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Characteristics of "reverse tolerance" to amphetamine-induced locomotor stimulation in mice
I A Chaudhry1, S A Turkanis, R Karler
1Department of Pharmacology, University of Utah School of Medicine, Salt Lake City 84132.
Abstract:
The characteristics of chronically administered amphetamine on the locomotor and anticonvulsant effects were studied in adult CF-1 mice. The influence of dose of the drug and interdose interval on the development of "reverse tolerance" to the locomotor stimulation was investigated, in addition to the selectivity of the response and the persistence of the change in pharmacodynamics. Once-daily treatment with 6 mg/kg amphetamine for 4 weeks resulted in a 2-3 fold increase in locomotor activity. The increase in responsiveness, however, was limited to the first period of 2 weeks and there was no subsequent change in pharmacodynamics during the last 2 weeks of treatment. After 36 days of withdrawal, the response had not returned to that of control, illustrating the persistence of the effect. The results of varying the interdose interval indicated that "reverse tolerance" occurred even when the interval was as long as 14 days. These results represent additional evidence of the persistence of the phenomenon. Selectivity of the changes in the CNS was illustrated by the cross-reactivity with a motor-stimulant dose of cocaine but not with that of morphine. Selectivity was also demonstrated by the failure of "reverse tolerance" to develop to the anticonvulsant effects of amphetamine, which also appear to be mediated dopaminergically.
Insights
Chronic amphetamine administration in mice leads to persistent increases in locomotor activity, demonstrating "reverse tolerance" that lasts even after withdrawal. This heightened response was specific to motor stimulation and did not affect anticonvulsant effects.
Area of Science:
- Neuropharmacology
- Behavioral Neuroscience
Background:
- Chronic drug administration can alter central nervous system (CNS) responses.
- Understanding the development and persistence of altered drug effects, such as
- reverse tolerance
- is crucial for predicting long-term outcomes.
Purpose of the Study:
- To investigate the characteristics of chronically administered amphetamine on locomotor and anticonvulsant effects in mice.
- To examine the influence of dose and interdose interval on the development of "reverse tolerance" to amphetamine's locomotor stimulation.
- To assess the selectivity and persistence of these pharmacodynamic changes.
Main Methods:
- Adult CF-1 mice received daily 6 mg/kg amphetamine for 4 weeks.
- Locomotor activity and anticonvulsant effects were measured.
- Interdose intervals and cross-reactivity with cocaine and morphine were analyzed.
Main Results:
- Once-daily amphetamine treatment for 4 weeks increased locomotor activity 2-3 fold, with this effect plateauing after 2 weeks.
- The enhanced locomotor response persisted for at least 36 days after drug withdrawal.
- "Reverse tolerance" to locomotor stimulation occurred even with a 14-day interdose interval.
- This phenomenon was selective, as "reverse tolerance" did not develop to amphetamine's anticonvulsant effects.
Conclusions:
- Chronic amphetamine administration induces persistent changes in locomotor activity in mice.
- The development of "reverse tolerance" to locomotor stimulation is dose- and interval-dependent and shows long-term persistence.
- Amphetamine's effects on locomotor activity and seizure threshold are differentially affected by chronic administration, suggesting selective neurochemical adaptations.