Miller Michelle L, Branch Marc N
Department of Psychology, University of Florida, Gainesville, FL 32611-2250, USA.
Psychopharmacology (Berl). 2002 Oct;163(3-4):302-9. doi: 10.1007/s00213-002-1085-3. Epub 2002 May 28.
Tolerance to behavioral effects of cocaine can be produced by exposure to varying doses. The degree to which tolerance develops may depend on dose order.
To investigate the relationships between three sequences of doses of cocaine in a daily, variable-dosing regimen and the development of tolerance to effects on schedule-controlled behavior.
Twelve pigeons responded daily under a fixed-ratio 20 schedule of reinforcement, and performance was investigated under a range of doses of cocaine (0.3-10.0 mg/kg, i.m.) by administering the drug once every 7 days (acute effects). After determination of acute effects of cocaine, the drug was administered daily with dose varying from day to day. Dose order varied systematically across three groups of four pigeons; doses were delivered in ascending, descending, or "sawtooth" (ascending then descending) sequences. This variable-dosing regimen continued until drug effects were stable (at least 13 cycles through all doses).
During the acute-dosing regimen, response rates following small cocaine doses were similar to those under control conditions; following moderate-to-high doses, responding was diminished relative to control rates. During the variable-dosing regimen, tolerance to the rate-decreasing effects of cocaine was observed in all groups, regardless of the order in which the drug was delivered, and the magnitude of tolerance was similar across groups. Systematic differences in the rate of recovery from initial response decrements were observed across groups, with rate of recovery fastest under the ascending sequence.
These results suggest that dose order under a variable-dosing regimen does not significantly affect the final attainment of tolerance, although it may contribute to the speed with which tolerance develops.
接触不同剂量的可卡因可产生对其行为效应的耐受性。耐受性发展的程度可能取决于给药顺序。
研究在每日可变给药方案中，可卡因三种给药顺序与对按计划控制行为的效应耐受性发展之间的关系。
12只鸽子在固定比例20强化程序下每日做出反应，通过每7天给药一次（急性效应），研究一系列剂量（0.3 - 10.0毫克/千克，肌肉注射）可卡因对其行为表现的影响。在确定可卡因的急性效应后，每天给药，剂量逐日变化。四组鸽子每组三只，给药顺序系统变化；剂量按递增、递减或“锯齿形”（先递增后递减）顺序给药。这种可变给药方案持续到药物效应稳定（至少经历所有剂量13个周期）。
在急性给药方案期间，小剂量可卡因后的反应率与对照条件下相似；中等至高剂量后，反应相对于对照率降低。在可变给药方案期间，所有组均观察到对可卡因降低反应率效应的耐受性，无论药物给药顺序如何，且各组耐受性程度相似。各组在从初始反应降低中恢复的速率上存在系统差异，递增顺序下恢复速率最快。
这些结果表明，可变给药方案下的给药顺序虽可能影响耐受性发展的速度，但对耐受性的最终形成无显著影响。
