Tolerance to cocaine's effects following chronic administration of a dose without detected effects on response rate or pause

Abstract

To observe tolerance to drug effects on operant behavior, the dose that researchers have often selected for chronic administration is one that disrupts, but does not abolish, responding. Some evidence suggests that tolerance may develop after chronic administration of relatively smaller doses. The purpose of the present experiment was to assess systematically effects of chronic administration of a dose without detected effect on responding. Specifically, response rates and postreinforcement pauses of five pigeons key pecking under a three-component multiple fixed-ratio schedule of food reinforcement were observed under chronic cocaine administration. We evaluated the effects of a range of doses (1.0 mg/kg to 17.0 mg/kg) during acute administration. The largest dose that failed to alter responding acutely then was administered chronically (1.0 mg/kg for one pigeon, 3.0 mg/kg for three pigeons, and 5.6 mg/kg for one pigeon). After 30 consecutive sessions of chronic administration, smaller and larger doses occasionally were substituted for the chronic dose. Pigeons then received presession saline administration for 30 consecutive sessions, and the postchronic effects of the series of doses on responding were determined. All subjects developed tolerance to doses of cocaine that initially had caused large decreases in rate, with the magnitude of the effects varying across components of the multiple schedule and subjects. Specifically, tolerance generally was greatest in the components with smaller ratios. Following postchronic saline administration, tolerance was usually diminished. Overall, the results demonstrate that under these conditions, repeated experience with disruptive effects of cocaine on food-maintained responding is not a necessary factor in the development of tolerance.

How I Learned to Stop Worrying and Love Replication Failures

“…The drug's effect is studied by administering a range of doses. Figure 2 provides an example with results from an experiment by Minervini and Branch (2013). Responding of pigeons was maintained on an FR schedule of food reinforcement.…”

“…The effect is seen in all three pigeons, with some specific details in common: In none of the pigeons is there an effect of 1 mg/kg or 3 mg/kg, and in all of the pigeons responding is completely or almost completely suppressed at 10 mg/kg. What would have happened had Minervini and Branch (2013) confined their experiment to just two doses, say, 1 mg/kg and 3 mg/kg.? They might have questioned the efficacy of the drug.…”

“…The point of these examples is to demonstrate that broad manipulations of the sort conducted by Powell (1968) and Minervini and Branch (2013) can help us identify commonalities across subjects that are apparent even in the face of individual differences. By comparison, limited manipulation of the experimental variable can lead us astray.…”

Effects of Response-Independent Food Pellet Delivery on the Development of Tolerance to the Rate-Decreasing Effect of d-Amphetamine in Rats

“…To account for differences in lever-press rates between rats and components for the acute and chronic phases, lever-press rates were expressed as a proportion of average lever-press rates obtained when saline was tested for each rat. Calculating AUC in this manner allowed drug effects to be compared between components for rats in both groups (Macaskill and Branch, 2012;Minervini and Branch, 2013). A tolerance ratio (Hughes et al, 2005) was then calculated for each rat to quantify the extent to which tolerance developed.…”

“…Future research could examine more systematically the extent to which dose size influences the development of tolerance under conditions similar to those used in the present study. It would also be of interest to examine the extent to which providing non-contingent food pellets influences the development of tolerance to repeated administration of a drug dose that does not produce a loss in reinforcement (see Minervini and Branch, 2013).…”