Abstinence-dependent dissociable central amygdala microcircuits control drug craving.

We recently reported that social choice-induced voluntary abstinence prevents incubation of methamphetamine craving in rats. This inhibitory effect was associated with activation of protein kinase-Cδ (PKCδ)-expressing neurons in central amygdala lateral division (CeL). In contrast, incubation of craving after forced abstinence was associated with activation of CeL-expressing somatostatin (SOM) neurons. Here we determined the causal role of CeL PKCδ and SOM in incubation using short-hairpin RNAs against PKCδ or SOM that we developed and validated. We injected two groups with shPKCδ or shCtrlPKCδ into CeL and trained them to lever press for social interaction (6 d) and then for methamphetamine infusions (12 d). We injected two other groups with shSOM or shCtrlSOM into CeL and trained them to lever press for methamphetamine infusions (12 d). We then assessed relapse to methamphetamine seeking after 1 and 15 abstinence days. Between tests, the rats underwent either social choice-induced abstinence (shPKCδ groups) or homecage forced abstinence (shSOM groups). After test day 15, we assessed PKCδ and SOM, Fos, and double-labeled expression in CeL and central amygdala medial division (CeM). shPKCδ CeL injections decreased Fos in CeL PKCδ-expressing neurons, increased Fos in CeM output neurons, and reversed the inhibitory effect of social choice-induced abstinence on incubated drug seeking on day 15. In contrast, shSOM CeL injections decreased Fos in CeL SOM-expressing neurons, decreased Fos in CeM output neurons, and decreased incubated drug seeking after 15 forced abstinence days. Our results identify dissociable central amygdala mechanisms of abstinence-dependent expression or inhibition of incubation of craving.

Cued for risk: Evidence for an incentive sensitization framework to explain the interplay between stress and anxiety, substance abuse, and reward uncertainty in disordered gambling behavior.

Gambling disorder is an impairing condition confounded by psychiatric co-morbidity, particularly with substance use and anxiety disorders. Yet, our knowledge of the mechanisms that cause these disorders to coalesce remains limited. The Incentive Sensitization Theory suggests that sensitization of neural "wanting" pathways, which attribute incentive salience to rewards and their cues, is responsible for the excessive desire for drugs and cue-triggered craving. The resulting hyper-reactivity of the "wanting' system is believed to heavily influence compulsive drug use and relapse. Notably, evidence for sensitization of the mesolimbic dopamine pathway has been seen across gambling and substance use, as well as anxiety and stress-related pathology, with stress playing a major role in relapse. Together, this evidence highlights a phenomenon known as cross-sensitization, whereby sensitization to stress, drugs, or gambling behaviors enhance the sensitivity and dopaminergic response to any of those stimuli. Here, we review the literature on how cue attraction and reward uncertainty may underlie gambling pathology, and examine how this framework may advance our understanding of co-mordidity with substance-use disorders (e.g., alcohol, nicotine) and anxiety disorders. We argue that reward uncertainty, as seen in slot machines and games of chance, increases dopaminergic activity in the mesolimbic pathway and enhances the incentive value of reward cues. We propose that incentive sensitization by reward uncertainty may interact with and predispose individuals to drug abuse and stress, creating a mechanism through which co-mordidity of these disorders may emerge.

Patient Experience of Head and Neck Surgery With Free Flap Reconstruction.

Importance: Major head and neck surgery with microvascular free tissue transfer reconstruction is complex, with considerable risk of morbidity. Little is known about patients' experiences, including decision-making prior to, and regret following, free flap surgery. Objective: To characterize patient experiences and decision regret of patients undergoing head and neck reconstructive free flap surgery. Design, Setting, and Participants: This mixed-methods cohort study comprising semistructured interviews was conducted June to August 2021 at a single tertiary academic cancer center. Participants underwent head and neck reconstructive surgery with microvascular free tissue transfer (flap) more than 3 months before recruitment (range, 3 months to 4 years). Interview transcripts were qualitatively analyzed for themes. Participants also completed a Decision Regret Scale questionnaire. Exposure: Microvascular free flap surgery for head and neck reconstruction. Main Outcomes and Measures: Thematic analysis of interviews, decision regret score. Results: Seventeen participants were interviewed. Median (IQR) age was 61 (52-70) years. Overall, 7 participants were women (49%), and 10 of 17 were men (59%). The most common free flap was fibula (8/17, 47%). Three major themes with 9 subthemes were identified: theme 1 was the tremendous effect of preoperative counseling on surgical decision-making and satisfaction, with subthemes including (1) importance of clinical care team counseling on decision to have surgery; (2) emotional context colors preoperative understanding and retention of information; (3) expectation-setting affects satisfaction with preoperative counseling; and (4) desire for diversified delivery of preoperative information. Theme 2 was coexisting and often conflicting priorities, including (1) desire to survive above all else, and (2) desire for quality of life. Theme 3 was perception of surgery as momentous and distressing, including (1) surgery as a traumatic event; (2) centrality of mental health, emotional resolve, and gratitude to enduring surgery and recovery; and (3) sense of accomplishment in recovery. On the Decision Regret Scale, most participants had no regret (n = 8, 47%) or mild regret (n = 5, 29%); 4 had moderate-to-severe regret (24%). Conclusions and Relevance: In this mixed-methods cohort study, patient experiences surrounding major head and neck reconstructive free flap surgery were described. Opportunities to improve support for this complex and vulnerable population, and to mitigate decision regret, were identified.

