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[Characteristics of reverse tolerance to ambulation-increasing effect of methylphenidate after repeated
Abstract:
Effects of repeated administration of methylphenidate (MPD) 2, 4, 8 and 16 mg/kg, sc on ambulatory activity in adult male mice of old strain were studied. The ambulatory activity of each mouse was measured by a tilting-type activity cage for 90-150 min after the drug administration. The repeated administration of MPD 2 and 4 mg/kg at intervals of 3-4 days, and 4 mg/kg at intervals of 7 days produced an augmentation in the sensitivity of the mice, i.e., a reverse tolerance, to the ambulation-increasing effect of the drug. However, the repeated administration of MPD 4 mg/kg at intervals of 1 day, and 8 and 16 mg/kg at intervals of 3-4 days did not produce the reverse tolerance to it. The mice repeatedly given 16 mg/kg at intervals of 3-4 days exhibited an augmentation in stereotyped behaviors. The reverse tolerance, once produced, was well maintained 45 days after cessation of the repeated administration. Only a little reverse tolerance to MPD was produced in the mice repeatedly given the drug in their home cage, in which the mice were group-housed, and the extent was significantly less than that observed in the mice given the drug in the activity cage. In addition, the mice showing the reverse tolerance to MPD demonstrated an increase in sensitivity to methamphetamine as compared with the saline-given control mice. The present results suggest that the characteristics of reverse tolerance to the ambulation-increasing effect of MPD is almost identical with that after methamphetamine.
Insights
Repeated methylphenidate (MPD) administration can increase sensitivity to its effects, known as reverse tolerance. This phenomenon, observed with specific dosing schedules, persists long after drug cessation and also enhances sensitivity to methamphetamine.
Area of Science:
- Neuroscience
- Pharmacology
- Behavioral Science
Background:
- Methylphenidate (MPD) is a central nervous system stimulant.
- Understanding the long-term effects of MPD administration, including tolerance and reverse tolerance, is crucial for its therapeutic application and abuse potential assessment.
Purpose of the Study:
- To investigate the development of reverse tolerance to the ambulation-increasing effects of methylphenidate (MPD) in adult male mice.
- To examine the influence of different dosing frequencies and administration environments on MPD-induced reverse tolerance.
- To assess the cross-sensitization between MPD and methamphetamine.
Main Methods:
- Adult male mice of an old strain were administered varying doses of MPD (2, 4, 8, 16 mg/kg) subcutaneously.
- Ambulatory activity was measured using a tilting-type activity cage.
- Repeated administration protocols varied in dose, interval (1, 3-4, or 7 days), and location (activity cage vs. home cage).
- Stereotyped behaviors and sensitivity to methamphetamine were also assessed.
Main Results:
- Repeated MPD administration at 2 and 4 mg/kg (3-4 day intervals) or 4 mg/kg (7-day interval) induced reverse tolerance to its ambulation-increasing effects.
- Reverse tolerance was not observed with daily 4 mg/kg MPD or higher doses (8, 16 mg/kg) at 3-4 day intervals.
- Mice receiving 16 mg/kg MPD showed increased stereotyped behaviors.
- Reverse tolerance persisted for at least 45 days after drug cessation.
- Administration in a home cage environment resulted in less reverse tolerance compared to the activity cage.
- Mice exhibiting reverse tolerance to MPD showed increased sensitivity to methamphetamine.
Conclusions:
- The development of reverse tolerance to MPD is dependent on the dosing schedule and administration environment.
- Reverse tolerance to MPD is a stable phenomenon that can persist long-term.
- MPD-induced reverse tolerance is associated with cross-sensitization to methamphetamine, suggesting shared neurobiological mechanisms.