Dopamine transmission at D1 and D2 receptors in the nucleus accumbens contributes to the expression of incubation of cocaine craving.

Relapse represents a consistent clinical problem for individuals with substance use disorder. In the incubation of craving model of persistent craving and relapse, cue-induced drug seeking progressively intensifies or 'incubates' during the first weeks of abstinence from drug self-administration and then remains high for months. Previously, we and others have demonstrated that expression of incubated cocaine craving requires strengthening of excitatory synaptic transmission in the nucleus accumbens core (NAcc). However, despite the importance of dopaminergic signaling in the NAcc for motivated behavior, little is known about the role that dopamine (DA) plays in the incubation of cocaine craving. Here we used fiber photometry to measure DA transients in the NAcc of male and female rats during cue-induced seeking tests conducted in early abstinence from cocaine self-administration, prior to incubation, and late abstinence, after incubation of craving has plateaued. We observed DA transients time-locked to cue-induced responding but their magnitude did not differ significantly when measured during early versus late abstinence seeking tests. Next, we tested for a functional role of these DA transients by injecting DA receptor antagonists into the NAcc just before the cue-induced seeking test. Blockade of either D1 or D2 DA receptors reduced cue-induced cocaine seeking after but not before incubation. We found no main effect of sex in our experiments. These results suggest that DA contributes to incubated cocaine seeking but the emergence of this role reflects changes in postsynaptic responsiveness to DA rather than presynaptic alterations.

Resilience of the primary healthcare system: perspectives of German stakeholders at primary care interfaces during the second wave of the COVID-19 pandemic.

Introduction: Worldwide, the primary care sector played a key role in coping with the challenges of the SARS-CoV-2 pandemic. Methods: The aim of this study was to explore the resilience of the German primary healthcare system during the second wave of the pandemic from the perspective of identified interface stakeholders, i.e., representatives of hospitals, district offices, and medical associations. Qualitative data from interviews and focus groups were analyzed according to a resilience framework. Results: The main findings include a gap in knowledge transfer, unstructured allocation of responsibilities, and a resulting unregulated flow of patients. Social brokers supported care coordination and knowledge transfer. The response to the capacity to cope with uncertainties was slow and chaotic at the system level and heterogeneous at the individual level. Building on previous relationships fostered functioning communication, while competition in primary care was identified as a barrier to resilience. Conclusion: Implications for further research and for strengthening the resilience of primary care can be derived based on this study.

Improved green and red GRAB sensors for monitoring dopaminergic activity in vivo.

Dopamine (DA) plays multiple roles in a wide range of physiological and pathological processes via a large network of dopaminergic projections. To dissect the spatiotemporal dynamics of DA release in both dense and sparsely innervated brain regions, we developed a series of green and red fluorescent G-protein-coupled receptor activation-based DA (GRABDA) sensors using a variety of DA receptor subtypes. These sensors have high sensitivity, selectivity and signal-to-noise ratio with subsecond response kinetics and the ability to detect a wide range of DA concentrations. We then used these sensors in mice to measure both optogenetically evoked and behaviorally relevant DA release while measuring neurochemical signaling in the nucleus accumbens, amygdala and cortex. Using these sensors, we also detected spatially resolved heterogeneous cortical DA release in mice performing various behaviors. These next-generation GRABDA sensors provide a robust set of tools for imaging dopaminergic activity under a variety of physiological and pathological conditions.

(p)ppGpp and moonlighting RNases influence the first step of lipopolysaccharide biosynthesis in Escherichia coli.

