Inhibition of a cortico-thalamic circuit attenuates cue-induced reinstatement of drug-seeking behavior in “relapse prone” male rats

Abstract

Rationale Relapse often occurs when individuals are exposed to stimuli or cues previously associated with the drug-taking experience. The ability of drug cues to trigger relapse is believed to be a consequence of incentive salience attribution, a process by which the incentive value of reward is transferred to the reward-paired cue. Sign-tracker (ST) rats that attribute enhanced incentive value to reward cues are more prone to relapse compared to goal-tracker (GT) rats that primarily attribute predictive value to such cues. Objectives The neurobiological mechanisms underlying this individual variation in relapse propensity remains largely unexplored. The paraventricular nucleus of the thalamus (PVT) has been identified as a critical node in the regulation of cue-elicited behaviors in STs and GTs, including cue-induced reinstatement of drug-seeking behavior. Here we used a chemogenetic approach to assess whether "top-down" cortical input from the prelimbic cortex (PrL) to the PVT plays a role in mediating individual differences in relapse propensity. Results Chemogenetic inhibition of the PrL-PVT pathway selectively decreased cue-induced reinstatement of drug-seeking behavior in STs, without affecting behavior in GTs. In contrast, cocaine-primed drug-seeking behavior was not affected in either phenotype. Furthermore, when rats were characterized based on a different behavioral phenotype-locomotor response to novelty-inhibition of the PrL-PVT pathway had no effect on either cue-or drug-induced reinstatement. Conclusions These results highlight an important role for the PrL-PVT pathway in vulnerability to relapse that is consequent to individual differences in the propensity to attribute incentive salience to discrete reward cues.

Biological sex influences the contribution of sign-tracking and anxiety-like behavior toward remifentanil self-administration.

“…STs and goal-trackers (GTs) of either sex did not differ in their self-administration of remifentanil under a low/no shock FR1 schedule (reported in males by Chang et al, 2022). Furthermore, we did not find that STs were any more prone to cue-induced reinstatement than GTs, which (at least in males) is in contrast to the increased reinstatement in GTs seen with cocaine (Kuhn et al, 2022; Saunders & Robinson, 2011; Saunders et al, 2013b). However, our finding that tendency to attribute incentive value to reward cues is not associated with cue-induced reinstatement of opioid seeking is not without precedent, as other groups have published corroborating reports (Chang et al, 2022; Martin et al, 2022a).…”

Biological Sex Influences the Contribution of Sign-Tracking and Anxiety-Like Behaviour toward Remifentanil Self-Administration

“…Sign-trackers (STs) and goal-trackers (GTs) of either sex did not differ in their self-administration of remifentanil under a low/no shock FR1 schedule (reported in males by (Chang et al, 2022)). Furthermore, we did not find that STs were any more prone to cue-induced reinstatement than GTs, which (at least in males) is in contrast to the increased reinstatement in GTs seen with cocaine (Kuhn et al, 2022; Saunders & Robinson, 2011; Saunders et al, 2013b). However, our finding that tendency to attribute incentive value to reward cues is not associated with cue-induced reinstatement of opioid seeking is not without precedent, as other groups have published corroborating reports (Chang et al, 2022; Martin et al, 2022a).…”

Optogenetic stimulation of infralimbic cortex projections to the paraventricular thalamus attenuates context‐induced renewal

“…Moreover, silencing PL inputs to the pPVT attenuates cue‐induced reinstatement of cocaine seeking (Giannotti et al, 2018). Furthermore, silencing PL inputs to both the aPVT and the middle‐to‐posterior PVT attenuates cue‐induced reinstatement of cocaine seeking in sign trackers but not in goal trackers (Kuhn et al, 2021). However, silencing PL inputs to the pPVT has been shown to have no effect on cue‐induced reinstatement of operant sucrose seeking (Giannotti et al, 2018).…”

“…In rats, specific inhibition of PL inputs to the pPVT attenuates cue‐induced reinstatement of cocaine seeking (Giannotti et al, 2018). Moreover, inhibition of PL inputs to both the aPVT and the middle‐to‐posterior PVT attenuates cue‐induced reinstatement of cocaine seeking in sign tracker but not in goal‐tracker rats (Kuhn et al, 2021). Together, these findings support the role of PL projections to the PVT in driving the expression of drug seeking after extinction and suggest that this pathway may be particularly important for promoting drug seeking in rats with a propensity to attribute incentive salience to drug cues.…”