The role of psychosis and clozapine load in excessive checking in treatment-resistant schizophrenia: longitudinal observational study.

BACKGROUND: A significant proportion of people with clozapine-treated schizophrenia develop 'checking' compulsions, a phenomenon yet to be understood. AIMS: To use habit formation models developed in cognitive neuroscience to investigate the dynamic interplay between psychosis, clozapine dose and obsessive-compulsive symptoms (OCS). METHOD: Using the anonymised electronic records of a cohort of clozapine-treated patients, including longitudinal assessments of OCS and psychosis, we performed longitudinal multi-level mediation and multi-level moderation analyses to explore associations of psychosis with obsessiveness and excessive checking. Classic bivariate correlation tests were used to assess clozapine load and checking compulsions. The influence of specific genetic variants was tested in a subsample. RESULTS: A total of 196 clozapine-treated individuals and 459 face-to-face assessments were included. We found significant OCS to be common (37.9%), with checking being the most prevalent symptom. In mediation models, psychosis severity mediated checking behaviour indirectly by inducing obsessions (r = 0.07, 95% CI 0.04-0.09; P < 0.001). No direct effect of psychosis on checking was identified (r = -0.28, 95% CI -0.09 to 0.03; P = 0.340). After psychosis remission (n = 65), checking compulsions correlated with both clozapine plasma levels (r = 0.35; P = 0.004) and dose (r = 0.38; P = 0.002). None of the glutamatergic and serotonergic genetic variants were found to moderate the effect of psychosis on obsession and compulsion (SLC6A4, SLC1A1 and HTR2C) survived the multiple comparisons correction. CONCLUSIONS: We elucidated different phases of the complex interplay of psychosis and compulsions, which may inform clinicians' therapeutic decisions.

Sex- and estrous-related response patterns for alcohol depend critically on the level of compulsion-like challenge.

Alcohol use disorder is a substantial social and economic burden. During the last years, the number of women with drinking problems has been increasing, and one main concern is that they are particularly more vulnerable to negative consequences of alcohol. However, little is known about female-specific response patterns for alcohol, and potential underlying differences in brain mechanisms, including for compulsion-like alcohol drinking (when intake persists despite adverse consequences). We used lickometry to assess behavioral microstructure in adult Wistar male and female rats (n = 28-30) during alcohol-only drinking or moderate- or higher-challenge alcohol compulsion (10 or 60 mg/l quinine in alcohol, respectively). Estrous stages were determined and related to drinking levels and patterns of responding to alcohol, as was ovariectomy. Our findings showed that females (where we didn't determine estrus stage) had similar total licks in a session as males, but significantly longer licking bouts under alcohol-only and moderate-challenge, suggesting greater persistence. Further, greater intake under alcohol-only and moderate-challenge was related to faster licking in males, while female consumption was not related to licking speed. Thus, females could have increased persistence without greater vigor, unlike males. However, under higher-challenge, faster licking did predict higher intake in females, similar to males. To better understand female higher-challenge responding, we examined drinking in relation to phases of the estrous cycle. Higher-challenge had longer bouts only in late diestrus. In addition, ovariectomy led to longer bouts only under higher-challenge, suggesting that conditions with reduced hormone levels could increase female persistence for alcohol under higher-challenge. However, ovariectomy also reduced alcohol-only and moderate-challenge drinking but did not reduce bout length. Thus, intake level and response strategy could be regulated somewhat differently by ovarian hormones. Finally, moderate-challenge licking speed was less variable during early diestrus, and we previously showed more stereotyped responding specifically under moderate-challenge in males. By combining behavioral microstructure and sex- and estrus-related changes in drinking patterns, our results suggest that females have greater persistence for alcohol under lower-challenge drinking, while late diestrus and ovariectomy unmasked greater persistence under higher-challenge. Together, our novel insights could help develop more effective and personalized treatments for problematic alcohol use.

