Biomedical subjects

H Kuribara

Publications and source records attributed to H Kuribara.

At least 55 records · Page 3Linked to original sources

PubMed1995

Synergistic activation of rat brain phospholipase D by ADP-ribosylation factor and rhoA p21, and its inhibition by Clostridium botulinum C3 exoenzyme.

An activator of rat brain phospholipase D (PLD) that is distinct from the already identified PLD activator, ADP-ribosylation factor (ARF), was partially purified from bovine brain cytosol by a series of chromatographic steps. The partially purified preparation contained a 22-kDa substrate for Clostridium botulinum C3 exoenzyme ADP-ribosyltransferase, which strongly reacted with anti-rhoA p21 antibody, but not with anti-rac1 p21 or anti-cdc42Hs p21 antibody. Treatment of the partially purified PLD-activating factor with both C3 exoenzyme and NAD significantly inhibited the PLD-stimulating activity. These results suggest that rhoA p21 is, at least in part, responsible for the PLD-stimulating activity in the preparation. Recombinant isoprenylated rhoA p21 expressed in and purified from Sf9 cells activated rat brain PLD in a concentration- and GTP gamma S (guanosine 5'-O-(3-thiotriphosphate))-dependent manner. In contrast, recombinant non-isoprenylated rhoA p21 (fused to glutathione S-transferase) expressed in Escherichia coli failed to activate the PLD. This difference cannot be explained by a lower affinity of non-isoprenylated rhoA p21 for GTP gamma S, as the rates of [35S]GTP gamma S binding were very similar for both recombinant preparations and the GTP gamma S-bound form of non-isoprenylated rhoA p21 did not induce PLD activation. Interestingly, recombinant isoprenylated rhoA p21 and ARF synergistically activated rat brain PLD; a similar pattern was seen with the partially purified PLD-activating factor. The synergistic activation was inhibited by C3 exoenzyme-catalyzed ADP-ribosylation of recombinant isoprenylated rhoA p21 in a NAD-dependent manner. Inhibition correlated with the extent of ADP-ribosylation. These findings suggest that rhoA p21 regulates rat brain PLD in concert with ARF, and that isoprenylation of rhoA p21 is essential for PLD regulation in vitro.

ADP Ribose Transferases↗

PubMed1995

Modification of morphine sensitization by opioid and dopamine receptor antagonists: evaluation by studying ambulation in mice.

The repeated administration of morphine (10 mg/kg s.c.) at 3- to 4-day intervals caused sensitization to its ambulation-increasing effect. A mu-opioid receptor antagonist naloxone (0.03-1 mg/kg s.c.), and dopamine D1 and D2 receptor antagonists SCH 23390; R-(+)-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine HCl (0.01-0.1 mg/kg s.c.) and YM-09151-2 (nemonapride); cis-N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4- methylaminobenzamide (0.003-0.1 mg/kg s.c.), respectively, dose dependently reduced the ambulation increase caused by morphine as well as the sensitization to morphine, when one of them was combined with morphine in the repeated administration. Treatment with SCH 23390 or YM-09151-2, but not naloxone, 3 h after each morphine administration tended to enhance the morphine sensitization. Furthermore, when YM-09151-2 (0.1 mg/kg) was repeatedly administered to the morphine-naive mice 5 times at 3- to 4-day intervals, these mice showed a significant increase in morphine sensitivity. Although the morphine sensitization was partially reversible, repeated (5 times) treatment of the morphine-sensitized mice with SCH 23390 (0.1 mg/kg) resulted in a further enhancement in morphine sensitivity. The same treatment with YM-09151-2 (0.03 and 0.1 mg/kg) tended to increase the sensitivity. These results suggest that, in terms of ambulation in mice, an enhancement of dopaminergic neurotransmission through the agonistic action on mu-opioid receptors is responsible for induction of morphine sensitization.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Inhibition of methamphetamine sensitization by post-methamphetamine treatment with SCH 23390 or haloperidol.

