamines induces schizophrenia-like psychotic symptoms, namely amphetamine psychosis. When amphetamines are repeatedly administered to rodents, a reverse tolerance (behavioral sensitization) to the ambulation-increasing and/or stereotypy-producing effect is observed. The process of the reverse tolerance is affected by various factors. A clear reverse tolerance is produced when optimal doses of the drug (2 mg/kg, s.c. for mice, and 0.5-1 mg/kg, s.c., for rats) is administered at intervals of longer than 1 day rather than a shorter interval. Furthermore, the animal has to be put into a freely mobile situation during the presence of the acute drug effect. A cross reverse tolerance is observed between certain types of drugs that show an ambulation-increasing effect, although the potencies are different among the drugs. A reverse tolerance to the stereotypy (in particular sniffing and head-bobbing)-producing effect is also observed when comparatively higher doses of methamphetamine are repeatedly administered. The process is qualitatively identical with the reverse tolerance to the ambulation-increasing effect produced by the repeated administration of comparatively smaller doses. The reverse-tolerance, once established, to both ambulation-increasing and stereotypy-producing effects is almost irreversible even with various treatments such as repeated post-treatment with antipsychotics. The characteristics of reverse tolerance to methamphetamine in animals might be closely correlated to the amphetamine psychosis in humans. It is also necessary to search for a method that effectively reduces the established reverse tolerance to amphetamines.

Cross interaction between methamphetamine and scopolamine by means of ambulatory activity in mice.

Interaction between methamphetamine (MAP; 1 and 2 mg/kg, s.c.) and scopolamine (SCP; 0.5 and 2 mg/kg, s.c.) was investigated by means of ambulatory activity in mice of the dd strain. The single administration of MAP and SCP increased the ambulatory activity in a dose-dependent manner. The repeated administration of SCP, 5 times at intervals of 3-4 days, elicited a tolerance to its ambulation-increasing effect. The SCP-experienced mice showed no marked change in their sensitivity to the ambulation-increasing effect of MAP. However, when MAP was additionally administered, these mice showed a reverse tolerance to MAP. Such repeated administration of MAP was effective for attenuating the SCP-tolerance. On the other hand, the repeated MAP administration produced not only reverse tolerance to MAP itself but also cross reverse tolerance to SCP. However, as observed in the drug-naive mice, the MAP-experienced mice also exhibited tolerance to the additionally administered SCP. The repeated SCP administration scarcely modified the acquired MAP-reverse tolerance. The present results suggest that a cross reverse tolerance from MAP to SCP, but not from SCP to MAP, is developed in this mouse strain. It is also suggested that the reverse tolerance to MAP and tolerance to SCP appear regardless of the pretreatment of SCP and MAP, respectively, and that the reverse tolerance to MAP is well-maintained.

Effects of Repeated Administration of Pentazocine on Ambulatory Activity in Mice: Comparison with the Effects of Morphine and Methamphetamine

Effects of single and repeated administration of pentazocine (5 times at intervals of 3-4 days) were compared with those of morphine and methamphetamine by means of ambulatory activity in mice. The interactions among these 3 drugs were also investigated. Pentazocine (25 mg/kg, s.c.), morphine (10 and 20 mg/kg, s.c.) and methamphetamine (2 mg/kg, s.c.) significantly increased the activity, and the effect progressively enhanced (defined here as development of reverse tolerance) during the repeated administration schedule. The induction of reverse tolerance to pentazocine was less dependent on the environmental conditions, and it was abolished within 2 months. A cross reverse tolerance was demonstrated from methamphetamine to pentazocine and to morphine, and from morphine to pentazocine. However, no significant cross reverse tolerance was induced from pentazocine to morphine and to methamphetamine, and from morphine to methamphetamine. The present results suggest that pentazocine possesses an ambulation-increasing effect, although the characteristics are different from that of either morphine or methamphetamine.

