Role of preexisting inhibitory control deficits vs. drug use history in mediating insensitivity to aversive consequences in a rat model of polysubstance use

Abstract

Rationale The nature and predictors of insensitivity to aversive consequences of heroin + cocaine polysubstance use are not well characterized. Objectives Translational methods incorporating a tightly controlled animal model of drug self-administration and measures of inhibitory control and avoidance behavior might be helpful for clarifying this issue. Methods The key approach for distinguishing potential contributions of pre-existing inhibitory control deficits vs. drug use history in meditating insensitivity to aversive consequences was comparison of two rat strains: Wistar (WIS/Crl), an outbred strain, and the spontaneously hypertensive rat (SHR/NCrl), an inbred strain shown previously to exhibit heightened cocaine and heroin self-administration and poor inhibitory control relative to WIS/Crl. Results In separate tasks, SHR/NCrl displayed greater impulsive action and compulsive-like behavior than WIS/Crl prior to drug exposure. Under two different schedules of drug delivery, SHR/NCrl self-administered more cocaine than WIS/Crl, but self-administered a similar amount of heroin + cocaine as WIS/Crl. When half the session cycles were punished by random foot shock, SHR/NCrl initially were less sensitive to punishment than WIS/Crl when self-administering cocaine, but were similarly insensitive to punishment when self-administering heroin + cocaine. Based on correlation analyses, only trait impulsivity predicted avoidance capacity in rats self-administering cocaine and receiving yoked-saline. In contrast, only amount of drug use predicted avoidance capacity in rats self-administering heroin + cocaine. Additionally, baseline drug seeking and taking predicted punishment insensitivity in rats self-administering cocaine or heroin + cocaine. Conclusions Based on the findings revealed in this animal model, human laboratory research concerning the nature and predictors of insensitivity to aversive consequences in heroin and cocaine polysubstance vs. monosubstance users is warranted. Supplementary Information The online version contains supplementary material available at 10.1007/s00213-022-06134-4.

Repeated Cocaine Intake Differentially Impacts Striatal D2/3 Receptor Availability, Psychostimulant-Induced Dopamine Release, and Trait Behavioral Markers of Drug Abuse

“…Although there are conflicting studies concerning the predictive value of impulsivity and novelty-seeking on drug abuse, and how these traits are impacted by drug exposure, our findings align with previous studies [17,31,32] which show that both behavioral traits predict higher rates of cocaine intake, even though novelty-seeking can also result from drug use in low novelty-seekers. Unlike novelty-seeking, impulsivity was not affected following cocaine exposure, regardless of the baseline levels of impulsivity.…”

“…Studies performed in rodents to disambiguate whether impulsivity and novelty-seeking are causes or consequences of drug abuse have produced mixed results. Rats with high impulsivity, as identified by enhanced premature responding during behavioral inhibition tasks, exhibit increased rates of cocaine [16,17], nicotine [18], and alcohol [19] self-administration (SA), indicating that impulsive actions predics drug intake, although other studies failed to replicate this finding [20][21][22][23][24]. Moreover, the effect of drug exposure on impulsive action in rodents is unclear, with some studies showing either no alteration [25][26][27] or a worsening [24,[28][29][30] in impulsivity.…”

Neural signatures of opioid-induced risk-taking behavior in the prelimbic prefrontal cortex

“…In our experiments, conditioning with opioid drugs (morphine or fentanyl) led to the formation of contextual reward memory and subsequent risk-taking behavior. These results resemble those from prior rodent studies using opioid self-administration punished by electrical footshocks, which reported near complete suppression of opioid seeking as a function of footshock intensity [6,7,[10][11][12][13][14][15]19]. However, similar studies have reported either incomplete suppression of opioid seeking or divergent behavioral responses that resulted in subgroups of either punishment-sensitive or punishment-resistant animals [8,9].…”

“…To investigate potential causality between opioid use and increased risky decision making, prior studies have attempted to model risky opioid use in laboratory animals. Results have shown that rodents will continue to seek opioids even when they must risk the threat of painful stimuli (e.g., electrical footshocks) to do so [6][7][8][9][10][11][12][13]. Other studies have made further attempts to model the use of opioids in a risky context by introducing an electrified barrier that animals had to cross to obtain the drug [14][15][16][17][18][19].…”

Nicotine but not saline self-administering or yoked control conditions produces sustained neuroadaptations in the accumbens shell

“…A widely-used procedure for demonstrating specificity of effect during drug self-administration sessions is to include a yoked control condition that passively receives either the psychoactive drug or saline ( Lecca et al, 2007 ; Mathieson et al, 2022 ). Generally, a yoked-saline design is used as a control when assessing for the pharmacological effects of nicotine and possible neuroadaptations elicited by the drug ( Palmatier et al, 2007 ; Gipson et al, 2013b ; Pittenger et al, 2018 ; Jin et al, 2020 ).…”