Methamphetamine (2 mg/kg SC) increased ambulation in mice for about 3 h, with a peak effect at around 40 min after the administration, and its repeated administration induced sensitization. Both SCH 23390 (0.03 mg/kg SC) and haloperidol (0.4 mg/kg SC), dopamine D1 and D2 receptor antagonists, respectively, completely inhibited not only the acute stimulant effect of methamphetamine but also its sensitization when repeated methamphetamine was repeatedly combined with either of these drugs. Moreover, treatment with SCH 23390 2-5 h or haloperidol 1-5 h after each methamphetamine administration significantly antagonized methamphetamine sensitization. The maximal inhibitory effect was observed in the schedules of 3-h post-methamphetamine treatment for both drugs. However, treatments with SCH 23390 or haloperidol at 0.5 h, 6 h and 24 h after methamphetamine had no such inhibitory effect. The mice treated with SCH 23390 or haloperidol after each saline administration (the control administration for methamphetamine) did not show significant change in the sensitivity to methamphetamine. These results suggest that methamphetamine has an effect on both dopamine D1 and D2 receptors for several hours even after cessation of its acute stimulant effect, and that such an effect is involved in the induction of sensitization to the stimulant effect of methamphetamine on ambulation in mice.

Animals↗

PubMed1995

Contrasting effects on methamphetamine sensitization of ceruletide, a cholecystokinin-like decapeptide, and haloperidol.

Ceruletide, a cholecystokinin-like decapeptide, and haloperidol show neuroleptic actions through inhibition of dopamine release and blockade of dopamine receptors, respectively. In this study, the effects of both drugs on methamphetamine sensitization were assessed by means of ambulation in mice. The enhancement in ambulation increase caused by five repeated administrations of methamphetamine (2 mg/kg, SC) at 3- to 4-day intervals was dose-dependently reduced when it was administered simultaneously with ceruletide (0.01-0.1 mg/kg, SC) or haloperidol (0.03-0.3 mg/kg, SC). However, only haloperidol could inhibit the induction of methamphetamine sensitization as assessed by challenge with methamphetamine alone. Post-treatment with ceruletide (0.03 mg/kg) 3 h after each methamphetamine accelerated, whereas such post-treatment with ceruletide (0.1 mg/kg) or haloperidol (0.03-0.3 mg/kg) delayed, the induction of methamphetamine sensitization. On the other hand, mice given five pretreatments with ceruletide (0.01-0.1 mg/kg) or haloperidol (0.03-0.3 mg/kg) at 3- to 4-day intervals did not exhibit any significant change in the sensitivity to methamphetamine. The present results suggest that, in contrast to the dose-dependent inhibition of methamphetamine sensitization in the simultaneous administration and post-treatment schedules, although both drugs can antagonize the acute stimulant effect of methamphetamine.

Animals↗

PubMed1995

Repeated ketamine administration produces up-regulation of muscarinic acetylcholine receptors in the forebrain, and reduces behavioral sensitivity to scopolamine in mice.

To study the effects of repeated ketamine administration on central muscarinic acetylcholine receptors (mAchRs), ddY male mice were administered subcutaneous doses of 25 mg/kg ketamine every 3 days for a total of five times. Receptor binding assays of mAchR were carried out in the forebrain (FB), cerebellum (CB) and brainstem (BS), using [3H]quinuclidinyl benzilate ([3H]QNB) as a ligand. In addition, we examined whether repeated ketamine (12.5, 25 and 50 mg/kg) or saline (five times) could modify the hyperlocomotion induced by scopolamine (0.5 mg/kg, SC) (a muscarinic antagonist), using a behavior-pharmacological technique. Repeating the ketamine administration resulted in a significant increase in the receptor density value (Bmax) for [3H]QNB only in FB, dependent on the numbers of administrations (1270 +/- 33 fmol/mg protein for a single dose, 1620 +/- 59 for four treatments, 1738 +/- 70 for five treatments without any change in apparent affinity (defined as the reciprocal of the dissociation constant) (Kd). A competitive inhibition study of repeated (5 times) administration of ketamine failed to detect any subtype-specific changes in mAchRs. Repeated ketamine administration reduced the scopolamine-induced hyperlocomotion in a dose-related way, and the changes were significant at 50 mg/kg. Our results suggest that repeated ketamine administration produces an up-regulation of mAchRs, and this change may be associated with altered Ach transmission in the central nervous system.

Animals↗

PubMed1995

Modification of cocaine sensitization by dopamine D1 and D2 receptor antagonists in terms of ambulation in mice.

