On the positive and negative affective responses to cocaine and their relation to drug self-administration in rats

Abstract

Rationale: Acute cocaine administration produces an initial rewarding state followed by a dysphoric/anxiogenic "crash."

Objective: The objective of this study was to determine whether individual differences in the relative value of cocaine's positive and negative effects would account for variations in subsequent drug self-administration.

Methods: The dual actions of cocaine were assessed using a conditioned place test (where animals formed preferences for environments paired with the immediate rewarding effects of 1.0mg/kg i.v. cocaine or aversions of environments associated with the anxiogenic effects present 15-min postinjection) and a runway test (where animals developed approach-avoidance "retreat" behaviors about entering a goal box associated with cocaine delivery). Ranked scores from these two tests were then correlated with each other and with the escalation in the operant responding of the same subjects observed over 10 days of 1- or 6-h/day access to i.v. (0.4 mg/inj) cocaine self-administration.

Results: Larger place preferences were associated with faster runway start latencies (r s = -0.64), but not with retreat frequency or run times; larger place aversions predicted slower runway start times (r s = 0.62), increased run times (r s = 0.65), and increased retreats (r s = 0.62); response escalation was observed in both the 1- and 6-h self-administration groups and was associated with increased CPPs (r s = 0.58) but not CPAs, as well as with faster run times (r s = -0.60).

Conclusions: Together, these data suggest that animals exhibiting a greater positive than negative response to acute (single daily injections of) cocaine are at the greatest risk for subsequent escalated cocaine self-administration, a presumed indicator of cocaine addiction.

Keywords: Cocaine; Cocaine addiction; Conditioned place test; Drug abuse; Drug aversion; Drug reward; Drug self-administration; Extended access; Operant runway; Opponent processes.

Figure 1

Schematic representation of the experimental protocol depicting the order of events, dependent measures, and group designations in each of three tests conducted sequentially: the place conditioning, runway, then self-administration test.

Figure 2

Mean (±SEM) Difference Scores (time spent in the cocaine-paired environment on test day minus the time spent there prior to conditioning). The score above the X-axis reflects a shift toward the side associated with cocaine (a conditioned place preference; CPP) while the score below the line represents avoidance of the cocaine-paired environment (conditioned place aversions; CPA). Each group’s mean difference score was significantly different from “0” (+ p<.002; # p<.05). The two groups also performed differentially from one another (**p<.0.01).

Figure 3

Mean (+SEM) Start Latency, Run Time and Retreat Frequency on the first (white bars) and final (dark bars) trial for rats running a straight alley for single daily injections of i.v. cocaine. Separate repeated measures t-tests confirmed changes in performance over the course of testing. *p<.05, **p<.01.

Figure 4

Mean (±SEM) earned cocaine infusions/trial for the 6-hr (top) and 1-hr (bottom) groups over the course of a 10-day test self-administration period. While both groups exhibited statistically reliable increases in responding over trials (1-h group, p<.01; 6-h group, p<.0003) the average rate of rise in responding (i.e., the average slope of the response curves) was greater in the 6-h than 1-h group (p<.001).

Figure 5

Mean (±SEM) number of earned cocaine infusions during the first and last trial/day for the 1-h and 6-h self-administration groups. The four bars to the left reflect reinforced responding during the first hour of testing while the two bars to the right show the change in responding over the entire 6-h session for the extended-access group alone. *p<.05, **p<.01

Figure 6

Spearman rank-order correlations between measures in the Conditioned Place Test and the Runway Test. CPP = conditioned place preference; CPA = conditioned place aversion. Animals with the numerically lowest CPP/CPA ranks (e.g., ranks 1 or 2) exhibited the smallest preferences or aversions; higher ranked animals (e.g. ranks of 9 or 10) exhibited larger preferences or aversions. Animals with numerically lower ranks for start latency had shorter (faster) mean response initiation times over the course of runway testing, while those with higher ranks exhibited longer (slower) start times. Subjects with numerically lower ranked retreat frequencies exhibited fewer retreats than those with higher ranks. For Run Times, subjects with lower ranks entered the goal box sooner (shorter run times) than animals with higher ranks (longer run times). The correlations show that larger CPPs were associated with faster start times but not with retreat frequency or run time, while larger CPAs were associated with slower start times, longer run times, and greater retreat frequency. *p<.05

Figure 7

Spearman rank-order correlations between Run Times and Retreat Frequency in the runway. Animals that emitted the most retreats before entering the goal box tended to record longer Run Times (i.e., took longer to enter the goal box). Open circles identify subjects in the 6-hr self-administration group; closed circles identify subjects in the 1-hr group. *p<.05

Figure 8

Spearman rank-order correlations computed on the response escalation of subjects in the Self-administration test (based on their ranked percentage increase in reinforced responding from Trial 1 of Trial 10) and their ranked scores in the Conditioned Place Preference (CPP) test (top left), the Conditioned Place Aversion (CPA) test (top right), the frequency of retreats exhibited in the Runway Test (bottom left), and their average run-times in the Runway test (bottom right). Animals with the numerically lower CPP/CPA ranks exhibited the smallest preferences or aversions; higher ranked animals exhibited larger preferences or aversions. Animals with numerically lower ranks for retreat frequency exhibited fewer retreats than those with higher ranks, while for Run Times, subjects with lower ranks entered the goal box sooner (shorter run times) than animals with higher ranks (longer run times). Larger CPPs, but not CPAs, were associated with a greater escalation in self-administration responding. In the runway test, escalations in self-administration responding were associated with shorter run-times and marginally fewer retreats (p=0.051). Open circles identify subjects in the 6-hr self-administration group; closed circles identify subjects in the 1-hr group. *p<.05