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

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Reverse Tolerance to Ambulation-Increasing Effects of Methamphetamine and Morphine in 6 Mouse Strains Reverse Tolerance to Ambulation-Increasing Effects of Methamphetamine and Morphine in 6 Mouse Strains Hisashi KURIBARA and Sakutaro TADOKORO Division for Behavior Analysis, Behavior Research Institute, Gunma University School of Medicine, 3-39-22 Showa-machi, Maebashi 371, Japan Accepted October 20, 1988 Abstract-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 meth amphetamine (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 de grees of the reverse tolerance in either methamphetamine or morphine. Further more, the reverse tolerance to methamphetamine and morphine was sometimes transferable, although such cross interaction varied among mouse strains. A repeated drug administration frequently probable that there is an intimate interaction results in an alteration in sensitivities to the between the ambulation-increasing effect of drug effects, eliciting tolerance and/or reverse methamphetamine and morphine in mice. tolerance (c.f. 1-3). It is also highly probable When drug effects are investigated in mice, that a prior drug treatment yields various it should be recognized that there are many changes in sensitivities to the other drugs. mouse strains and that the behavioral charac Methamphetamine and morphine, proto teristics and drug sensitivities as well as the types of stimulants and narcotic-analgesics, neuronal activities are different among the respectively, increase ambulatory activity in mouse strains (10, 11 ). For one of the most mice, and the effects progressively enhance typical examples, after administration of when these drugs are repeatedly adminis morphine, the C57BL/6 strain shows a major tered at intervals of longer than 1 day (4, 5). increase, whereas the DBA/2 strain shows The ambulation-increasing effect of meth little change, in the ambulatory activity. amphetamine appears through a stimulant Hence, the purposes of this experiment action on central catecholaminergic, in par were to study the effects of single and re ticular dopaminergic, systems (6). The peated administration of methamphetamine catecholaminergic systems have been con and morphine on the ambulatory activity in 6 sidered to be involved in the stimulant effect mouse strains and to study changes in the of narcotic-analgesics (7-9). It is therefore sensitivities to morphine and methamphet amine in the mice that experienced repeated methamphetamine was administered to the administration of methamphetamine and mice that had been treated with either meth morphine, respectively. amphetamine or morphine, respectively, (cross drug administration). The schedules of the Materials and Methods repeated drug administration and the doses Animals: The 6 mouse strains used were dd, of drugs were taken from previous studies ICR, BALB/c, C57BL/6, C3H/He and DBA/2. (4, 5) to be optimum for inducing reverse Only male mice were used in this experiment. tolerance to the ambulation-increasing effect These mouse strains were chosen according of methamphetamine and morphine in mice. to our series of studies on mouse strain dif The measurement of ambulatory activity ferences (12, 13). The dd strain mice were was conduced between 10:00-16:00. provided by the Institute of Experimental Statistical analysis: The mean overall am Animal Research, Gunma University School bulatory activity counts for 3 hr after the drug of Medicine. The other 5 strains of mice were administration were calculated in each group. purchased from Charles River Japan, Inc. At first, repeated measures analysis of variance Groups of 10 mice were housed in standard of the overall data were examined. If there aluminum or acrylfiber cages of 30 (W)x20 were significant overall effects, comparisons (D) x 10 (H) cm in a controlled room (temper between the individual means were carried ature: 22±2°C and light period: 6:00-18:00), out by the two-tailed Student's t-test. When and they were freely given solid diet (MF: P values were equal to or less than 0.05, they Oriental Yeast Co.) and tap water except were taken to indicate significant differences. during times of the experiment. When the mice were 7 weeks of the age, the experiment was Results started. The single