Opioid use disorder (OUD) and opioid‐related deaths remain a significant public health crisis having reached epidemic status globally. OUDs are defined as chronic, relapsing conditions often characterized by compulsive drug seeking despite the deleterious consequences of drug taking. The use of nicotine‐containing products has been linked to increased likelihood of prescription opioid misuse, and there exists a significant comorbidity between habitual nicotine use and opioid dependence. In rodent models, nicotine administration nearly doubles the amount of opioids taken in intravenous self‐administration paradigms. Here, we examined the effect of acute systemic nicotine administration in male rats on responding for the synthetic opioid remifentanil (RMF) in a contextual punishment paradigm using either an exteroceptive punisher (foot‐shock) or an interoceptive punisher (histamine). Nicotine administration, relative to saline, increased RMF intake in both unpunished and punished contexts, regardless of form of punishment, and resulted in significantly higher motivation to obtain RMF in the previously punished context, as measured by progressive ratio breakpoint. Additionally, regardless of context, nicotine‐treated rats were slower to extinguish RMF responding following drug removal and displayed higher levels of cue‐induced reinstatement than saline‐treated controls. Furthermore, these data support that, compared with histamine adulteration, contingent foot‐shock is a more potent form of punishment, as histamine punishment failed to support contextual discrimination between the unpunished and punished contexts. In contrast to RMF administration, augmentation of responding for an audiovisual cue by nicotine pretreatment was lost following contextual punishment. In conclusion, acute nicotine administration in adult male rats significantly enhances compulsive‐like responding for RMF that persists despite contingent punishment of drug‐directed responding.

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Background Intermittent access to ethanol drives persistent escalation of intake and rapid transition from moderate to compulsive‐like drinking. Intermittent ethanol drinking may facilitate escalation of intake in part by altering aversion‐sensitive neural substrates, such as the insular cortex (IC), thus driving greater approach toward stimuli previously treated as aversive. Methods We conducted a series of experiments in rats to examine behavioral and neural responses associated with escalation of ethanol intake. First, taste reactivity analyses quantified the degree to which intermittent brief‐access ethanol exposure (BAEE) alters sensitivity to the aversive properties of ethanol. Next, we determined whether pharmacological IC inhibition facilitated ethanol escalation. Finally, given that the IC is primary gustatory cortex, we employed psychophysical paradigms to assess whether escalation of ethanol intake induced changes in ethanol taste. These paradigms measured changes in sensitivity to the intensity of ethanol taste and whether escalation in intake shifts the salient taste quality of ethanol by measuring the degree to which the taste of ethanol generalized to a sucrose‐like (“sweet”) or quinine‐like (“bitter”) percept. Results We found a near‐complete loss of aversive oromotor responses in ethanol‐exposed relative to ethanol‐naïve rats. Additionally, we observed significantly lower expression of ethanol‐induced c‐Fos expression in the posterior IC in exposed rats relative to naïve rats. Inhibition of the IC resulted in a modest, but statistically reliable increase in the acceptance of higher ethanol concentrations in naïve rats. Finally, we found no evidence of changes in the psychophysical assessment of the taste of ethanol in exposed, relative to naïve, rats. Conclusions Our results demonstrate that neural activity within the IC adapts following repeated presentations of ethanol in a manner that correlates with reduced sensitivity to the aversive hedonic properties of ethanol. These data help to establish that alterations in IC activity may be driving exposure‐induced escalations in ethanol intake.

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Background: Intermittent access to ethanol (EtOH) drives persistent escalation of intake and rapid transition from moderate to compulsive-like drinking. Intermittent EtOH drinking may facilitate escalation in part by altering aversion-sensitive neural substrates, such as the insular cortex (IC), thus driving greater approach toward stimuli previously treated as aversive. Methods: We conducted a series of experiments in rats to examine behavioral and neural responses associated with escalation of EtOH intake. First, taste reactivity analyses quantified the degree that intermittent brief-access ethanol exposure (BAEE) alters sensitivity to the aversive properties of EtOH. Next, we determined whether pharmacological IC inhibition facilitated EtOH escalation. Finally, given that IC is primary gustatory cortex, we employed psychophysical paradigms to assess whether escalation of EtOH intake induced changes in EtOH taste. These paradigms measured changes in sensitivity to the intensity of EtOH taste and whether escalation shifts the salient taste quality of EtOH by measuring the degree that the taste of EtOH generalized to a sucrose-like (sweet) or quinine-like (bitter) percept. Results: We found a near complete loss of aversive oromotor responses in EtOH-exposed relative to -naive rats. Additionally, we observed significantly reduced expression of EtOH-induced c-Fos expression in the posterior IC in exposed rats relative to naive rats. Inhibition of the IC resulted in a modest, but statistically reliable increase in acceptance of higher EtOH concentrations in naive rats. Finally, we found no evidence of changes in the psychophysical assessment of the taste of EtOH in exposed, relative to naive, rats. Conclusions: Our results demonstrate that neural activity within the IC adapts following escalation of EtOH intake in a manner that correlates with reduced sensitivity to the aversive hedonic properties of EtOH. These data further establish that IC may be driving exposure-induced escalations in EtOH intake and directly contributing to development of compulsive-like EtOH drinking.