Responses to novelty and vulnerability to cocaine addiction: contribution of a multi-symptomatic animal model

Abstract

Epidemiological studies have revealed striking associations between several distinct behavioral/personality traits and drug addiction, with a large emphasis on the sensation-seeking trait and the associated impulsive dimension of personality. However, in human studies, it is difficult to identify whether personality/behavioral traits actually contribute to increased vulnerability to drug addiction or reflect psychobiological adaptations to chronic drug exposure. Here we show how animal models, including the first multi-symptomatic model of addiction in the rat, have contributed to a better understanding of the relationships between different subdimensions of the sensation-seeking trait and different stages of the development of cocaine addiction, from vulnerability to initiation of cocaine self-administration to the transition to compulsive drug intake. We argue that sensation seeking predicts vulnerability to use cocaine, whereas novelty seeking, akin to high impulsivity, predicts instead vulnerability to shift from controlled to compulsive cocaine use, that is, addiction.

Figure 1.

Progressive ratio schedule of reinforcement. The progressive ratio schedule of reinforcement used in the present model is more behaviorally demanding than the ones classically used (Richardson and Roberts 1996). (Left panel) Various PR series, with j = 0.2 being the most extensively used one. As illustrated in the middle (ratio requirement) and right (cumulative responses) panels, the progressive ratio schedule of cocaine reinforcement used in the present model is far more behaviorally demanding than the classically used ones. Thus, whereas the 15th infusion requires 225 lever presses in the j = 0.2 procedure, it requires 515 lever presses for 2870 cumulative responses in the current model.

Figure 2.

Punishment schedule. The schedule is the following: As for basal training sessions, an animal earns a cocaine infusion after completion of an FR5. However, the first instrumental response leads to the illumination of a green cue light signaling the presence of the shock. When an FR4 is completed within 5 min, rats receive an electric shock (0.4 mA, 2 sec); if not, the sequence is reinitialized. When FR5 is reached within a minute, rats receive an electric shock (0.4 mA, 2 sec) and then a cocaine infusion paired with its conditioned stimulus (CS). Then the shock-paired stimulus turns off. The schedule can reinitiate at the end of the time-out period, that is, 40 sec after the infusion. If, within a minute, animals do not complete the fifth lever press of the FR5 sequence, leading to the shock–cocaine presentation, the shock-associated stimulus turns off and the sequence is reinitiated.

Figure 3.

Selection strategy of 3crit and 0crit rats. A dichotomous approach to the diagnosis of addiction-like behavior can be implemented in preclinical models of addiction on the understanding that some, but not all, animals chronically exposed to drug self-administration eventually develop one or more behavioral features resembling a clinical criterion for drug addiction as defined in the DSM-IV. Thus, we have operationally defined three addiction-like criteria, namely, (A) increased motivation to take the drug, (B) an inability to refrain from drug seeking, and (C) maintained drug use despite aversive consequences. For each of the three addiction-like criteria, animals are ranked according to their score. If a rat’s score is included in the 30%–40% highest percentile of the distribution, this rat is considered positive for that addiction-like criterion and is given an arbitrary criterion score of 1. Then the arbitrary criteria scores for each of the three addiction-like criteria are added, and consequently four distinct groups are identified according to the number of positive scores: 0-criteria, 1-criterion, 2-criteria, and 3-criteria rats. (Data analyzed from Deroche-Gamonet et al. 2004.)

Figure 4.

Behavioral characteristics associated with an addiction-like behavior. According to the selection strategy, rats positive for none of the 3 criteria (0crit rats) show low scores in the three addiction-like criteria, namely, (A) increased motivation to take the drug, (B) an inability to refrain from drug seeking, and (C) maintained drug use despite aversive consequences; whereas rats positive for the three addiction-like criteria (3crit rats) show the highest scores. 0crit rats are resistant to addiction, whereas 3crit rats are considered “addicted” and represent 15%–20% of the population initially exposed to cocaine (E). Importantly, scores in each of the three addiction-like criteria are linearly related to the number of positive criteria met (A–C). A similar picture is observed for the addiction score (D), calculated as the sum of the normalized scores in the three criteria. Importantly, the behavioral differences between 0crit and 3crit rats are not attributable to differential levels of cocaine intake, because throughout protracted exposure, 3crit and 0crit rats do not differ in this measure (F). Although selected on three addiction-like criteria, 3crit rats display complementary features of drug addiction, such as the inability to limit drug intake when offered extended access to cocaine (G) and high vulnerability to relapse, as measured by reinstatement of cocaine seeking behavior by increasing doses of noncontingent cocaine infusions (H). (Panels A–C and E–H are adapted from Deroche-Gamonet et al. 2004; reprinted, with permission, from the author. Panel D is adapted from Belin et al. 2009a; reprinted, with permission, from the author.)

Figure 5.

High novelty preference rats display all of the behavioral features of addiction-like behavior for cocaine. (A) HNP rats show higher addiction score than LNP rats. (B–D) HNP rats also scored higher on each of the three addiction-like criteria, namely, motivation for cocaine, inability to refrain from drug seeking, and maintained drug use despite aversive consequences. In marked contrast, HR rats differed from LR rats in none of these behavioral measures. (E) In contrast to the HR/LR trait, HNP rats, with or without overlapping HR or LR phenotype (HNP-LR or HNP-HR), are heavily clustered in the compulsive subpopulation of the bimodal distribution of maintained drug use despite aversive consequences, that is, compulsive cocaine self-administration. (Panels B–D adapted from Belin et al. 2011; reprinted, with permission, from the author.)