Motor impulsivity but not risk-related impulsive choice is associated to drug intake and drug-primed relapse

Abstract

Introduction: Motor impulsivity and risk-related impulsive choice have been proposed as vulnerability factors for drug abuse, due to their high prevalence in drug abusers. However, how these two facets of impulsivity are associated to drug abuse remains unclear. Here, we investigated the predictive value of both motor impulsivity and risk-related impulsive choice on characteristics of drug abuse including initiation and maintenance of drug use, motivation for the drug, extinction of drug-seeking behavior following drug discontinuation and, finally, propensity to relapse.

Methods: We used the Roman High- (RHA) and Low- Avoidance (RLA) rat lines, which display innate phenotypical differences in motor impulsivity, risk-related impulsive choice, and propensity to self-administer drugs. Individual levels of motor impulsivity and risk-related impulsive choice were measured using the rat Gambling task. Then, rats were allowed to self-administer cocaine (0.3 mg/kg/infusion; 14 days) to evaluate acquisition and maintenance of cocaine self-administration, after which motivation for cocaine was assessed using a progressive ratio schedule of reinforcement. Subsequently, rats were tested for their resistance to extinction, followed by cue-induced and drug-primed reinstatement sessions to evaluate relapse. Finally, we evaluated the effect of the dopamine stabilizer aripiprazole on reinstatement of drug-seeking behaviors.

Results: We found that motor impulsivity and risk-related impulsive choice were positively correlated at baseline. Furthermore, innate high levels of motor impulsivity were associated with higher drug use and increased vulnerability to cocaine-primed reinstatement of drug-seeking. However, no relationships were observed between motor impulsivity and the motivation for the drug, extinction or cue-induced reinstatement of drug-seeking. High levels of risk-related impulsive choice were not associated to any aspects of drug abuse measured in our study. Additionally, aripiprazole similarly blocked cocaine-primed reinstatement of drug-seeking in both high- and low-impulsive animals, suggesting that aripiprazole acts as a D_2/3R antagonist to prevent relapse independently of the levels of impulsivity and propensity to self-administer drugs.

Discussion: Altogether, our study highlights motor impulsivity as an important predictive factor for drug abuse and drug-primed relapse. On the other hand, the involvement of risk-related impulsive choice as a risk factor for drug abuse appears to be limited.

Keywords: aripiprazole; cocaine; dopamine; drug abuse; motor impulsivity; risk-related impulsive choice; self-administration (SA).

FIGURE 1

Baseline performances in the rGT. Differences between RHA (n = 15) and RLA rats (n = 15) in the percentage of premature responses (A) and choice scores (B) averaged across 3 consecutive rGT sessions at baseline. (C) Proportions of RHA and RLA rats in the optimal (n = 22) and the non-optimal group (n = 8). Differences in choice scores (D) and premature responses (E) between optimal and non-optimal rats. (F) Negative correlation between choice scores and percentages of premature responding in the rGT. Data are represented as mean ± SEM; *p < 0.05, **p < 0.01, ****p < 0.0001.

FIGURE 2

Behavioral differences in the acquisition and maintenance of cocaine SA. Cumulative proportions of rats reaching the SA acquisition criterion, comparing RHA (n = 15) and RLA (n = 15) rats (A), and optimal (n = 22) and non-optimal (n = 8) rats (B). Number of cocaine infusions between RHA and RLA rats (C), and between optimal and non-optimal rats (D) over the 15 days of cocaine SA. Total number of active and inactive responses over the 15 sessions of cocaine SA in RHA vs. RLA rats (E), and in optimal vs. non-optimal rats (F). Data are represented as mean ± SEM. *p < 0.05.

FIGURE 3

Relationships between impulsive action, risk-related impulsive choice and maintenance of cocaine SA. Correlations between the average number of infusions over the 3 last days of cocaine SA and the percentage of premature responses (A) and the choice score (B). Correlations between the average number of total active responses over the 3 last days of cocaine SA and the percentage of premature responses (C) and the choice score (D). n = 15 RHA rats; n = 15 RLA rats.

FIGURE 4

Behavioral differences in motivation for cocaine. Differences between RHA (n = 14) and RLA rats (n = 14) in BP (A), and in the total number of active responses (B) during PR. Correlation between the BP and the percentage of premature responses (C). Differences between optimal (n = 20) and non-optimal rats (n = 8) in BP (D), and in the total number of active responses (E) during PR. Correlations between the breakpoint and the choice score in the rGT (F). Data are represented as mean (± SEM) of the average of 3 PR sessions for each rat.

FIGURE 5

Behavioral differences in extinction and reinstatement of drug seeking behavior. Differences between RHA (n = 14) and RLA (n = 14) rats (A) and between optimal (n = 20) and non-optimal (n = 8) rats (B) in the nose-pokes decay during extinction of cocaine-seeking following discontinuation of the drug. Differences in active responses following presentation of the drug-paired cue, a priming injection of cocaine, aripiprazole or both aripiprazole and cocaine, between RHA and RLA rats (C) or between optimal and non-optimal rats (D). Data are presented as the mean ± SEM of total active responses. **p < 0.01 RHA rats vs. RLA rats.