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.

Genetic background and epigenetic modifications in the core of the nucleus accumbens predict addiction-like behavior in a rat model

“…The findings reported here are in contrast to those in outbred rats, for which there is no association between addiction liability and locomotor response to novelty (21,22,25,50). It is important to reiterate, however, that the bred lines exhibit differences in other traits that have been associated with addiction liability, including impulsivity (19), and these differences are not necessarily apparent in outbred LR/HR rats (22,23; see also ref.…”

“…One prominent example is a study demonstrating that the diagnostic criteria for addiction could be modeled in rats (25). With the emergence of this animal model of "addiction," it was reported that locomotor response to novelty-or "sensation-seeking" as measured in the rat-is not associated with addiction liability per se (21,25,50), but does remain a good predictor of the initial propensity to take drugs (22,51). Although the design of the present study did not permit phenotypic differences to emerge in the acquisition of drug-taking behavior as it is typically assessed (i.e.…”

Novel Cues Reinstate Cocaine-Seeking Behavior and Induce Fos Protein Expression as Effectively as Conditioned Cues

“…The rewarding properties of novelty have been documented in humans and animals (Bardo et al, 1989(Bardo et al, , 1996Besheer et al, 1999), and motivation for novelty predicts individual sensitivity to drug reward and reinforcement (Belin et al, 2011;Davis et al, 2008;Nadal et al, 2002;Pelloux et al, 2006;Piazza et al, 1989Piazza et al, , 2000Suto et al, 2001). We therefore suggest that the novel stimuli may have activated similar reinforcement and motivation processes as those involved in conditioned reinforcement-seeking behavior.…”

Toll-Like Receptor 4 Deficiency Causes Reduced Exploratory Behavior in Mice Under Approach-Avoidance Conflict

“…In addition, abnormal novelty-seeking behavior has been linked to many neuropsychiatric disorders. For example, high novelty-seekers are more susceptible to drugs of abuse than low novelty-seekers [51,52]. Reduced novelty-seeking is known to be associated with autism [6,7] and Alzheimer's disease [53].…”