Strategies to Increase Racial and Ethnic Diversity in the Surgical Workforce: A State of the Art Review.

OBJECTIVE: To evaluate strategies to increase racial and ethnic diversity in the surgical workforce among trainees and faculty across surgical specialties. DATA SOURCES: Embase, OVID/Medline, and Web of Science Core Collection. REVIEW METHODS: A review of US-based, peer-reviewed articles examining the effect of targeted strategies on racial and ethnic diversity in the surgical workforce was conducted from 2000 to 2020 with the PRISMA checklist and STROBE tool. Studies without an outlined strategy and associated outcomes were excluded. Eleven studies met inclusion criteria and were completed in general surgery, orthopaedic surgery, and otolaryngology-head and neck surgery. CONCLUSIONS: Efforts to increase exposure to surgery through internship programs and required clerkships with efforts to improve mentorship were common (6 of 11 [54.5%] and 3 of 11 [27.3%] studies, respectively). Three (27.3%) studies aimed to diversify the recruitment and selection process for the residency match and faculty hiring, and 2 (18.2%) aimed to increase representation among trainees, faculty, and leadership through holistic review processes paired with departmental commitment. Outcome metrics included surgical residency applications for individuals underrepresented in medicine, interview and match rates, faculty hiring, measures of a successful academic surgical career, and leadership representation. All strategies were successful in increasing diversity in the surgical workforce. IMPLICATIONS FOR PRACTICE: A convincing yet limited body of literature exists to describe strategies and outcomes that address racial and ethnic diversity in the surgical workforce. While future inquiry is needed to move this field of interest forward, the evidence presented provides a framework for surgical residency programs/departments to develop approaches to increase racial and ethnic diversity.

Dissociation Between Incubation of Cocaine Craving and Anxiety-Related Behaviors After Continuous and Intermittent Access Self-Administration.

Studies using either continuous or intermittent access cocaine self-administration procedures showed that cocaine seeking increases during abstinence (incubation of cocaine craving), and that this effect is higher after intermittent cocaine access. Other studies showed that cocaine abstinence is characterized by the emergence of stress- and anxiety-related states which were hypothesized to increase relapse vulnerability. We examined whether incubation of cocaine craving and anxiety-related behaviors are correlated and whether intermittent cocaine self-administration would potentiate these behaviors during abstinence. Male rats self-administered cocaine either continuously (6 h/day) or intermittently (5 min ON, 25 min OFF × 12) for 14 days, followed by relapse tests after 1 or 21 abstinence days. A group of rats that self-administered saline served as a control. Anxiety-related behaviors were measured on the same abstinence days, using the novelty induced-hypophagia test. Finally, motivation for cocaine was measured using a progressive ratio reinforcement schedule. Lever-presses after 21 abstinence days were higher than after 1 day and this incubation effect was higher in the intermittent access group. Progressive ratio responding was also higher after intermittent cocaine access. Intermittent and continuous cocaine access did not induce anxiety-like responses in the novelty-induced hypophagia test after 1 or 21 abstinence days. Independent of the access condition, incubation of cocaine seeking was not correlated with the novelty-induced hypophagia measures. Results suggest that cocaine-induced anxiety-related states during protracted abstinence do not contribute to incubation of cocaine craving. However, this conclusion is tentative because we used a single anxiety-related measure and did not test female rats.

Effects of nicotine exposure and anxiety on motivation for reward and gambling-like cues under reward uncertainty.

Reward uncertainty is a common characteristic of gambling and may powerfully enhance attraction to gambling-related cues, thus promoting maladaptive gambling behaviors in susceptible individuals. The co-occurrence of gambling disorder with tobacco use disorder (60.4%) suggests a common mechanism for their pathology, and comorbid anxiety (41.3%) might further promote the maintenance of these behaviors. However, it is unknown how nicotine or anxiety might contribute to cue and reward attraction, or promote disordered gambling behavior. In the present study, we investigated the effects of nicotine (0.4 mg/kg, SC) on the desire for uncertain rewards and their cues in male and female Sprague-Dawley rats. During an autoshaping task, rats learned to associate a lever + tone cue with the delivery of sucrose pellet rewards under either certain or uncertain (probability and magnitude) reward conditions. Subsequently, we tested the ability of gambling-like cues to serve as a conditioned reinforcer, and to promote motivation for sucrose rewards during a progressive ratio task. Finally, anxiety behavior was measured to examine its interaction with nicotine and uncertainty. Here, we found that nicotine enhanced attraction to the magazine under certain but not uncertain reward conditions, and increased cue-triggered behaviors. Conversely, in the progressive ratio task, exposure to uncertain conditions and nicotine enhanced motivation for reward, compared with certain conditions. These results suggest that nicotine may interact with both certain and uncertain reward conditions to increase cue-triggered behavior and enhance motivation for rewards, providing possible insight into the comorbid relationship between pathological gambling and tobacco use. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Operant Social Reward Decreases Incubation of Heroin Craving in Male and Female Rats.