Views of Nigerian civil servants about compulsory COVID-19 vaccination: A qualitative study.

BACKGROUND:  COVID-19 caused unforeseen global burden, although vaccine strategy rapidly stalled transmission and protected those at risk. Many governments made vaccination mandatory for public space access. AIM:  This study aimed to elucidate perception of Nigerian civil servants towards mandatory COVID-19 vaccination and elicited their recommendations. SETTING:  This study was conducted in twelve purposively selected states in the six geopolitical zones and the Federal Capital Territory (FCT), Nigeria. Relevant ministries, departments and agencies were selected within the study sites. METHODS:  It was a qualitative study that interviewed consenting civil servants. Ethical approval was obtained from the National Health Research Ethics Committee. Interviews were conducted in person, following a pre-test. Data was analysed using NVivo software version 12. RESULTS:  Most participants were willing to take the vaccine if their safety was assured. However, enforcement to do so was a hindrance. Most participants commended the government for the effort to curb COVID-19 transmission and create awareness but were displeased with planning and handling of misconceptions. They recommended a more committed approach to vaccine production and funding by the government. CONCLUSION:  Participants were willing to take the COVID-19 vaccines because the gains of protection outweighed the risks. They suggested a less involuntary approach through reinforcing awareness creation and avoiding threats.Contribution: There is limited qualitative research on perception of Nigerian civil servants regarding mandatory COVID-19 vaccination. Being the main driving force of Nigeria's public service, their views are invaluable. Findings could contribute to future policies in times of emergency.

Was It Just a Dream? Aging and Dreaming the Psychoanalytic Process.

By revisiting the last years of a long psychoanalytic treatment of a female patient, a psychoanalyst reflects on her own development as a clinician and on the changes in her experience of psychoanalytic generativity. An increasing ability to understand patient's shifts between creativity and destructiveness brings about a different understanding of the process of mourning, while the shared aging of the analytic dyad highlights the difficulty of ending an analysis that has become a way of life.

Sex differences in heart rate variability measures that predict alcohol drinking in rats.

Problem alcohol drinking continues to be a substantial cost and burden. In addition, alcohol consumption in women has increased in recent decades, and women can have greater alcohol problems and comorbidities. Thus, there is a significant need for novel therapeutics to enhance sex-specific, individualized treatment. Heart rate (HR) and HR variability (HRV) are of broad interest because they may be both biomarkers for and drivers of pathological states. HRV reflects the dynamic balance between sympathetic (SNS, 'fight or flight') and parasympathetic (PNS, 'rest and digest') systems. Evidence from human studies suggest PNS predominance in women and SNS in men during autonomic regulation, indicating the possibility of sex differences in risk factors and physiological drivers of problem drinking. To better understand the association between HRV sex differences and alcohol drinking, we examined whether alcohol consumption levels correlated with time domain HRV measures (SDNN and rMSSD) at baseline, at alcohol drinking onset, and across 10 min of drinking, in adult female and male Wistar rats. In particular, we compared both HRV and HR measures under alcohol-only and compulsion-like conditions (alcohol + 10 mg/L quinine), because compulsion can often be a significant barrier to treatment of alcohol misuse. Importantly, previous work supports the possibility that different HRV measures could be interpreted to reflect PNS versus SNS influences. Here, we show that females with higher putative PNS indicators at baseline and at drinking onset had greater alcohol consumption. In contrast, male intake levels related to increased potential SNS measures at drinking onset. Once alcohol was consumed, HR predicted intake level in females, perhaps a pharmacological effect of alcohol. However, HRV changes were greater during compulsion-like intake versus alcohol-only, suggesting HRV changes (reduced SNS in females, reduced PNS and increased HR in males) specifically related to aversion-resistant intake. We find novel and likely clinically relevant autonomic differences associated with biological sex and alcohol drinking, suggesting that different autonomic mechanisms may promote differing aspects of female and male alcohol consumption.