The progressive enhancement in the ambulation increase caused by the repeated five-time dosings of cocaine (10 mg/kg SC) at 3- to 4-day intervals was dose dependently reduced by simultaneous administration with the selective dopamine D1 and D2 receptor antagonists, SCH 23390; R(+)-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.01, 0.03, and 0.1 mg/kg SC) and YM-09151-2 (nemonapride); cis-N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4- methylaminobenzamide (0.01, 0.03, and 0.1 mg/kg SC), respectively. However, the mice given cocaine with SCH 23390 (0.03 mg/kg) or YM-09151-2 (0.03 and 0.1 mg/kg) demonstrated significantly higher sensitivity than the mice given cocaine alone to challenge cocaine. Both 2-h and 24-h posttreatments with SCH 23390 (0.01-0.1 mg/kg) after each cocaine administration, at which the acute stimulant effect of cocaine had disappeared, significantly and dose dependently enhanced the cocaine sensitization. In contrast, 2-h, but not 24-h, posttreatment with YM-09151-2 (0.01-0.1 mg/kg), slightly retarded the induction of cocaine sensitization. The present results suggest that the blockade of dopamine D1 receptors is responsible for a significant enhancement in the cocaine sensitization, independent of the timings of its administration, whereas the blockade of dopamine D2 receptors elicits time-dependent alterations in the cocaine sensitization, a strong enhancement in the simultaneous administration schedule, but a slight retardation in the early posttreatment schedule.

Animals↗

PubMed1995

Dopamine D1 receptor antagonist SCH 23390 retards methamphetamine sensitization in both combined administration and early posttreatment schedules in mice.

SCH 23390 [0.003-0.03 mg/kg, subcutaneously (SC)], a dopamine D1 receptor antagonist, dose-dependently inhibited the ambulation-stimulant effect of methamphetamine (MAP) (2 mg/kg, SC) in mice when two drugs were combined in repeated administrations at 3- to 4-day intervals, repeated five times. SCH 23390 (0.03 mg/kg), which was sufficient to abolish the acute effect of MAP completely throughout the repeated administrations, significantly inhibited the induction of MAP sensitization. Moreover, when the mice were posttreated with SCH 23390 (0.01 and 0.03 mg/kg) 3 h after each MAP administration, at which the ambulation-stimulant effect of MAP had almost disappeared, they showed a significant and dose-dependent retardation of the induction of MAP sensitization. However, the 24-h posttreatment with SCH 23390 had no such effect. The administration of SCH 23390 (0.003-0.03 mg/kg) alone in either the activity cage or the home cage, or saline in the activity cage with 3- or 24-h posttreatment with SCH 23390 (0.01 or 0.03 mg/kg) five times at 3- to 4-day intervals did not elicit any significant changes in MAP sensitivity. The present results indicate that an intense blockade of dopamine D1 receptors in the acute or subacute period after MAP administration causes retardation of MAP sensitization by means of ambulation in mice.

Animals↗

PubMed1995

Inhibition of cocaine sensitization by MK-801, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist: evaluation by ambulatory activity in mice.

Alterations of cocaine effects, which were induced by prior repeated 5-time administration of MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine) (i.p.) alone or in combination with cocaine (s.c.) at 3- to 4-day intervals, were investigated by means of ambulatory activity in mice. The repeated administration of either cocaine (10 and 20 mg/kg) alone or MK-801 (0.3 mg/kg) alone progressively enhanced each drug's effect. The enhanced effects of cocaine and MK-801 were estimated to be 1.8-2.2 times and about 1.4 times, respectively, as great as those at the 1st administration. Although the coadministration of MK-801 with cocaine produced a significant enhancement in the ambulation-increasing effect, the comparatively higher doses of MK-801 (0.3 and 1 mg/kg) acted not only to reduce cocaine sensitivity but also to inhibit the development of cocaine sensitization. Thus, the mice that had been given MK-801 (0.3 and 1 mg/kg) alone 5 times showed lower sensitivities to cocaine (20 mg/kg) than the mice given saline alone. The mice coadministered MK-801 (0.3 and 1 mg/kg) with cocaine (10 and 20 mg/kg) also exhibited lower sensitivities to cocaine (10 and 20 mg/kg) than those given cocaine alone. However, MK-801 could not ameliorate the established sensitization to cocaine. Similar interactions have been demonstrated between MK-801 at 1 mg/kg, but not 0.3 mg/kg, and methamphetamine. The present results indicate that MK-801 can inhibit the development of sensitization to cocaine at a lower dose than that required to inhibit methamphetamine sensitization.

