Withdrawal from escalated cocaine self-administration impairs reversal learning by disrupting the effects of negative feedback on reward exploitation: a behavioral and computational analysis

Abstract

Addiction is regarded as a disorder of inflexible choice with behavior dominated by immediate positive rewards over longer-term negative outcomes. However, the psychological mechanisms underlying the effects of self-administered drugs on behavioral flexibility are not well understood. To investigate whether drug exposure causes asymmetric effects on positive and negative outcomes we used a reversal learning procedure to assess how reward contingencies are utilized to guide behavior in rats previously exposed to intravenous cocaine self-administration (SA). Twenty-four rats were screened for anxiety in an open field prior to acquisition of cocaine SA over six daily sessions with subsequent long-access cocaine SA for 7 days. Control rats (n = 24) were trained to lever-press for food under a yoked schedule of reinforcement. Higher rates of cocaine SA were predicted by increased anxiety and preceded impaired reversal learning, expressed by a decrease in lose-shift as opposed to win-stay probability. A model-free reinforcement learning algorithm revealed that rats with high, but not low cocaine escalation failed to exploit previous reward learning and were more likely to repeat the same response as the previous trial. Eight-day withdrawal from high cocaine escalation was associated, respectively, with increased and decreased dopamine receptor D2 (DRD2) and serotonin receptor 2C (HTR2C) expression in the ventral striatum compared with controls. Dopamine receptor D1 (DRD1) expression was also significantly reduced in the orbitofrontal cortex of high cocaine-escalating rats. These findings indicate that withdrawal from escalated cocaine SA disrupts how negative feedback is used to guide goal-directed behavior for natural reinforcers and that trait anxiety may be a latent variable underlying this interaction.

Unlocking the reinforcement-learning circuits of the orbitofrontal cortex.

“…Substance-dependent individuals have difficulties making adaptive decisions in dynamic environments (Ersche, Roiser, Robbins, & Sahakian, 2008; Fillmore & Rush, 2006; Ghahremani et al, 2011) and similar deficits have been observed in animals following exposure to drugs of abuse (Groman, Rich, Smith, Lee, & Taylor, 2018; Jentsch, Olausson, De La Garza, & Taylor, 2002; Schoenbaum, Saddoris, Ramus, Shaham, & Setlow, 2004; Zhukovsky et al, 2019) suggesting that the decision-making deficits observed in addicted individuals are, in part, a consequence of chronic exposure to drugs of abuse (Jentsch & Taylor, 1999; Lucantonio, Stalnaker, Shaham, Niv, & Schoenbaum, 2012; Schoenbaum, Roesch, & Stalnaker, 2006; Schoenbaum & Shaham, 2008). Recent studies in humans and animals have suggested that these deficits may be linked to abnormalities in the processing of negative outcomes.…”

“…Recent studies in humans and animals have suggested that these deficits may be linked to abnormalities in the processing of negative outcomes. Substance dependent individuals and rats with a history of drug self-administration appear insensitive to negative outcomes (Ersche et al, 2016; Groman et al, 2018; Zhukovsky et al, 2019), which may be related to the disruptions in negative prediction error signaling that have been observed in substance-dependent individuals (Parvaz et al, 2015; Tanabe et al, 2013).…”

Prior Cocaine Use Alters the Normal Evolution of Information Coding in Striatal Ensembles during Value-Guided Decision-Making

“…Within the laboratory setting, prior drug experience impairs the ability of subjects to adapt behavior following changes in reward contingencies. Rat (Jentsch and Taylor, 2001;Egerton et al, 2005;Stalnaker et al, 2009;Sokolic et al, 2011;McCracken and Grace, 2013;Zhukovsky et al, 2019), monkey (Jentsch et al, 2002;Wright et al, 2013;Seip-Cammack and Shapiro, 2014), and human studies have found that prior drug experience impairs reversal learning, resulting in marked perseveration following the switch (Fillmore and Rush, 2006;Verdejo-García et al, 2007;Ersche et al, 2008; but see Patzelt et al, 2014). Rodents previously exposed to drugs also fail to demonstrate proper contingency degradation or outcome devaluation, suggesting that drugs of abuse disrupt flexible value-based decision-making (Dickinson et al, 2002;Miles et al, 2003;Schoenbaum and Setlow, 2005;Nelson and Killcross, 2006;Corbit et al, 2014; but see Hogarth et al, 2019).…”

Investigating the computational underpinnings of addiction

“…The main finding of Zhukovsky et al [3] is that higher rates of escalation of cocaine-taking behaviors were associated in the reversal-learning task with an increase in the degree of exploration (e.g., β-inverse temperature parameter), and an increase in the probability of repeating an unrewarded choice following cocaine self-administration. In contrast, the probability that the rats would repeat a rewarded choice was not affected, indicating that higher rates of escalation in cocaine use was associated with a selective deficit in their ability to integrate negative outcomes into their choice.…”

“…In their recent Neuropsychopharmacology article, Zhukovsky and colleagues [3] used a computational approach to interrogate the reinforcement-learning mechanisms that are altered following cocaine self-administration in rats. Zhukovsky et al first trained rats on a two-choice, spatial discrimination task whereby responses in one of the two locations was reinforced with delivery of food pellet.…”