The outer membrane (OM) protects Gram-negative bacteria from harsh environmental conditions and provides intrinsic resistance to many antimicrobial compounds. The asymmetric OM is characterized by phospholipids in the inner leaflet and lipopolysaccharides (LPS) in the outer leaflet. Previous reports suggested an involvement of the signaling nucleotide ppGpp in cell envelope homeostasis in Escherichia coli. Here, we investigated the effect of ppGpp on OM biosynthesis. We found that ppGpp inhibits the activity of LpxA, the first enzyme of LPS biosynthesis, in a fluorometric in vitro assay. Moreover, overproduction of LpxA resulted in elongated cells and shedding of outer membrane vesicles (OMVs) with altered LPS content. These effects were markedly stronger in a ppGpp-deficient background. We further show that RnhB, an RNase H isoenzyme, binds ppGpp, interacts with LpxA, and modulates its activity. Overall, our study uncovered new regulatory players in the early steps of LPS biosynthesis, an essential process with many implications in the physiology and susceptibility to antibiotics of Gram-negative commensals and pathogens.

Are aligners capable of inducing palatal bodily translation or palatal root torque of upper central incisors? A biomechanical in vitro study.

OBJECTIVES: Previous studies have shown that aligners have limited ability to control root movements. The purpose of this study was to investigate which modification geometry and foil thickness are optimal for generating the force-moment (F/M) systems required for palatal root torque of maxillary central incisors. MATERIALS AND METHODS: Tooth 11 was separated from a maxillary acrylic model and connected to a movement unit via a 3D F/M sensor. Different modification geometries (crescent, capsular, double-spherical) with different depths were digitally implemented in the labio-cervical region of tooth 11 to induce an increased contact force. We evaluated the F/M systems exerted by aligners with thicknesses of 0.4-1.0 mm. F/M measurements were taken with tooth 11 in the neutral position and during palatal displacement of tooth 11 (simulating its initial clinical movement). RESULTS: The mechanical requirements of palatal root torque are a palatally directed force (- Fy) and a palatal root torquing moment (- Mx). These requirements were reliably achieved with modification depths > 0.5 mm. The modification depth and foil thickness had a significant influence on - Fy magnitudes (linear mixed-effect models, p < 0.01). With the 0.75-mm aligners combined with 1.5-mm deep modifications, the palatal root torque range (palTR) started after an initial palatal crown displacement of 0.09, 0.12, and 0.12 mm for the capsular, crescent, and double-spherical modification geometries, respectively. CONCLUSIONS: A relatively early start of the palatal torque range (after a 0.1-mm palatal crown displacement) and appropriate - Fy magnitudes were achieved with 0.75-mm-thick aligners containing 1.5-mm deep capsular or crescent pressure regions. Subsequent clinical trials are required to confirm the clinical effects of these modifications. CLINICAL RELEVANCE: In vitro testing indicated that modified aligners are capable of generating the F/M components required for palatal root torque of upper central incisors.

Prevalence of temporomandibular disorders and bruxism in seniors.

BACKGROUND: Information on the prevalence of temporomandibular disorders (TMD) or possible/probable bruxism in seniors is heterogeneous and sparse. OBJECTIVES: To elucidate the prevalence of TMD and possible/probable bruxism in German adults aged 60 years and older. METHODS: Participants of the Interdisciplinary Longitudinal Study of Adult Development and Aging (ILSE) born between 1950-1952 (C1) and 1930-1932 (C2) were examined in 2014-2016 (fourth wave). The participants were surveyed and clinically examined by one calibrated examiner. Two questions of the Patient Health Questionnaire (PHQ) were utilised to evaluate self-reported bruxism. The clinical examination included signs of probable bruxism and the RDC/TMD examination protocol. RESULTS: Data from 191 participants were available. No RDC/TMD diagnosis was made in 83.2%. Of the participants, 15.2% received a single diagnosis and 1.6% multiple diagnoses that included disc displacements (9.4%) and degenerative joint diseases (8.9%). A total of 24.7% reported bruxism that included self-reported awake bruxism in 11.9% and sleep bruxism in 16.2%. Wear was clinically identified in 27.2% of the participants. No sex-related differences were observed. Significant differences were detected for probable bruxism between C1 (14.1%) and C2 (54.3%). CONCLUSION: In the German population aged 60 years and older, the prevalence of TMD is 16.8%. TMD is characterised by temporomandibular joint disorders, including disc displacements and degenerative joint disorders. Bruxism was observed in a quarter of the old population.