BACKGROUND: We recently reported that operant social choice-induced voluntary abstinence prevents incubation of methamphetamine craving. Here, we determined whether social choice-induced voluntary abstinence would prevent incubation of heroin craving. We also introduce a fully automatic social reward self-administration model that eliminates the intense workload and rat-human interaction of the original semiautomatic model. METHODS: In experiment 1, we trained male and female rats for social self-administration (6 days) and then for heroin self-administration (12 days). Next, we assessed relapse to heroin seeking after 1 and 15 abstinence days. Between tests, the rats underwent either forced or social choice-induced abstinence. In experiment 2, we developed a fully automatic social self-administration procedure by introducing a screen between the self-administration chamber and the social-peer chamber; the screen allows physical contact but prevents rats from crossing chambers. Next, we compared incubation of craving in rats with a history of standard (no-screen) or automatic (screen) social self-administration and social choice-induced abstinence. RESULTS: The time-dependent increase in heroin seeking after cessation of drug self-administration (incubation of craving) was lower after social choice-induced abstinence than after forced abstinence. There were no differences in social self-administration, social choice-induced abstinence, and incubation of craving in rats trained in the standard semiautomatic procedure versus the novel fully automatic procedure. CONCLUSIONS: Our study demonstrates the protective effect of rewarding social interaction on heroin self-administration and incubation of heroin craving and introduces a fully automatic social self-administration and choice procedure to investigate the role of volitional social interaction in drug addiction and other psychiatric disorders.

Distinguishing between predictive and incentive value of uncertain gambling-like cues in a Pavlovian autoshaping task.

The flashing lights and celebratory sounds that dominate slot-machine gambling are believed to promote engagement and motivation to keep playing. However, these cues are often presented in the absence of reward, and previous research suggests that this reward uncertainty, which degrades their predictive value, also increases their incentive value. Here, we used autoshaping to tease apart the impact of reward uncertainty on the predictive and incentive value of a conditioned stimulus (CS) using serial cues. Each CS trial began with the presentation of a predictive CS1, followed by a CS2, holding primarily incentive value, because of its proximity to sucrose reward delivery, under Certain (100%-1) or Uncertain (50%-1- 2-3) reward conditions. Subsequently, we tested the impact of amphetamine and nicotine on cue attraction, and the ability of these cues to either serve as a conditioned reinforcer, or promote motivation for sucrose during a progressive ratio task. Finally, we measured anxiety behavior, and examined its interaction with each cue and uncertainty. Our results suggest that reward uncertainty increases attraction to the incentive CS2 and its ability to trigger motivation and reward-seeking. However, although the CS2 is largely ignored under Certain conditions, both CS1 and CS2 become conditioned reinforcers for both groups. Finally, amphetamine reduced the attraction of the CS1 for both groups but had no effect on the attraction of the CS2. These results suggest that reward uncertainty recruits and increases the incentive value of cues with limited predictive value and highlights the distinction between cue attraction, reward-seeking and conditioned reinforcer properties.

Incubation of Cocaine Craving After Intermittent-Access Self-administration: Sex Differences and Estrous Cycle.

BACKGROUND: Studies using continuous-access drug self-administration showed that cocaine seeking increases during abstinence (incubation of cocaine craving). Recently, studies using intermittent-access self-administration showed increased motivation to self-administer and seek cocaine. We examined whether intermittent cocaine self-administration would potentiate incubation of craving in male and female rats and examined the estrous cycle's role in this incubation. METHODS: In experiment 1, male and female rats self-administered cocaine either continuously (8 hours/day) or intermittently (5 minutes ON, 25 minutes OFF × 16) for 12 days, followed by relapse tests after 2 or 29 days. In experiments 2 and 3, female rats self-administered cocaine intermittently for six, 12, or 18 sessions. In experiment 4, female rats self-administered cocaine continuously followed by relapse tests after 2 or 29 days. In experiments 3 and 4, the estrous cycle was measured using a vaginal smear test. RESULTS: Incubation of cocaine craving was observed in both sexes after either intermittent or continuous drug self-administration. Independent of access condition and abstinence day, cocaine seeking was higher in female rats than in male rats. In both sexes, cocaine seeking on both abstinence days was higher after intermittent drug access than after continuous drug access. In female rats, incubation of craving after either intermittent or continuous drug access was significantly higher during estrus than during non-estrus; for intermittent drug access, this effect was independent of the training duration. CONCLUSIONS: In both sexes, intermittent cocaine access caused time-independent increases in drug seeking during abstinence. In female rats, the time-dependent increase in drug seeking (incubation) is critically dependent on the estrous cycle phase.