Effects of YM-09151-2, a Potent and Selective Dopamine D2 Antagonist, on the Ambulation-Increasing Effect of Methamphetamine in Mice

The ambulation-increasing effect of methamphetamine (2 mg/kg, s.c.) was markedly reduced by YM-09151-2 at 0.01 mg/kg, s.c, in drug-naive mice. The development of reverse tolerance to the ambulation-increasing effect of methamphetamine was also inhibited almost completely when 0.01 mg/kg, s.c, of YM-09151-2 was administered concomitantly in each administration. However, YM-09151-2, at 0.01 mg/kg, was partially suppressed the effect of methamphetamine in mice that exhibited reverse tolerance to methamphetamine.

Effects of YM-09151-2, a potent and selective dopamine D2 antagonist, on the ambulation-increasing effect of methamphetamine in mice.

The ambulation-increasing effect of methamphetamine (2 mg/kg, s.c.) was markedly reduced by YM-09151-2 at 0.01 mg/kg, s.c., in drug-naive mice. The development of reverse tolerance to the ambulation-increasing effect of methamphetamine was also inhibited almost completely when 0.01 mg/kg, s.c., of YM-09151-2 was administered concomitantly in each administration. However, YM-09151-2, at 0.01 mg/kg, was partially suppressed the effect of methamphetamine in mice that exhibited reverse tolerance to methamphetamine.

Behavioral Study on Mergocriptine (CBM36-733) by Ambulatory Activity in Mice: Repeated Administration and Interaction with Methamphetamine

Effects of repeated administration of mergocriptine (CBM36-733: CBM), a long-acting ergot derivative with an agonistic action on both dopamine D1 and D2 receptors, as well as interaction between CBM and methamphetamine (MAP: 2 mg/kg, s.c.), were investigated by ambulatory activity in mice. CBM at 4 mg/kg significantly suppressed the ambulatory activity, but significantly increased it at 1 6 mg/kg in the drug-naive mice. However, 4 and 8 mg/kg of CBM were effective for increasing the ambulatory activity when these doses were repeatedly administered for 9 times at intervals of 7 days. The same treatment with 16 mg/kg of CBM produced a reverse tolerance to the ambulation-increasing effect. The mice that had received CBM at 1 and 2 mg/kg, but not 4–16 mg/kg, demonstrated a significantly lower sensitivity to MAP than the saline-experienced mice. On the other hand, the repeated MAP administration induced not only a reverse tolerance to itself, but also a cross reverse tolerance to 8 and 1 6 mg/kg of CBM. Furthermore, the established reverse tolerance to MAP was scarcely attenuated by the repeated treatment with any doses of CBM, but rather enhanced by 8 and 1 6 mg/kg of CBM. The present results indicate that, although the dose-effect relations are partially different, the behavioral characteristics of CBM were almost idential with those of bromocriptine, another long-acting ergot derivative having antagonistic and agonistic actions on dopamine D1 and D2 receptors, respectively.

各種中枢作用薬によるマウスの自発運動促進に対するＣｅｒｕｌｅｔｉｄｅの抑制効果

Behavioral characteristics of ceruletide, a cholecystokinin-like decapeptide, were investigated by means of ambulatory activity in mice. Ceruletide at 100 and 300 micrograms/kg, i.p. slightly but significantly decreased the mouse's activity for 20 min. Therefore, 100 micrograms/kg of ceruletide was used in the experiment of combined administration with the central-acting drugs. Ceruletide reduced the increased activity which was produced by methamphetamine (2 mg/kg, s.c.), ephedrine (80 mg/kg, i.p.), methylphenidate (4 mg/kg, s.c.), cocaine (20 mg/kg, s.c.), mazindol (2.5 mg/kg, s.c.), apomorphine (0.5 mg/kg, s.c.), bromocriptine (8 mg/kg, i.p.), scopolamine (0.5 mg/kg, s.c.), caffeine (10 mg/kg, s.c.) and morphine (20 mg/kg, s.c.) with different potencies and durations. The mice that had experienced ceruletide at 3 micrograms/kg for 5 times at intervals of 3-4 days demonstrated a significant increase in the sensitivity to methamphetamine, although the same treatment with 10-300 micrograms/kg of ceruletide was without effect. On the other hand, when 3-300 micrograms/kg of ceruletide was combined with 2 mg/kg of methamphetamine, the development of reverse tolerance to the ambulation-increasing effect of methamphetamine was inhibited dependently on the doses of ceruletide. However, the reverse tolerance to methamphetamine once established was scarcely modified by ceruletide when it was administered afterwards.

