A Neuronal Ensemble in the Rostral Agranular Insula Tracks Cocaine-Induced Devaluation of Natural Reward and Predicts Cocaine Seeking

Abstract

In substance use disorders, negative affect associated with drug withdrawal can elicit strong drug craving and promote relapse. One brain region implicated in those processes is the rostral agranular insular cortex (RAIC), although precisely how this region encodes negative affect associated with drug seeking is unknown. Here, a preclinical model was used where RAIC activity was examined in male Sprague Dawley rats during intraoral infusions of a sweet (saccharin) paired with impending but delayed access to cocaine self-administration, and for comparative purposes, during the sweet predicting saline self-administration or injection of lithium chloride (LiCl), or during intraoral infusions of a bitter taste (quinine). Consistent with previous work, cocaine-paired saccharin, LiCl-paired saccharin, and quinine all elicited aversive taste reactivity. However, the aversive taste reactivity elicited by the cocaine-paired tastant was qualitatively different from that evoked by the other two agents. Furthermore, differences in taste reactivity were reflected in RAIC cell firing, where distinct shifts in neural signaling were observed specifically after cocaine but not LiCl conditioning. Notably, low motivation for cocaine (indicated by low loading and slower latencies to lever press) was correlated with this shift in RAIC signaling, but aversive (gaping) responses were not. Collectively, these findings indicate that cocaine-paired tastants elicit unique aspects of aversive behaviors that differ from traditional conditioned taste aversion (LiCl) or quinine and that the RAIC plays a role in modulating drug-seeking behaviors driven by drug-induced dysphoria (craving), but not negative affect per se. In substance use disorders, negative affect associated with drug cues can elicit craving and promote relapse; however, the underlying neurocircuitry of this phenomenon is unknown. Here, we investigated the role of the rostral agranular insula cortex (RAIC) in these processes using a preclinical model wherein intraoral delivery of a sweet is paired with delayed access to cocaine self-administration. The taste comes to elicit negative affect that predicts heightened drug seeking. Here, we found that a population of RAIC neurons became inhibited during presentation of the cocaine-paired tastant (when negative affect is high) and that this inhibitory neural profile predicted lower drug seeking. These findings suggest that the RAIC may function to oppose cue-induced cocaine craving and help reduce motivation for the drug.

Postretrieval Microinjection of Baclofen Into the Agranular Insular Cortex Inhibits Morphine-Induced CPP by Disrupting Reconsolidation

“…The AI is the main output domain of the IC, which can send projections to the amygdalo-frontostriatal circuitry (critical in drug addiction) and receive inputs from the polysensory regions of the GI and the adjacent DI (Shi and Cassell, 1998;Gabbott et al, 2003;Reynolds and Zahm, 2005;Kimura et al, 2010;Contreras et al, 2012). From the perspective of nerve fiber connections between these regions, the AI is more likely to participate in behavioral addiction (Moschak et al, 2018). Moreover, it is an indispensable and ideal region that can influence hedonic, motivational, and executive cognitive information processing in relapse circuitry.…”

Prelimbic Cortical Neurons Track Preferred Reward Value and Reflect Impulsive Choice during Delay Discounting Behavior

“…Electrophysiological recordings. Electrophysiological procedures have been described in detail previously (Day et al, 2011;West et al, 2014;Moschak et al, 2018). Briefly, before the start of each session, the subject was connected to a flexible recording cable attached to a commutator (Med Associates), which allowed virtually unrestrained movement within the chamber.…”

Prior cocaine exposure increases firing to immediate reward while attenuating cue and context signals related to reward value in anterior insula

“…Traditionally, the insula has been described as an interoceptive center (Craig, 2010, 2002; Damasio et al, 2000; Naqvi and Bechara, 2010), but is also thought to contribute to functions related to reward processing and decision-making (Burke and Tobler, 2011; Droutman et al, 2015; Mesulam and Mufson, 1982; Ongur and Price, 2000; Preuschoff et al, 2008; Rogers-Carter and Christianson, 2019). Consistent with these functions, recent work has shown that firing in insula correlates to the anticipation and delivery of both positive and negative outcomes (Guillem et al, 2010; Jo and Jung, 2016; Kusumoto-Yoshida et al, 2015; Mizoguchi et al, 2015; Moschak et al, 2018; Samuelsen et al, 2012; Vincis et al, 2020; Wittmann et al, 2020). Here, we ask if outcome-related neural correlates in insula are disrupted by chronic cocaine-self administration in rats performing a reward-guided decision-making task.…”

“…Satiety, for example, reduces insula activity for both food (Livneh et al, 2017) and water (Livneh et al, 2020; Namboodiri and Stuber, 2020). Other work has shown that when a previously appetitive sucrose solution is paired with delayed (as opposed to immediate) access to cocaine, insula activity also seems to reflect the reduced preference of this once favorable reward, even though the sucrose itself has not changed (Moschak et al, 2018). Our work expands on these studies by demonstrating signals in the insula related to cues, context, and differently valued rewards, and how chronic cocaine exposure profoundly affects insula activity in reward-guided decision-making.…”