Neural Activity in the Anterior Insula at Drinking Onset and Licking Relates to Compulsion-Like Alcohol Consumption.

Much remains unknown about the etiology of compulsion-like alcohol drinking, where consumption persists despite adverse consequences. The role of the anterior insula (AIC) in emotion, motivation, and interoception makes this brain region a likely candidate to drive challenge-resistant behavior, including compulsive drinking. Indeed, subcortical projections from the AIC promote compulsion-like intake in rats and are recruited in heavy-drinking humans during compulsion for alcohol, highlighting the importance of and need for more information about AIC activity patterns that support aversion-resistant responding. Single-unit activity was recorded in the AIC from 15 male rats during alcohol-only and compulsion-like consumption. We found three sustained firing phenotypes, sustained-increase, sustained-decrease, and drinking-onset cells, as well as several firing patterns synchronized with licking. While many AIC neurons had session-long activity changes, only neurons with firing increases at drinking onset had greater activity under compulsion-like conditions. Further, only cells with persistent firing increases maintained activity during pauses in licking, suggesting roles in maintaining drive for alcohol during breaks. AIC firing was not elevated during saccharin drinking, similar to lack of effect of AIC inhibition on sweet fluid intake in many studies. In addition, we observed subsecond changes in AIC neural activity tightly entrained to licking. One lick-synched firing pattern (determined for all licks in a session) predicted compulsion-like drinking, while a separate lick-associated pattern correlated with greater consumption across alcohol intake conditions. Collectively, these data provide a more integrated model for the role of AIC firing in compulsion-like drinking, with important relevance for how the AIC promotes sustained motivated responding more generally.

Detention of children and adolescents under mental health legislation: a scoping review of prevalence, risk factors, and legal frameworks.

BACKGROUND: For individuals with severe mental illness, involuntary assessment and/or treatment (hereafter detention) can be a necessary intervention to support recovery and may even be lifesaving. Despite this, little is known about how often these interventions are used for children and adolescents. METHODS: This global scoping review set out to: (1) map the current evidence around mental health detentions of children and adolescents (< 18 years); (2) identify the clinical, sociodemographic, and behavioural factors associated with detention; and (3) document the views of professionals and young people on the implementation of mental health legislation. RESULTS: After searching databases of peer-reviewed literature and citation chaining, 42 articles from 15 jurisdictions were included. About one fifth of psychiatric admissions in national register data were detentions, however trends were only available for a few high-income Western countries. The circumstances justifying detention and the criteria authorising detention varied between studies, with a mix of clinical factors and observed behaviours reported as the reason(s) warranting/precipitating a detention. Particular groups were more likely to experience detention, such as children and adolescents from minority ethnic communities and those with a documented history of abuse. There was a notable absence of qualitative research exploring the views of professionals or children and adolescents on detention. CONCLUSION: Further research is needed to explore the impact of detention on those aged < 18 years, including national register-based studies and qualitative studies. This is particularly relevant in nations currently undergoing legislative reform.

Local structural and functional MRI markers of compulsive behaviors and obsessive-compulsive disorder diagnosis within striatum-based circuits.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a classic disorder on the compulsivity spectrum, with diverse comorbidities. In the current study, we sought to understand OCD from a dimensional perspective by identifying multimodal neuroimaging patterns correlated with multiple phenotypic characteristics within the striatum-based circuits known to be affected by OCD. METHODS: Neuroimaging measurements of local functional and structural features and clinical information were collected from 110 subjects, including 51 patients with OCD and 59 healthy control subjects. Linked independent component analysis (LICA) and correlation analysis were applied to identify associations between local neuroimaging patterns across modalities (including gray matter volume, white matter integrity, and spontaneous functional activity) and clinical factors. RESULTS: LICA identified eight multimodal neuroimaging patterns related to phenotypic variations, including three related to symptoms and diagnosis. One imaging pattern (IC9) that included both the amplitude of low-frequency fluctuation measure of spontaneous functional activity and white matter integrity measures correlated negatively with OCD diagnosis and diagnostic scales. Two imaging patterns (IC10 and IC27) correlated with compulsion symptoms: IC10 included primarily anatomical measures and IC27 included primarily functional measures. In addition, we identified imaging patterns associated with age, gender, and emotional expression across subjects. CONCLUSIONS: We established that data fusion techniques can identify local multimodal neuroimaging patterns associated with OCD phenotypes. The results inform our understanding of the neurobiological underpinnings of compulsive behaviors and OCD diagnosis.

