The impact of drugs of abuse on executive function: characterizing long-term changes in neural correlates following chronic drug exposure and withdrawal in rats

Abstract

Addiction has long been characterized by diminished executive function, control, and impulsivity management. In particular, these deficits often manifest themselves as impairments in reversal learning, delay discounting, and response inhibition. Understanding the neurobiological substrates of these behavioral deficits is of paramount importance to our understanding of addiction. Within the cycle of addiction, periods during and after withdrawal represent a particularly difficult point of intervention in that the negative physical symptoms associated with drug removal and drug craving increase the likelihood that the patient will relapse and return to drug use in order to abate these symptoms. Moreover, it is often during this time that drug induced deficits in executive function hinder the ability of the patient to refrain from drug use. Thus, it is necessary to understand the physiological and behavioral changes associated with withdrawal and drug craving-largely manifesting as deficits in executive control-to develop more effective treatment strategies. In this review, we address the long-term impact that drugs of abuse have on the behavioral and neural correlates that give rise to executive control as measured by reversal learning, delay discounting, and stop-signal tasks, focusing particularly on our work using rats as a model system.

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

“…Altogether, these results replicate previous findings that rats demonstrate a preference for higher-valued rewards through their choices and reaction times, and that responding is biased towards high-valued rewards in animals previously exposed to cocaine (Brockett et al, 2018; Burton et al, 2018b, 2017; Vázquez et al, 2019). Interestingly, in contrast to previous studies, we found that cocaine-exposed rats were overall more accurate on forced-choice trials ( Fig .…”

“…Notably, we have not observed these context signals in any other brain area that we have recorded from in rats performing this task (Brockett et al, 2018; Bryden et al, 2011; Burton et al, 2018b, 2017, 2015,2014b, 2014a; Kashtelyan et al, 2012; Roesch et al, 2007, 2006, 2012; Roesch and Bryden, 2011; Takahashi et al, 2017; Vázquez et al, 2019). Thus, context-related signals related to delay and size blocks appear to be unique to insula.…”

“…Further, encoding of more immediate delivery of reward was more prominent in cocaine-exposed rats. Overall, these results suggest that heightened reward responding and lower cue and context selectivity in insula may contribute to increased impulsivity and poor decision-making observed after chronic drug use (Brockett et al, 2018; Burton et al, 2018b; Mendez et al, 2010; Roesch et al, 2007; Simon et al, 2007; Vázquez et al, 2019).…”

“…We have shown across several studies that rats prefer immediate over delayed reward, and large over small reward, and that rats are overall more motivated during the ‘size’ block context (Burton et al, 2018b, 2017; Roesch et al, 2007; Roesch and Bryden, 2011; Vázquez et al, 2019). Further, we have shown that rats that had previously self-administered cocaine for two weeks are more sensitive to value manipulations and exhibit faster reaction times months after drug exposure (Brockett et al, 2018; Burton et al, 2018a, 2017; Vázquez et al, 2019).…”

Prior cocaine self-administration impairs attention signals in anterior cingulate cortex

“…Cocaine disrupts NAc's ability to encode reward predictions and expectancies during delays preceding reward delivery [23]. It also impairs signed prediction error signals generated by VTA-DA neurons, and alters encoding in DLS, in line with elevated response biases on free-choice trials [23,58]. We suspect that artificially stimulating ACC in cocaine-exposed rats will repair many of these problems, via mechanisms that focus neural resources to task events following expectancy violationsleading to better prediction and error encoding in both NAc and VTA-DA neurons, and stronger cognitive control over DLS.…”