Sensitization of the reinforcing effects of self-administered cocaine in rats: effects of dose and intravenous injection speed

Abstract

Speed of drug onset is assumed to be an important determinant of the abuse liability of a drug. Studies in human and non-human primates suggest that the subjective and reinforcing effects of cocaine can be influenced by route of administration and/or speed of intravenous injection. Sensitization to the reinforcing effects of cocaine was studied in rats and the effects of various injection durations (i.e. speed of injection) on the development of sensitization was examined using a progressive ratio schedule. In addition, the effects of cocaine dose on sensitization and the effects of injection duration on the acute reinforcing effects of cocaine were examined. The initial study demonstrated that the development of sensitization (i.e. progressive increases in breakpoints) was dose-dependent. A robust sensitization of the reinforcing effects of cocaine was replicated in animals receiving cocaine at the highest rate (i.e. shortest duration; 5 s), but not in animals receiving the same dose over 25 or 50 s. Subsequent testing revealed that injection duration did not have profound effects on the acute reinforcing effects of cocaine (assessed by breakpoints or rate of responding on a fixed ratio schedule). These findings are similar to recent studies demonstrating that the development of sensitization, but not the acute responsivity, to cocaine's locomotor-activating effects are influenced by rate of intravenous injection. Taking these findings together, we hypothesize that the process of drug addiction involves both the acute reinforcing effects and the development of sensitization.

Fig. 1

Effects of cocaine dose on the development of sensitization of the reinforcing effects. Animals with limited initial exposure were tested on the PR schedule with different cocaine doses (n = 6-7 per group). Data are expressed as mean (± SEM) breakpoints. Asterisks indicate significant difference from the first day of testing. Breakpoints maintained by 0.75 and 1.5 mg/kg per injection increased across days (P < 0.05); by contrast, 0.38 or 3.0 mg/kg per injection failed to produce such sensitization.

Fig. 2

Effects of injection speed on the development of sensitization to the reinforcing effects of cocaine. Animals responded on a PR schedule maintained by cocaine (1.5 mg/kg per injection) delivered over 5 s for one session (data points over ‘5 s’), and over the subsequent 14 sessions; responding was maintained by cocaine delivered over different durations (5, 25 or 50 s; n = 6-7 per group). Symbols represent mean (± SEM) breakpoints. Asterisks indicate significant differences between 5-s and the 25- and 50-s groups; ‘+’ symbols represent significant differences from the first day of PR testing (P < 0.05). The highest injection speed (i.e. shortest duration) resulted in sensitization, whereas longer durations failed to result in sensitization.

Fig. 3

Effects of injection speed on cocaine’s acute reinforcing effects in animals showing or not showing sensitization. Following testing on a PR schedule for 14 days at a particular injection speed (see Fig. 2), animals were tested with each injection duration during PR and FR sessions. (A) Breakpoints maintained in animals with a history of 5-s injection durations (i.e. sensitized animals) were higher than those in the 25- and 50-s groups, regardless of the current injection speed conditions (F_2,55 = 12.84, P < 0.05). Data are represented as mean (± SEM) breakpoints. (B) Rate of intake (injections per hour) increased as the speed of injection decreased across all groups. There were no differences among these curves across groups (speed: F_2,34 = 3.83, P < 0.05; group: F_2,16 = 0.11, P > 0.05).