Behavioral effects of NC-1100, 1-(3,4-dimethoxyphenyl)-2-(4-diphenylmethylpiperazinyl) ethanol dihydrochloride--on ambulatory activity, discrete lever-press response and shuttle avoidance response in mice

Single administration of NC-1100 (3, 10 or 30 mg/kg, p.o.) produced no marked change in the ambulatory activity and discrete lever-press avoidance response. However, 100 mg/kg of this drug produced a toxic effect which was characterized by salivation, tremor, clonic convulsion, etc., but none of the mice died. NC-1100 enhanced the ambulation-increasing effect of methamphetamine (2 mg/kg, s.c.) at 3 and 10 mg/kg, while it failed to modify that of scopolamine (0.5 mg/kg, s.c.). NC-1100, at 100 mg/kg, suppressed both the established discrete lever-press and shuttle avoidance responses, probably due to non-specific and toxic effects. When NC-1100 at 10 mg/kg was administered, the response rate increased only in the shuttle avoidance situation in which the avoidance established mice were used. Furthermore, when NC-1100 at 30 mg/kg was administered immediately before the start of the training session, the avoidance rate increased. However, there was no marked change in the avoidance rate in the 2nd training session which was conducted 24 hr after the 1st training session without the drug administration. Additionally, the response rate increased in the 1st and 2nd training sessions after 10 and 30 mg/kg of NC-1100. The present results suggest that NC-1100 may show a behavior-facilitating effect, although its effect is mild and different from that of typical central stimulants such as methamphetamine.

Enhancement of ambulation-increasing effect of methamphetamine by peripherally-administered 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (R-THBP) in mice.

Behavioral effects of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (R-THBP), a co-factor for tyrosine hydroxylase and tryptophan hydroxylase, were investigated by means of ambulatory activity in mice. Single administration of R-THBP (50 and 100 mg/kg, s.c.) showed no significant effect on the mouse's ambulatory activity for 5 hr. The ambulation-increasing effect of methamphetamine (2 mg/kg, s.c.) was dramatically enhanced and prolonged by the pretreatment with R-THBP (100 mg/kg, s.c.) 0, 2, 6, 12 and 24 hr before, but not 18 or 36 hr before, the methamphetamine administration. However, when combined administration of R-THBP (100 mg/kg, s.c., 2 hr before) with methamphetamine (2 mg/kg, s.c.) was repeated at intervals of 3-4 days, the enhancement by R-THBP of the methamphetamine effect was observed only in the 1st and 2nd administration, but not in the later administration. The pretreatment with R-THBP (100 mg/kg, s.c., 2 hr before) enhanced the ambulation-increasing effect of ephedrine (80 mg/kg, i.p.), but failed to modify those of cocaine (20 mg/kg, s.c.), mazindol (2.5 mg/kg, s.c.), bromocriptine (8 mg/kg, i.p.), morphine (20 mg/kg, s.c.) and scopolamine (0.5 mg/kg, s.c.). It is noteworthy that R-THBP differentially modifies the ambulation-increasing effect of the above-mentioned drugs.

P-483 - Enhancement of ambulation-increasing effect and changes of brain monoamine levels produced by daily administration of nicotine in rats

P-483 - Enhancement of ambulation-increasing effect and changes of brain monoamine levels produced by daily administration of nicotine in rats

Enhancement of Ambulation-lncreasing Effect of Methamphetamine by Peripherally-Administered 6R-L-Erythro-5,6,7,8-Tetrahydrobiopterin (R-THBP) in Mice