Analysis of Variance↗

PubMed1995

Delayed effects of ethanol, caffeine and nicotine assessed by wheel-running and drinking in mice.

Effects of ethanol, caffeine and nicotine, pleasurable substances, on wheel-running and drinking in mice that were housed under a 12 : 12-hr light-dark schedule (lighting period ; 6 : 00-18 : 00) were investigated. All drug administrations were carried out at 11: 00, a mid-light period. Although ethanol (0.8-2.4 g/kg p.o.) scarcely changed both the wheel-running and drinking during the light period, it was followed by a strong suppression of both behaviors during the coming dark period (18 : 00-6 : 00). The same treatment with caffeine (1-10 mg/kg s.c.) produced significant increase in the drinking during the light period, but suppression of the wheel-running during the dark period. Nicotine (0.1-1 mg/kg s.c.) significantly suppressed the wheel-running, but not drinking, during the dark period. The coadministration of nicotine (0.1-1 mg/kg) with ethanol (2.4 g/kg) reduced the behavioral suppression during the dark period. Whereas nicotine (0.1-1 mg/kg) reduced the increased drinking during light period by caffeine (10 mg/kg), but enhanced the caffeine-induced behavioral suppression during the dark period. These results indicate that the administration of pleasurable substances in the mid-light period results in a delayed effect which is characterized by a suppression of either and/or both wheel-running and drinking during the coming dark period starting 7 hr after the administration, and that nicotine acts to antagonize the effect of ethanol, but contrally to enhance the effect of caffeine.

Animals↗

PubMed1995

Haloperidol and restraint differently inhibit the induction of sensitization to the ambulation-increasing effect of methamphetamine in mice.

Haloperidol (HPD: 0.4 mg/kg, sc) completely abolished not only the ambulatory stimulation by methamphetamine (MAP: 2 mg/kg, sc) but also the induction and expression of MAP sensitization in the combined administration schedule. HPD also significantly reduced the induction of MAP sensitization when the mice were treated with HPD at 1/12, 1/4, 1, 2, 3, 4 or 5 hr but not at 1/2 hr or later than 6 hr, after each administration of MAP. The inhibition by the 3-hr post-treatment with HPD was as strong as that by the combined administration. On the other hand, a restraint of abulation for 3 hr (putting the mouse in a small jar) significantly inhibited the induction of MAP sensitization when it was started at 0/4 hr, but not at 1/2-6 hr, after each MAP administration. The inhibitory effects of restraint, starting at 0-1/4 hr, were almost equivalent to those of the post-treatments with HPD at the same times. The post treatments with HPD + restraint showed similar inhibitory effects on MAP sensitization to those of HPD alone. The repeated administration of saline together with post-treatment with either HPD, restraint or HPD + restraint did not change MAP sensitivity. These results suggest that a couple of free movement in the activity cage and stimulation of dopamine receptors for longer than 1/2 hr immediately after administration of MAP, and an agonistic effect on dopamine receptors during 1-5 hr after MAP are responsible for perfect induction of the MAP sensitization in terms of ambulation in mice.

Analysis of Variance↗

PubMed1995

Evaluation of acute and sub-acute effects of cocaine by means of circadian variation in wheel-running and drinking in mice.

The effects of cocaine on wheel-running and drinking activities in mice, housed under a 12-h light-dark schedule (lighted period; 6:00-18:00 h), were investigated through long continuous observation. Cocaine (20 and 40 mg/kg, sc), administered at 11:00 h, acutely increased wheel-running and drinking, but it was followed by a sub-acute suppression of the spontaneous increment in both of these behaviors during the coming dark period (18:00-6:00 h). Such behavioral accelerating and suppressing effects of cocaine did not change throughout the whole course of administration, which was repeated five times at 3- to 5-day intervals. In addition to these findings, wheel-running and drinking spontaneously increased during the light period and decreased during the dark period on the day after the drug administration. On the other hand, the repeated administration of cocaine at 18:00 h never increased, but rather acutely suppressed both behaviors during the dark period, and no trends in the behavioral changes on the next day were clearly shown. These results suggest that the effects of cocaine on wheel-running and drinking differ depending on the time of day of the administration.

Animals↗

PubMed1995

[Assessment of anxiolytics (1)--Geller-type conflict tests].