drug administration: Figure 1 Procedure: The ambulatory activity of the shows dose-effect relationships for metham mouse was measured using a tilting-type phetamine (upper panel) and morphine ambulometer (AM B-10, O'hara & Co., Ltd.). (lower panel) on the ambulatory activity in Mice were individually placed in plexiglas the 6 strains of mice. activity cages with a diameter of 20 cm, and The activity counts after saline adminis the ambulatory activities were measured for tration were higher in the order of DBA/2, 30 min and 180 min before and after each BALB/c, dd, ICR, C3H/He and C57BL/6 . drug administration, respectively. The ratio between the highest (DBA/2) and The drugs used were methamphetamine lowest (C57BL/6) counts was estimated to HCI (Dainippon Pharm. Co.) and morphine be about 3.3. HCI (Takeda Chemical Co.). These drugs Methamphetamine increased the ambula were dissolved in physiological saline vehicle tory activity in all the strains in a dose and administered subcutaneously (s.c.) at a dependent manner. The effect attained a peak fixed dose volume of 0.1 ml/10 g body weight at 40-50 min and persisted for about 3 hr regardless of the drug doses. after the administration in all 6 strains. The Before starting the drug administration, rank order of sensitivity to methamphetamine mice in each strain were randomly divided was estimated to be ICR, dd, DAB/2, C3H/ into 7 groups of 20-40. Each group of mice He, BALB/c and C57BL/6. was treated with one of the following re Morphine increased the ambulatory ac gimens: administration of saline; metham tivity in 5 strains: dd, ICR, BALB/c, C57BL/6 phetamine at 1, 2 or 4 mg/kg; or morphine at and C3H/He, with a peak effect at 50-60 min 5, 10 or 20 mg/kg. Two groups of mice that and a duration of about 3 hr. The DBA/2 were injected with 2 mg/kg methamphetamine strain of mice showed no significant change or 10 mg/kg morphine were further treated in the ambulatory activity at any doses of with 4 additional administrations of the cor morphine. Thus, the rank order of sensitivity responding drug at intervals of 3-4 days to morphine was estimated to be C3H/He, (repeated drug administration). Four days C57BL/6, ICR, dd, BALB/c and DBA/2. after the 5th administration, morphine or The repeated drug administration: Figure 2 Fig. 1. Dose-effect relationships for methamphetamine (1, 2 and 4 mg/kg, s.c.; upper panel) and morphine (5, 10 and 20 mg/kg, s.c.; lower panel) on the ambulatory activity of drug-naive mice in 6 strains. N=20-40. *: Significant difference from saline (dose=0) treated control value within the same strain (P<0.05). shows the mean overall ambulatory activity tivity counts in the 1st and 5th administration counts after the repeated administration of was 0.996. 2 mg/kg of methamphetamine (left panel) and The repeated administration of morphine 10 mg/kg of morphine (right panel), respec induced reverse tolerance to its ambulation tively, in the 6 mouse strains. increasing effect except for the DBA/2 strain. The repeated administration of metham As compared with the corresponding ac phetamine induced reverse tolerance to its tivity counts in the 1st administration within ambulation-increasing effect in all the strains. each strain, a significant increase in the counts As compared with the corresponding activity was demonstrated in the 2nd and later ad counts in the 1st administration within each ministration in the C3H/He strain, in the 3rd strain, a significant increase in the counts was and later in the C57BL/6, in the 4th and later demonstrated in the 3rd and later administra in the dd and BALB/c strains, and in the 5th tions in the dd, ICR, C3H/He and DBA/2 in the ICR strain. The DBA/2 strain exhibited strains, in the 4th and later in the BALB/c no significant change in the activity counts strain, and in the 5th in the C57BL/6 strain. throughout the 5 times administration of The correlation coefficient between the ac morphine. The correlation coefficient be Fig. 2. Effects of repeated administration of methamphetamine (2 mg/kg , s.c.; left panel) and morphine (10 mg/kg, s.c.: right panel) on ambulatory activity in 6 mouse strains. The drug administration was carried out 5 times at intervals of 3-4 days, and the mouse's ambulatory activity was observed for 3 hr after each drug administration.
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