Punishment resistance for cocaine is associated with inflexible habits in rats.

Addiction is characterized by continued drug use despite negative consequences. In an animal model, a subset of rats continues to self-administer cocaine despite footshock consequences, showing punishment resistance. We sought to test the hypothesis that punishment resistance arises from failure to exert goal-directed control over habitual cocaine seeking. While habits are not inherently permanent or maladaptive, continued use of habits under conditions that should encourage goal-directed control makes them maladaptive and inflexible. We trained male and female Sprague Dawley rats on a seeking-taking chained schedule of cocaine self-administration. We then exposed them to four days of punishment testing in which footshock was delivered randomly on one-third of trials. Before and after punishment testing (four days pre-punishment and ≥ four days post-punishment), we assessed whether cocaine seeking was goal-directed or habitual using outcome devaluation via cocaine satiety. We found that punishment resistance was associated with continued use of habits, whereas punishment sensitivity was associated with increased goal-directed control. Although punishment resistance for cocaine was not predicted by habitual responding pre-punishment, it was associated with habitual responding post-punishment. In parallel studies of food self-administration, we similarly observed that punishment resistance was associated with habitual responding post-punishment but not pre-punishment in males, although it was associated with habitual responding both pre- and post-punishment in females, indicating that punishment resistance was predicted by habitual responding in food-seeking females. These findings indicate that punishment resistance is related to habits that have become inflexible and persist under conditions that should encourage a transition to goal-directed behavior.

Punishment resistance for cocaine is associated with inflexible habits in rats.

Addiction is characterized by continued drug use despite negative consequences. In an animal model, a subset of rats continues to self-administer cocaine despite footshock consequences, showing punishment resistance. We sought to test the hypothesis that punishment resistance arises from failure to exert goal-directed control over habitual cocaine seeking. While habits are not inherently permanent or maladaptive, continued use of habits under conditions that should encourage goal-directed control makes them maladaptive and inflexible. We trained male and female Sprague Dawley rats on a seeking-taking chained schedule of cocaine self-administration (2 h/day). We then exposed them to 4 days of punishment testing, in which footshock (0.4 mA, 0.3 s) was delivered randomly on one-third of trials, immediately following completion of seeking and prior to extension of the taking lever. Before and after punishment testing (4 days pre-punishment and ≥4 days post-punishment), we assessed whether cocaine seeking was goal-directed or habitual using outcome devaluation via cocaine satiety. We found that punishment resistance was associated with continued use of habits, whereas punishment sensitivity was associated with increased goal-directed control. Although punishment resistance was not predicted by habitual responding pre-punishment, it was associated with habitual responding post-punishment. In parallel studies of food self-administration, we similarly observed that punishment resistance was associated with habitual responding post-punishment but not pre-punishment. These findings indicate that punishment resistance is related to habits that have become inflexible and persist under conditions that should encourage a transition to goal-directed behavior.

Escalation of alcohol intake is associated with regionally decreased insular cortex activity but not changes in taste quality.

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.

Acute nicotine treatment enhances compulsive-like remifentanil self-administration that persists despite contextual punishment.

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.