Differential Effect of Fixed Ratio Magnitude on the Rate of Lever-Pressing and Interinjection Intervals of Cocaine Self-Administration in Rats.

Background: Many features of self-administration behavior may be explained by reference to the properties of schedules of reinforcement. Schedules alter the probability of a behavior being reinforced and thereby increase, or decrease, the frequency of the behavior and fixed ratio (FR) magnitude reportedly alters the rate of responding to cocaine. A pharmacokinetic/pharmacodynamic interaction theory states that lever-pressing behavior is induced only when cocaine levels in the body are above the priming/remission threshold and below the satiety threshold-a range termed the compulsion zone. This theory successfully explains cocaine self-administration in rats on a progressive ratio and the FR1 schedule. Objectives: To determine the effects of high FR magnitude on the rate of self-administration of cocaine and the rate of lever-pressing behavior when cocaine levels are within the compulsion zone. Methods: Rats acquired cocaine self-administration on an FR1 schedule and then were switched to sessions that started with FR1 and then FR 5, 10, 20, or 50. An only FR1 session was run each week between FR1/FR50 sessions and then only FR1 sessions were conducted for several weeks. Results: Interinjection intervals at a unit dose of 3 µmol/kg were regular at both FR1 and FR50 but were longer by the time required to complete the 50 presses. When responding by rats was maintained under an FR50 schedule of cocaine presentations, compared to baseline FR1 sessions, dramatic increases in the number of lever-presses were observed after access to cocaine was terminated, a previously unreported finding. However, lever-pressing occurred only when cocaine levels were in the compulsion zone, and this duration was unchanged. The increase in lever-pressing persisted for weeks. Interinjection intervals at FR1 were not altered after exposure to FR50. Conclusions: Although previously considered key to understanding the regulation of cocaine self-administration behavior, FR magnitude simply increased interinjection intervals by the time required to complete 50 lever-presses. The dramatic increase in the rate of lever-pressing was caused by the high FR schedule rather than cocaine. The utility of the schedule-induced increase in the rate of lever-pressing is unclear. The compulsion zone theory provides a rational pharmacological basis for understanding cocaine self-administration behavior.

A closer look to neural pathways and psychopharmacology of obsessive compulsive disorder.

The intricate neural pathways involved in obsessive-compulsive disorder (OCD) affect areas of our brain that control executive functioning, organization, and planning. OCD is a chronic condition that can be debilitating, afflicting millions of people worldwide. The lifetime prevalence of OCD in the US is 2.3%. OCD is predominantly characterized by obsessions consisting of intrusive and unwanted thoughts, often with impulses that are strongly associated with anxiety. Compulsions with OCD encompass repetitive behaviors or mental acts to satisfy their afflicted obsessions or impulses. While these factors can be unique to each individual, it has been widely established that the etiology of OCD is complex as it relates to neuronal pathways, psychopharmacology, and brain chemistry involved and warrants further exploration.

Logics of Discovery II: Lessons from Poetry-Parataxis as a Method That Can Complement the Narrative Compulsion in Vogue in Contemporary Mental Health Care.

