A comparison of amphetamine- and methamphetamine-induced locomotor activity in rats: evidence for qualitative differences in behavior

Abstract

Rationale: Methamphetamine (METH) is typically characterized as a more potent psychostimulant than amphetamine (AMPH), but few studies have directly compared the effects of these drugs at low, behaviorally activating doses that tend not to produce focused stereotypy.

Objectives: The objective of the study was to compare the effects of AMPH or METH treatment on locomotor activity in an open-field arena, focusing on their ability to produce conditioned locomotor activity, sensitization, and cross-sensitization.

Materials and methods: Adult male rats were given AMPH or METH (0.5 or 1.0 mg/kg) for 5 days, with half of the rats presented with discrete, salient stimuli (S+) during the postinjection period. After a 3-day withdrawal, they were given three different injections on successive days: a saline challenge to assess conditioned responding, a drug challenge to assess sensitization, and a cross-sensitization test to the same dose of the drug with which they were not pretreated.

Results: Except in certain conditions, AMPH and METH were equipotent at activating locomotor activity. The exceptions included when rats were presented with S+ on acute and drug challenge days and in tests of cross-sensitization. There were no consistent differences in the magnitude of sensitization produced by AMPH or METH, and both drugs produced similar amounts of conditioned locomotion after a saline injection.

Conclusions: We have found specific conditions where METH is more potent than AMPH, but this study and others that used higher doses of these drugs are not consistent with the generalized characterization of METH as a more potent psychostimulant.

Figure 1

Cumulative (mean ± SEM) saline- or drug-induced locomotion (A, C) and rearing (B, D) for the 60-min period following injection (n = 8 rats/group). Shown in A and B are the data obtained on treatment day 1, when all rats received saline, and day 2, when they received AMPH or METH (0.5 or 1.0 mg/kg) in the presence (S+) or absence (S−) of a compound stimulus (flashing light and tone). ANOVA revealed no significant difference in the response to saline between groups, so these data were collapsed for presentation. Both doses of AMPH and METH significantly increased behavior over saline. * p < 0.05; ** p < 0.01; ^# p < 0.05, compared to 0.5 mg/kg AMPH, S+ group; ^## p < 0.01, compared to 1.0 mg/kg AMPH, S+ group. Shown in C and D are data obtained after AMPH or METH challenge (treatment day 11). For distance: * p < 0.05; *** p < 0.001; ^# p < 0.05, compared to 1.0 mg/kg AMPH, S− group; ^### p < 0.001, compared to 0.5 mg/kg AMPH, S+ group. For rearing: ** p < 0.01; ^# p < 0.05, compared to 1.0 mg/kg AMPH, S+ group.

Figure 2

Sensitization to AMPH- and METH-induced locomotion (A) and rearing (B), represented as the difference between activity during the 60-min period following the challenge (day 11) and acute (day 2) injections (n = 8 rats/group). Statistical analysis, which was performed on the raw data from the two injection days (see Results), revealed statistically significant sensitization for locomotion in all groups except the 0.5 mg/kg METH, S− group; sensitization to drug-induced rearing was only evident in the 0.5 mg/kg AMPH, S+ and the 1.0 mg/kg METH, S+ groups. The only significant difference in the magnitude of sensitization was between the 0.5 and 1.0 mg/kg dose of METH in the absence of the stimuli (S−). * p < 0.05

Figure 3

Locomotion and rearing following saline injection in rats treated repeatedly with AMPH or METH (A, B) or saline (C, D). A, B: Conditioned activity in the AMPH- or METH-exposed groups is represented as the difference between behavior following challenge (day 10) and acute (day 1) injections of saline, for the first 30 min following injection. Statistical analysis, which was performed on the raw data from the two injection days (see Results), revealed statistically significant conditioned locomotion in all groups except the 1.0 mg/kg AMPH, S− group; conditioned rearing was observed at the 0.5 mg/kg dose of both AMPH and METH, but only in the S+ group given METH at the 1.0 mg/kg dose. Due to an equipment malfunction, the 1.0 mg/kg AMPH, S− group is n = 7, while all other groups are n = 8. * p < 0.05; ** p < 0.01. C, D: Shown are data obtained from rats administered saline on Day 1 (n = 64) and a separate group (n = 4) given saline in the presence of stimuli (S+) on the second treatment day and again on a challenge day following repeated saline treatment.

Figure 4

Locomotion and rearing in rats (n = 8/group) treated repeatedly with METH and challenged with AMPH (A, B) or treated repeatedly with AMPH and challenged with METH (C, D). Shown is the cumulative behavior for the 60-min following injection for “Acute” groups (i.e., those given the noted drug/dose for the first time) and “Challenge” groups (i.e., those given a challenge with the same dose, but different drug from that which they were treated repeatedly). Cross-sensitization was defined as a significant increase in behavior in the Challenge compared to the Acute group. * p < 0.05; ** p < 0.01; *** p < 0.01.