The Geller-type conflict test and its modified tests, which are based on operant conditioning, have been applied for preclinical evaluation of the anxiolytic effect of drugs in parallel with the clinical use of benzodiazepines. Here, the author describes the experimental procedures of the Geller-type conflict test, including its modified tests, using mice and rats in detail. The effects of drugs, particularly benzodiazepines and 5-HT1A receptor agonists, on the established conflict behaviors in rats and mice are also presented.

Animals↗

PubMed1994

Early post-treatment with haloperidol retards induction of methamphetamine sensitization in mice.

The repeated administration of methamphetamine (2 mg/kg s.c.) at 3- to 4-day intervals induced sensitization to its ambulation-increasing effect in mice. When the simultaneous administration of methamphetamine with haloperidol (0.025, 0.1 and 0.4 mg/kg s.c.) was carried out, the acute ambulation-increasing effect as well as the development of sensitization were haloperidol-dose-dependently inhibited. Moreover, treatment with haloperidol (0.1 and 0.4 mg/kg) 3 h following each methamphetamine administration, which per se did not affect the acute ambulation increase caused by methamphetamine, could protect against the induction of methamphetamine sensitization in a dose-dependent manner, whereas treatment with haloperidol after 24 h did not show such protective action. The present results suggest that blockade of the dopamine receptors at an early period following each administration of methamphetamine may be responsible for the delay in development of methamphetamine sensitization as expressed by ambulatory activity of mice.

Animals↗

PubMed1994

The disruptive effects of ketamine on passive avoidance learning in mice: involvement of dopaminergic mechanism.

The involvement of dopaminergic mechanisms in ketamine-induced disruption of one trial step-through passive avoidance performance was assessed through the coadministration with the dopamine D1 antagonist SCH 23390, the dopamine D2 antagonist YM-091512 and the dopamine autoreceptor agonist at low doses, apomorphine, in mice. Pretraining (10 min before) administration of ketamine (0; saline, 2.5, 5 and 10 mg/kg SC) dose-dependently reduced the latency in the retention trial conducted 24 h after the training. However, ketamine did not affect the retention latency when administered immediately after the training or prior to retention. YM-09151-2 (0.01 and 0.03 mg/kg SC) and apomorphine (0.01 and 0.03 mg/kg SC), but not SCH 23390 (0.01 and 0.03 mg/kg SC), ameliorated the impaired reduction by ketamine (10 mg/kg) in a dose-dependent manner. These results suggest that ketamine obstructs the acquisition of the passive avoidance task, and that this effect is induced by stimulation of dopamine D2 receptors through dopamine release from the presynaptic terminals.

Animals↗

PubMed1994

Caffeine enhances the stimulant effect of methamphetamine, but may not affect induction of methamphetamine sensitization of ambulation in mice.

Methamphetamine (MAP: 1 and 2 mg/kg SC) and caffeine (CAF: 1, 3, 10 and 30 mg/kg SC) dose-dependently increased ambulation in mice. Repeated administration (5 times at 3 to 4-day intervals) of MAP, but not CAF, induced sensitization to its effect. Furthermore, the mice repeatedly receiving CAF showed no significant change in the sensitivity to MAP. Combined administration of MAP with CAF increased the effect. In the combinations of MAP (1 mg/kg) with CAF (3, 10 and 30 mg/kg), and MAP (2 mg/kg) with CAF (1 and 3 mg/kg), the effect was enhanced by the repeated administration. However, MAP sensitization was not modified by the combination with CAF in the repeated administration schedule, except in the combination of MAP (1 mg/kg) with CAF (30 mg/kg). The ambulation-increasing effects of MAP (1 mg/kg), CAF (10 mg/kg) and combination of MAP with CAF were almost equivalently inhibited by SCH 23390 (0.01 and 0.1 mg/kg SC) and YM-09151-2 (0.01 and 0.1 mg/kg SC). However, the inhibitory effects of apomorphine (0.05 mg/kg SC) and N6-(L-phenylisopropyl)-adenosine (0.1 and 0.2 mg/kg SC) were stronger for CAF than for MAP and the combination, and those of alpha-methyl-p-tyrosine (200 mg/kg IP, 4 h before) and reserpine (1 mg/kg SC, 4 h before) were stronger for MAP and CAF alone than for the combination. The present results suggest that, although the combination of MAP and CAF enhances the ambulation-increasing effect through an interaction at dopaminergic system, CAF may not significantly modify the induction of MAP sensitization in mice.