This paper highlights the limitations of narrative logic in mental health care, and in particular of "narrative vigilance"-the tendency to watch over experience via narrativisation, and to tether the concrete particulars of experience to the hypothetical structure of a narrative signification. Narrative logic is grounded in hypotaxis-the syntactic structuring whereby a discourse is characterised by different levels of subordination using linking words that connect, especially in terms of temporal and explanatory consequentiality. I offer an alternative approach based on parataxis-the practice of placing phrases or parts of speech next to each other without subordinating conjunctions. Sentences are juxtaposed without a clear connection; the contrast may generate novel and unexpected combinations between these dissimilar fragments. After distinguishing between parataxis and psychopathological phenomena like disturbances of association, I take inspiration from the work and life of a poet, Johann Christian Friedrich Hölderlin (1770-1843), considered among the greatest. He suffered for half his life from a severe form of mental illness that would perhaps, today, be diagnosed as schizophrenia. In the poems written during his illness, hypotaxis and narrative vigilance seem to blur, and parataxis takes centre stage. The fading of narrative structure in no way coincides with the absence of meaningfulness. Rather, meaningfulness is left to parataxis itself, that is, to the recombining power of words, sentences, and images. Parataxis itself can provide meaningfulness or, at least, provide the soil in which it can germinate. The void of narration opens the door for the fullness of "emergent" connections. In the final part of the paper, with the help of Freud's ideas on the relationship between "analysis" and "synthesis" in psychoanalytic treatment, some implications are derived about the relevance of parataxis to the logics of discovery in psychotherapeutic care, especially that of persons with severe mental conditions.

Exploring Psychological Constructs in People Receiving Treatment for Addictive Eating Behaviours: "I Hate Loving Food as Much as I Do".

Research into the complexities of addictive eating behaviours continues to develop, as a deeper understanding of this construct beyond self-report diagnostic tools emerges. In this study, we undertook structured interviews with 40 participants engaged in a personality-based management program for addictive eating, to gain insight into what situations lead people with addictive eating behaviours to overeat, and how they believe their lives would be different if they had control over their eating. A phenomenological analysis to explore compulsion and control in the context of food experiences for participants was used to construct two main themes of the addictive eating paradox and striving to transition from 'other' to 'normal'. The addictive eating paradox identified multiple contradictory experiences of a situation, e.g., 'loving food' but 'hating food'. Striving to transition from 'other' to 'normal' encompassed the idea that participants envisaged that by gaining control over their eating they could become 'normal'. This study emphasises the need to provide support and strategies to help people navigate paradoxical thoughts and presents new ideas to increase the effectiveness of interventions for individuals struggling with the complex self-beliefs held by those with addictive eating behaviours.

The Relationship Between Family Accommodation and Anxiety Sensitivity in Obsessive-Compulsive Disorder.

Objective Anxiety sensitivity (AS) is an issue that has gained importance in obsessive-compulsive disorder (OCD) in recent years. Family accommodation (FA) is the participation of family members in compulsions and rituals. The objectives of this study were to (1) investigate the relationship between FA and AS in OCD and (2) determine the frequency and types of FA in a Turkish OCD sample. Methods This cross-sectional study was conducted with 81 OCD patients. The Yale-Brown Obsession Compulsion Scale (YBOCS), Family Accommodation Scale-Patient Form (FAS-PF), Anxiety Sensitivity Index-3 (ASI-3), Beck Depression Inventory (BDI), and Beck Anxiety Inventory (BAI) were administered to the patients. Results Family accommodation was extremely prevalent among family members of OCD patients. There were significant relationships between FA and ASI-3 total, ASI-3 cognitive subscale, ASI-3 psychical subscale, YBOCS, and BAI scores. In addition, ASI-3 total, ASI-3 cognitive subscale, and ASI-3 psychical subscale were significant predictors for family accommodation above and beyond the OCD severity. Conclusions The present study identified a significant association between anxiety sensitivity and family accommodation in OCD. Anxiety sensitivity is a relievable psychological trait. Alleviating anxiety sensitivity can decrease accommodating behaviors and may be beneficial in OCD treatment. Anxiety sensitivity may be a novel potential treatment target for OCD.