Behavioral effects of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (R-THBP), a co-factor for tyrosine hydroxylase and tryptophan hydroxylase, were investigated by means of ambulatory activity in mice. Single administration of R-THBP (50 and 100 mg/kg, s.c.) showed no significant effect on the mouse’s ambulatory activity for 5 hr. The ambulation-increasing effect of methamphetamine (2 mg/kg, s.c.) was dramatically enhanced and prolonged by the pretreatment with R-THBP (100 mg/kg, s.c.) 0, 2. 6, 12 and 24 hr before, but not 18 or 36 hr before, the methamphetamine administration. However, when combined administration of R-THBP (100 mg/kg, s.c, 2 hr before) with methamphetamine (2 mg/kg, s.c.) was repeated at intervals of 3-4 days, the enhancement by R-THBP of the methamphetamine effect was observed only in the 1st and 2nd administration, but not in the later administration. The pretreatment with R-THBP (100 mg/kg, s.c, 2 hr before) enhanced the ambulation-increasing effect of ephedrine (80 mg/kg, i.p.), but failed to modify those of cocaine (20 mg/kg, s.c), mazindol (2.5 mg/kg, s.c), bromocriptine (8 mg/kg, i.p.), morphine (20 mg/kg, s.c.) and scopolamine (0.5 mg/kg, s.c). It is noteworthy that R-THBP differentially modifies the ambulation-increasing effect of the above-mentioned drugs.

Reverse Tolerance to Ambulation-Increasing Effects of Methamphetamine and Morphine in 6 Mouse Strains

Effects of single administration of methamphetamine (1, 2 and 4 mg/kg, s.c.) and morphine (5, 10 and 20 mg/kg, s.c.) and repeated administration of methamphetamine (2 mg/kg, s.c.) and morphine (10 mg/kg, s.c.) on ambulatory activity were investigated in 6 mouse strains: dd, ICR, BALB/c, C57BL/6, C3H/He and DBA/2. Although there were differences in the drug sensitivities among mouse strains, methamphetamine and morphine increased the ambulatory activity in all the strains except for the DBA/2 strain that showed an increase only after morphine. Repeated 5 times administration of methamphetamine at intervals of 3–4 days induced a reverse tolerance (an enhancement in the sensitivity) to the ambulation-increasing effect in all the strains with a marked degree in dd, ICR, C3H/He and DBA/2 strains and a slight degree in BALB/c and C57BL/6 strains. The same treatment with morphine induced reverse tolerance to the effect of morphine markedly in C57BL/6 and C3H/He strains and moderately in dd, ICR and BALB/c strains, but the DBA/2 strain showed no significant change in the ambulatory activity throughout the repeated 5 times administration of morphine. There was positive correlation between the initial drug sensitivities of animals and the degrees of the reverse tolerance in either methamphetamine or morphine. Furthermore, the reverse tolerance to methamphetamine and morphine was sometimes transferable, although such cross interaction varied among mouse strains.

How environment affects conditioned drug tolerance

We have demonstrated that repeated administration of methamphetamine (MAP) l-2mg/kg, s.c. in a tilting-type round activity cage with a diameter of 20 cm (20 cm-cage) at 1-7 day intervals produces progressive enhancement of the ambulation-increasing effect (AIE), showing sensitization (reverse tolerance) in mice. However, almost no sensitization was observed when mice had been pretreated with the same doses of MAP but confined in a narrow environment repeatedly. In this experiment, changes in the spnsitization were investigated in mice after repeated pretreatments with MAP at 2 mg/kg at 3 - 4 day interval for 4 times in activity cages of 5 different sizes (5, 10, 15, 30 and 40 cm in diameter) in comparison with that of in the 20 cm-cage. AIE obtained after MAP in the 5- and 10-cm cages was not enhanced, whereas AIE was significantly enhanced in the cages of more than 15 cm in diameter. There was no significant difference in the enhanced AIE among the 4 groups that received the same pretreatment repeatedly in the cages of 15, 20, 30 and 40 cm in diameter. The present results suggest that in accordance with the all-or-none law, development of the sensitization is affected by the size of the activity cage in which the animals have repeatedly experienced the acute drug effect.