Animals↗

PubMed1994

Potentiation of the ambulation-increasing effect induced by combined administration of MK-801 with ethanol in mice.

Although both MK-801 (dizocilpine: 0.1 mg/kg, IP) and ethanol (1.6 nd 2.4 g/kg, PO) only slightly increased ambulatory activity in mice, their combination produced a marked enhancement of the ambulation-increasing effect. The combination of MK-801 (0.03 mg/kg) with ethanol (1.6 and 2.4 g/kg) also elicited a significant increase in the mouse's ambulation. A significant enhancement of the effect was produced by the combination of ketamine (3 and 10 mg/kg) with ethanol only (2.4 g/kg). The ambulation increment induced by the combination of MK-801 (0.1 mg/kg) plus ethanol (1.6 g/kg) was dose-dependently inhibited by YM-09151-2 (0.0001-0.01 mg/kg IP), SCH 23390 (0.001-1 mg/kg IP), reserpine (0.1-1 mg/kg, IP) and ceruletide (0.00001-0.001 mg/kg, IP), and the highest dose of each drug was effective for complete inhibition of the ambulation. Naloxone (0.05-5 mg/kg IP), apomorphine (0.001-0.1 mg/kg IP) and alpha-methyl-p-tyrosine (50-200 mg/kg, IP) partially reduced the ambulatory activity induced by the combination of MK-801 with ethanol. These results suggest that the dopaminergic system, particularly via presynaptic changes in the release of stored dopamine, as well as the opioid system, are involved in the interaction of MK-801 with ethanol.

Animals↗

PubMed1994

Modification by caffeine of the sensitization to methamphetamine and cocaine in terms of ambulation in mice.

The repeated administration of caffeine (CAF: 1, 3 and 10 mg/kg s.c.) alone 5 times at 3- to 4-day intervals did not produce any significant change in the sensitivity to the ambulation-increasing effects of CAF itself, methamphetamine (MAP: 1 and 2 mg/kg s.c.) and cocaine (COC: 10 and 20 mg/kg s.c.). Whereas, the repeated administration of MAP (1 and 2 mg/kg) and COC (10 and 20 mg/kg) produced sensitization to the individual drug effects. The combination of MAP or COC with CAF potentiated the effect, and sensitization was produced by the repeated 5-time administrations of the following combinations: MAP (1 mg/kg) with CAF (3 and 10 mg/kg), MAP (2 mg/kg) with CAF (1 and 3 mg/kg), COC (10 mg/kg) with CAF (1 mg/kg) and COC (20 mg/kg) with CAF (1 and 3 mg/kg). Moreover, the mice given COC (10 mg/kg) with CAF (3 and 10 mg/kg) and COC (20 mg/kg) with CAF (1 and 3 mg/kg) exhibited significantly higher sensitivity to challenge COC than those given COC alone. However, the sensitivities to challenge MAP of the mice given MAP with CAF were almost the same with those given MAP alone. These results suggest that, in terms of ambulation in mice, the combination of MAP or COC with CAF elicits potentiation of the acute stimulant effect, and that CAF is responsible in enhancement of COC sensitization, but not MAP sensitization.

Animals↗

PubMed1994

Effects of dopamine antagonism on methamphetamine sensitization: evaluation by ambulatory activity in mice.

SCH 23390 (SCH: 0.001-0.03 mg/kg SC) and YM-09151-2 (YM: 0.001-0.03 mg/kg SC), the selective dopamine D1 and D2 antagonists, respectively, reduced dose-dependently the ambulation-increasing effect of methamphetamine (MAP: 2 mg/kg SC) in mice. The sensitization to MAP was inhibited when it was administered in combination with SCH (0.003-0.03 mg/kg) or YM (0.003-0.03 mg/kg) in the repeated administration regimen. The inhibitory action of YM on the MAP sensitization was more prominent than that of SCH. However, the repeated treatment with either SCH or YM could not ameliorate the established MAP sensitization. Rather, the repeated treatment with the highest dose of YM (0.03 mg/kg) increased the MAP sensitivity in both the MAP-sensitized and drug-naive mice. SCH had no such action. The present results suggest that the dopamine D2 receptors are more intimately involved than the dopamine D1 receptors in the increased sensitivity to MAP induced by the repeated treatment with MAP itself, behavioral sensitization, or dopamine antagonists, denervation supersensitivity.

Animals↗