The cocaine compulsion zone theory explains the reinstatement of lever pressing behavior in rats in response to a single cocaine dose.

A single non-contingent dose of cocaine reinstates extinguished lever pressing behavior in rats trained to self-administer cocaine. This represents a model of relapse in cocaine use disorder and the number of lever presses has been the standard measure. Lever pressing behavior during self-administration occurs only when cocaine levels are below the satiety threshold and above the remission/priming threshold, a range termed the compulsion zone. Calculated cocaine levels at the time of each lever press during an FR1 self-administration session and following a single non-contingent dose of cocaine were compared. The mean latency to lever pressing behavior was dose dependent and ranged from 1 to 11 min after cocaine doses of 2 or 12 µmol/kg, respectively. This is consistent with higher cocaine doses producing levels above satiety threshold that take more time to fall back to that threshold. The level of cocaine when lever pressing occurred was similar whether cocaine was self-administered or after a single dose of cocaine. The number of lever presses after a single cocaine dose was variable and poorly dose dependent. The latency to the start of lever pressing behavior is a more reliable dependent measure than the number of lever presses. In addition, lever pressing behavior occurs only when cocaine levels are within the compulsion zone. The compulsion zone theory not only explains maintained cocaine self-administration behavior, but also explains the reinstatement of lever pressing behavior in response to a single non-contingent cocaine dose.

Long term outcomes and causal modelling of compulsory inpatient and outpatient mental health care using Norwegian registry data: Protocol for a controversies in psychiatry research project.

OBJECTIVES: Compulsory mental health care includes compulsory hospitalisation and outpatient commitment with medication treatment without consent. Uncertain evidence of the effects of compulsory care contributes to large geographical variations and a controversy on its use. Some argue that compulsion can rarely be justified and should be reduced to an absolute minimum, while others claim compulsion can more frequently be justified. The limited evidence base has contributed to variations in care that raise issues about the quality/appropriateness of care as well as ethical concerns. To address the question whether compulsory mental health care results in superior, worse or equivalent outcomes for patients, this project will utilise registry-based longitudinal data to examine the effect of compulsory inpatient and outpatient care on multiple outcomes, including suicide and overall mortality; emergency care/injuries; crime and victimisation; and participation in the labour force and welfare dependency. METHODS: By using the natural variation in health providers' preference for compulsory care as a source of quasi-randomisation we will estimate causal effects of compulsory care on short- and long-term trajectories. CONCLUSIONS: This project will provide valuable insights for service providers and policy makers in facilitating high quality clinical care pathways for a high risk population group.

Freud's Red Thread: Explorations of the Unconscious Sense of Guilt.

The concept of an "unconscious sense of guilt" bedevils Freud throughout his life, rearing its head in at least twenty-four of his major works and working behind the scenes in many others. In a sense, we can see Freud's oeuvre, and psychoanalysis more generally, as a discourse of unconscious guilt. While Freud frames the oedipus complex as the central defining dynamic of human experience, the unconscious sense of guilt is arguably the underbelly that both precedes and exceeds that complex. By unraveling a range of complexities within Freud's conceptualization of unconscious guilt, we will come to see that guilt is an unavoidable by-product of the human condition, intrinsically interwoven with libidinal desire.

Remembering, repeating and working-through as a step in Freud's ongoing struggle with the "what", "why" and "how" of analytic knowing in the curative process.