Effects of buflomedil on ambulatory activity and discrete avoidance responses in mice

Behavioral effects of buflomedil, 4-(1-pyrrolidinyl)-1-(2,4,6-trimethoxyphenyl)-1-butanone hydrochloride, a vasoactive drug, were investigated by means of ambulatory activity and the discrete lever-press and shuttle avoidance responses in mice. Single administration of buflomedil (1,3,10,30 and 100 mg/kg, p.o.) produced no marked change in the ambulatory activity and the discrete lever-press avoidance response. However, the ambulation-increasing effect of methamphetamine (2 mg/kg, s.c.) was suppressed by 30 mg/kg of buflomedil. The avoidance-suppressing effect of chlorpromazine (1 mg/kg, s.c.) was enhanced by 3 approximately 100 mg/kg of buflomedil, but the avoidance-suppressing effect of physostigmine (0.2 mg/kg, s.c.) was not modified by the same doses of buflomedil. On the other hand, the acquisition of the discrete shuttle avoidance response was not affected markedly by buflomedil 3, 10 and 30 mg/kg, p.o.) when the drug was administered immediately before the start of training. The present results suggest that buflomedil shows a central suppressing effect, probably through catecholaminergic neuronal systems, and that the effect is detectable only by the combined administration with typical psychoactive drugs.

Enhancement of ambulation-increasing effect produced by repeated administration of methamphetamine in rats and neurochemical changes in catecholaminergic neurons.

Male rats of the Wistar strain were repeatedly given methamphetamine (MAP) at 0.5 mg/kg, s.c., 10 times at a fixed interval of 4 days in different environmental situations. The effects of MAP administration on ambulatory activity and neurochemical parameters in the brain were investigated. MAP (0.5 mg/kg) markedly increased ambulatory activity. The ambulation-increasing effect of MAP was progressively enhanced without accompanying stereotyped behaviors when the drug was repeatedly given in the activity cage. The once enhanced effect was considered to be irreversible. In addition, the pretreatment with MAP in the activity cage produced a decrease in the maximum density of 3H-spiperone binding sites in the striatum and that of 3H-WB4101 binding sites in the cortex and hippocampus, with decreases in catecholamine and increases in its metabolites. However, the enhancement of the ambulation-increasing effect of MAP and changes in the binding sites or catecholamine metabolism were scarcely observed when the drug was repeatedly given to the rats in the narrow cage where horizontal ambulation of the animals was strongly impaired. These results suggest that the enhancing effect of MAP is closely related to the environmental situations to which the animals have been exposed to under the drug effect. Moreover, it is indicated that there is a correlation between the enhancement of the ambulation-increasing effect of MAP and changes in the neurochemical parameters. The enhancing effect of MAP is supposed to have been partially caused by changes in cerebral catecholaminergic systems, in particular an increase in catecholamine turnover.

Enhancement of Ambulation-Increasing Effect Produced by Repeated Administration of Methamphetamine in Rats and Neurochemical Changes in Catecholaminergic Neurons

Male rats of the Wistar strain were repeatedly given methamphetamine (MAP) at 0.5 mg/kg, s.c., 10 times at a fixed interval of 4 days in different environmental situations. The effects of MAP administration on ambulatory activity and neurochemical parameters in the brain were investigated. MAP (0.5 mg/kg) markedly increased ambulatory activity. The ambulation-increasing effect of MAP was progressively enhanced without accompanying stereotyped behaviors when the drug was repeatedly given in the activity cage. The once enhanced effect was considered to be irreversible. In addition, the pretreatment with MAP in the activity cage produced a decrease in the maximum density of 3H-spiperone binding sites in the striatum and that of 3H-WB4101 binding sites in the cortex and hippocampus, with decreases in catecholamine and increases in its metabolites. However, the enhancement of the ambulation-increasing effect of MAP and changes in the binding sites or catecholamine metabolism were scarcely observed when the drug was repeatedly given to the rats in the narrow cage where horizontal ambulation of the animals was strongly impaired. These results suggest that the enhancing effect of MAP is closely related to the environmental situations to which the animals have been exposed to under the drug effect. Moreover, it is indicated that there is a correlation between the enhancement of the ambulation-increasing effect of MAP and changes in the neurochemical parameters. The enhancing effect of MAP is supposed to have been partially caused by changes in cerebral catecholaminergic systems, in particular an increase in catecholamine turnover.