Less is more: prolonged intermittent access cocaine self-administration produces incentive-sensitization and addiction-like behavior

Abstract

Rationale Contemporary animal models of cocaine addiction focus on increasing the amount of drug consumption to produce addiction-like behavior. However, another critical factor is the temporal pattern of consumption, which in humans is characterized by intermittency, both within and between bouts of use. Objective To model this we combined prolonged access to cocaine (~70 days in total) with an intermittent access self-administration procedure (IntA), and used behavioral-economic indicators to quantify changes in motivation for cocaine. Results IntA produced escalation of intake, a progressive increase in cocaine demand (incentive-sensitization), and robust drug- and cue-induced reinstatement of drug-seeking behavior. We also asked whether rats that vary in their propensity to attribute incentive salience to reward cues (sign-trackers, STs vs. goal-trackers, GTs) vary in the development of addiction-like behavior. Although STs were more motivated to take cocaine after limited drug experience, after IntA, STs and GTs no longer differed on any measure of addiction-like behavior. Conclusions Exposure to large quantities of cocaine is not necessary for escalation of intake, incentive-sensitization or other addiction-like behaviors (IntA results in far less total cocaine consumption than ‘long access’ procedures). Also, the ST phenotype may increase susceptibility to addiction, not because STs are inherently susceptible to incentive-sensitization (perhaps all individuals are at risk), but because this phenotype promotes continued drug use, subjecting them to incentive-sensitization. Thus, the pharmacokinetics associated with the IntA procedure is especially effective in producing a number of addiction-like behaviors, may be valuable for studying associated neuroadaptations, and for assessing individual variation in vulnerability.

Transient inactivation of the paraventricular nucleus of the thalamus enhances cue-induced reinstatement in goal-trackers, but not sign-trackers

“…6d). These data further highlight the notion that GTs and STs capture different forms of reward learning, both of which may be relevant to addiction liability (Saunders and Robinson 2010, Saunders et al 2013, Saunders et al 2014, Kawa et al 2016, Pitchers et al 2017), and both of which appear to be mediated by the PVT (Haight and Flagel 2014, Haight et al 2015, Haight et al 2017). …”

“…In contrast, for STs, a faster decrease in responding during extinction resulted in fewer pokes into the active port during reinstatement. This differential relationship between the rate of extinction and subsequent cue-induced drug-seeking behavior in GTs and STs has not been previously reported, but further highlights the distinct learning mechanisms that may underlie different forms of addiction liability in these two phenotypes (Saunders and Robinson 2010, Saunders et al 2013, Saunders et al 2014, Kawa et al 2016, Pitchers et al 2017). Moreover, the fact that these relationships were obscured in both phenotypes following inactivation of the PVT suggests that this nucleus is important for linking prior experiences with subsequent behavior, and does so via its differential role in the learning mechanisms underlying individual variation in cue-motivated behaviors (Haight and Flagel 2014, Haight et al 2015, Haight et al 2017).…”

“…For example, rats that sign-track to food-associated cues do the same to cues associated with drugs of abuse, including cocaine and opioids (Yager et al 2013, Yager et al 2015). In addition, relative to GTs, STs are more impulsive (Flagel et al 2010, Lovic et al 2011), have higher cocaine break-points (Saunders et al 2011), and are more susceptible to cue-induced reinstatement of drug-seeking behavior (Saunders et al 2010, Saunders et al 2013, see also Kawa et al 2016). Thus, the sign-tracker/goal-tracker animal model supports the long-standing notion that Pavlovian incentive learning processes are critical to drug-motivated behaviors (Bolles 1972, Bindra 1978, Toates 1981, Stewart et al 1984, Robinson and Berridge 1993).…”

The neuroscience of cognitive-motivational styles: Sign- and goal-trackers as animal models.

“…Given that STs have been demonstrated to be vulnerable for addiction-like behaviors (see also Kawa, Bentzley, & Robinson, 2016), our initial experiments on the attentional capacities of STs and GTs were guided by the hypothesis that STs exhibit a relatively weak degree of top-down attentional control when compared with GTs, and this relative “deficit” would render them to be inordinately attracted to drug-associated cues.…”

Adolescent cocaine exposure enhances goal-tracking behavior and impairs hippocampal cell genesis selectively in adult bred low-responder rats

“…These unexpected results may indeed be due to inherent predispositions in the selectively-bred rat lines, as discussed above; yet, it should also be noted that recent data suggests that sign- and goal-trackers may be equally susceptible to addiction (Kawa et al 2016), but via different (genetic and neural) pathways. Thus, while sign-trackers are more responsive to discrete drug-associated cues (Flagel et al 2011; Yager et al 2014) and more likely to exhibit cue- and drug-induced reinstatement of drug-seeking behavior relative to goal-trackers (Saunders and Robinson 2010, 2011) after relatively brief periods of cocaine self-administration, both phenotypes exhibit addiction-related behaviors following prolonged intermittent access to cocaine (Kawa et al 2016). In addition, goal-trackers have been shown to exhibit enhanced reinstatement of drug-seeking behavior in response to drug-associated contexts (Saunders et al 2014).…”