In this paper the author offers a new reading of Freud's "Remembering, Repeating and Working-through", examining the complex nature of central concepts that Freud presents within it. She demonstrates the text's special role in an ongoing effort of Freud's to articulate and ground the heart of his analytic insight that knowledge cures. While the insight itself is very well-known, the fact that Freud struggled throughout his life with its articulation and grounding is not. The struggle centered on questions pertaining to how analytic knowing could, not only enlighten the patient, but actually change his unconscious dynamics, and why the patient, having already "opted" for pathology in place of knowing would come to accept it; and ultimately, what was the nature of the knowledge offered in analysis and the individual's relationship to it that allowed for such dramatic changes to occur. The author briefly presents some of her earlier work on Freud's struggle with these issues and how Melanie Klein resolved them. It is in this context that she demonstrates how in Remembering, Repeating and Working-through" Freud may be seen to be taking important steps towards developing his ideas on analytic knowing and in ways that anticipate Klein's resolutions. This points to the close tie between Klein's and Freud's thinking on the nature of the analytic process and the person's desire for self-knowledge on which it relies, brings out the richness of this thinking and grounds its value to contemporary psychoanalysis.

[PLAID-Care: Research into the reduced use of coercion in France]. / PLAID-Care : une recherche sur le moindre recours à la coercition en France.

The use of coercion is a common practice in psychiatry despite its deleterious effects and insufficient evidence of benefits. It is so deeply rooted that the mention of establishments that make little use of it arouses a form of incredulity. However, the history of psychiatry and the international literature provide numerous examples of a psychiatry that is hardly coercive and numerous experiences of a reduction in the use of seclusion and/or restraint in psychiatric facilities. Today, in France, there are also less coercive establishments, which, for example, do not use mechanical restraint, have all their units open, or have reduced their use of seclusion and restraint. With regard to the stated policy objectives of reducing the use of coercion, it is surprising that most of these facilities receive little attention. PLAID-Care research aims to contribute to the visibility and analysis of these institutions and the factors involved in the reduced use of coercion. While these factors have already been identified in the international literature, the research is based on the multiplication of disciplinary perspectives (nursing, sociology, anthropology, geography) and the mobilization of a multi-level analytical framework that allows us to embrace their multiplicity and better understand their articulation. The originality of the research also lies in its historical dimension, which allows us to understand, on the scale of an institution, how a policy and practices aiming at the least recourse emerge and are consolidated. The project timeline is divided in three tasks: firstly, an inventory of "low-coercion" facilities in France; secondly, we will select and research four traditionally "low-coercion" facilities in France; thirdly we will focus on recently emerged "low-coercion" practices. PLAID-Care aims to revitalize French research on this theme which to date has been relatively lagging behind the numerous international studies. It will bring together and articulate the knowledge, tools and forms of organization and collaboration that contribute to making a policy of lesser use of coercion operational.

Animal models of compulsion alcohol drinking: Why we love quinine-resistant intake and what we learned from it.

Alcohol Use Disorder (AUD) ranks among the most prevalent mental disorders, extracting ~$250 billion/year in the US alone and producing myriad medical and social harms. Also, the number of deaths related to problem drinking has been increasing dramatically. Compulsive alcohol drinking, characterized by intake that persists despite negative consequences, can be particularly important and a major obstacle to treatment. With the number of people suffering from AUD increasing during the past years, there is a critical need to understand the neurobiology related to compulsive drives for alcohol, as well as the development of novel AUD pharmacological therapies. Here we discuss rodent compulsion-like alcohol drinking (CLAD) models, focusing on the two most widely used adverse stimuli to model rodent compulsion-like responding, quinine adulteration of alcohol and footshook-resistant alcohol intake. For both cases, the goal is to uncover behavior patterns and brain circuits that underlie drive for alcohol even in the face of negative consequences. We discuss caveats, benefits, and potential brain mechanisms, of models for consequence-resistant responding for alcohol more generally, and especially highlight some advantages of quinine-resistance over footshook-resistance. Further, since this review contributes to a Special issue focused on Molecular Aspects of Compulsive Drug Use, we discuss our new findings showing how the noradrenergic system is related to CLAD responding. In particular, we comment on the importance of α1 and ß adrenergic receptors (ARs) as potential targets for treating AUD.