High-novelty-preference rats are predisposed to compulsive cocaine self-administration

Abstract

Sensation/novelty-seeking is amongst the best markers of cocaine addiction in humans. However, its implication in the vulnerability to cocaine addiction is still a matter of debate, as it is unclear whether this trait precedes or follows the development of addiction. Sensation/novelty-seeking trait has been identified in rats on the basis of either novelty-induced locomotor activity (high-responder (HR) trait) or novelty-induced place preference (high-novelty-preference trait (HNP)). HR and HNP traits have been associated with differential sensitivity to psychostimulants. However, it has recently been demonstrated that HR rats do not develop compulsive cocaine self-administration (SA) after protracted exposure to the drug, thereby suggesting that at least one dimension of sensation/novelty seeking in the rat is dissociable from the vulnerability to switch from controlled to compulsive cocaine SA. We therefore investigated whether HNP, as measured as the propensity to choose a new environment in a free choice procedure, as opposed to novelty-induced locomotor activity, predicts the vulnerability to, and the severity of, addiction-like behavior for cocaine. For this, we identified HR/LR rats and HNP/LNP rats before any exposure to cocaine. After 60 days of cocaine SA, each rat was given an addiction score based on three addiction-like behaviors (persistence of responding when the drug is signaled as not available, high breakpoint under progressive ratio schedule and resistance to punishment) that resemble the clinical features of drug addiction, namely inability to refrain from drug seeking, high motivation for the drug and compulsive drug use despite adverse consequences. We show that, as opposed to HR rats, HNP rats represent a sub-population predisposed to compulsive cocaine intake, displaying higher addiction scores than LNP rats. This study thereby provides new insights into the factors predisposing to cocaine addiction, supporting the hypothesis that addiction is sustained by two vulnerable phenotypes: a 'drug use prone' phenotype such as HR which brings an individual to develop drug use and an 'addiction prone' phenotype, such as HNP, which facilitates the shift from sustained to compulsive drug intake and addiction.

Figure 1

Novelty-induced locomotor activity and novelty preference are unrelated behavioral traits. (a) High-responder rats (HR, n=10) displayed greater locomotor activity than low-responder rats (LR, n=10) throughout a 2 h exposure to a novel inescapable environment. (b) However, LR and HR rats did not differ in their novelty seeking when given the opportunity to choose between a familiar and a novel compartment, as they spend the same percentage of time in the new compartment. (c) High-novelty-preference rats (HNP, n=10) spent more time in the new compartment than low-novelty-preference rats (LNP, n=10). (d) However, HNP and LNP rats did not differ in their locomotor response to a novel inescapable environment.

Figure 2

A sub-population of rats develops addiction-like behavior after chronic exposure to cocaine self-administration. a–c Representation of the distribution of each addiction-like criterion. Data are represented as frequencies of observations for each range of score. The whole population (n=40) was log-normal distributed for both motivation for cocaine (measured by the breakpoint during a progressive ratio session; a) and inability to refrain from cocaine seeking when it was not available and signaled as so (non-reinforced active nose-pokes; b). However, resistance to punishment (maintenance of drug use and drug seeking despite contingent electric foot-shocks as measured by self-infusions as a percentage of baseline) was best characterized by a bimodal distribution, with a specific normal subpopulation, on the right side of the general distribution, prone to compulsive cocaine intake (c; see Table 1 for more details). (d) Addiction scores of 0crit (addiction resistant rats), 1crit, 2crit and 3crit (addicted) rats. After 60 days of cocaine SA, 0, 1, 2 and 3 addiction-like criteria rats were identified and their addiction score was computed from their respective scores in each of the addiction-like criteria. 3crit rats (n=6) were the only group whose score was above the standard deviation (2.49) and 0crit, addiction resilient, rats (n=16) were the only group with negative scores.

Figure 3

Novelty preference, but not locomotor reactivity to novelty, predicts the development of cocaine addiction-like behavior. Not only did high-novelty-preference (HNP) rats show higher addiction score than low-novelty-preference (LNP) rats (a) but they scored higher on each of the three addiction-like criteria, namely motivation for cocaine (measured by the breakpoint during a progressive ratio session; b) and inability to stop seeking cocaine when it was not available and signaled as so (non-reinforced active nose-pokes; c) and resistance to punishment (maintenance of drug use and drug seeking despite contingent electric foot-shocks; d), compared with LNP rats, HNP rats even showed a progressive development of this inability to refrain from drug seeking over time that has been previously described for 3crit addicted rats (e). These behavioral differences between HNP and LNP rats could not be attributable to differential cocaine intake, as the two groups have been exposed to the same amount of cocaine throughout the experiment (f). When compared with low-responder (LR) rats, high-responder (HR) rats showed no difference in the addiction-like behavioral measures, thereby illustrating that locomotor reactivity to novelty, as opposed to novelty preference, does not predict addiction-like behavior for cocaine.

Figure 4

Dimensional analysis of the theoretical relationships between addiction-like behavior, novelty preference and locomotor reactivity to novelty in the rat. A principal component analysis, with the addiction score, the percentage of time spent in the new compartment of a novelty-induced place preference procedure and the total photocell beam breaks in a 2 h novelty-induced locomotor activity session as variables, revealed two factors explaining 77% of the total variance of the model. The first factor, which accounts for 46% of the model, represents the novelty preference/addiction dimension, as the variables used for these two constructs load heavily (>70%) on this factor. However, factor 2, which is orthogonal to the first one, represents the dimension relative to reactivity to novelty, as its representative variable, ie, novelty-induced locomotor activity loads (85%) almost alone on this factor.