Role of dose order in the development of tolerance to effects of cocaine on schedule-controlled behavior in pigeons

摘要

Rationale: Tolerance to behavioral effects ofncocaine can be produced by exposure to varying doses.nThe degree to which tolerance develops may depend onndose order. Objective: To investigate the relationshipsnbetween three sequences of doses of cocaine in andaily, variable-dosing regimen and the development ofntolerance to effects on schedule-controlled behavior.nMethods: Twelve pigeons responded daily under a fixedration20 schedule of reinforcement, and performancenwas investigated under a range of doses of cocainen(0.3–10.0 mg/kg, i.m.) by administering the drug oncenevery 7 days (acute effects). After determination of acuteneffects of cocaine, the drug was administered daily withndose varying from day to day. Dose order varied systematicallynacross three groups of four pigeons; doses werendelivered in ascending, descending, or “sawtooth”n(ascending then descending) sequences. This variabledosingnregimen continued until drug effects were stablen(at least 13 cycles through all doses). Results: During thenacute-dosing regimen, response rates following small cocainendoses were similar to those under control conditions;nfollowing moderate-to-high doses, respondingnwas diminished relative to control rates. During the variable-ndosing regimen, tolerance to the rate-decreasingneffects of cocaine was observed in all groups, regardlessnof the order in which the drug was delivered, and thenmagnitude of tolerance was similar across groups.nSystematic differences in the rate of recovery fromninitial response decrements were observed across groups,nwith rate of recovery fastest under the ascending sequence.nConclusions: These results suggest that dose ordernunder a variable-dosing regimen does not significantlynaffect the final attainment of tolerance, althoughnit may contribute to the speed with which tolerancendevelops.