Sexual function improves as depressive symptoms decrease during treatment with escitalopram: results of a naturalistic study of patients with major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is closely associated with sexual dysfunction, which may worsen during treatment with selective serotonin reuptake inhibitors (SSRIs) due to the side effects of pharmacologic treatment. AIM: To examine the association between sexual function and severity of MDD in drug-naïve patients as compared with healthy controls and how treatment with SSRIs affects sexual function over time in individuals with MDD. Interaction with gender and treatment response was examined. METHODS: In 92 patients with MDD, we measured MDD severity with 6- and 17-item versions of the Hamilton Depression Rating Scale (HDRS6 and HDRS17) and the level of sexual function with the Changes in Sexual Functioning Questionnaire at baseline and 4, 8, and 12 weeks after initiating treatment with escitalopram. Baseline sexual function was compared with the sexual function of 73 healthy controls. Linear regression models were used to assess differences in sexual function between healthy controls and patients and change in sexual function from baseline to week 12. Linear mixed models were used to assess differences in change in sexual function between treatment response groups. OUTCOMES: Outcomes included total scores on the HDRS6, HDRS17, and Changes in Sexual Functioning Questionnaire and changes in total scores from baseline to week 12. RESULTS: Unmedicated patients with MDD reported impaired sexual function as compared with healthy controls. Level of sexual function was not associated with severity of MDD at baseline. Patients' sexual function improved significantly during treatment, which was coupled with amelioration of depressive symptoms. Treatment response groups (remitters, intermediate responders, nonresponders) did not predict change in sexual function. Gender had no effect on sexual dysfunction symptoms during treatment. CLINICAL IMPLICATIONS: Major depression is a risk factor for sexual problems, and improvement in sexual function was coupled with amelioration of depressive symptoms. STRENGTHS AND LIMITATIONS: Among its strengths, this was a naturalistic study reflecting real-world settings in clinical practice. It additionally included a baseline measurement of sexual function and MDD severity on drug-naïve patients prior to the initiation of treatment. Finally, the follow-up of 12 weeks extends beyond the acute phase of treatment in which previous research has observed a peak in sexual side effects. In terms of limitations, there was no placebo arm; thus, the study cannot attribute the effects on sexual function to treatment with antidepressants per se. Also, the patients were young, which may have served as a protective factor against sexual side effects. CONCLUSION: Sexual dysfunction was strongly associated with MDD and improved in parallel with overall symptoms of depression across a standard 12-week treatment with SSRI antidepressants. CLINICAL TRIAL REGISTRATION: NCT02869035 (https://clinicaltrials.gov/ct2/show/NCT02869035).

MultipleXed Population Selection and Enrichment single nucleus RNA sequencing (XPoSE-seq) enables sample identity retention during transcriptional profiling of rare populations.

Single nucleus RNA-sequencing is critical in deciphering tissue heterogeneity and identifying rare populations. However, current high throughput techniques are not optimized for rare target populations and require tradeoffs in design due to feasibility. We provide a novel snRNA pipeline, MulipleXed Population Selection and Enrichment snRNA-sequencing (XPoSE-seq), to enable targeted snRNA-seq experiments and in-depth transcriptomic characterization of rare target populations while retaining individual sample identity.

Resilience of the primary health care system - German primary care practitioners' perspectives during the early COVID-19 pandemic.

BACKGROUND: Primary care is a relevant pillar in managing not only individual, but also societal medical crises. The COVID-19 pandemic has demanded a rapid response from primary care with interventions in the health care system. The aim of this paper was to explore the responses of primary care practitioners (PCP) during the early COVID-19 pandemic and to analyze these with a view on the resilience of the primary health care system from the PCPs perspective. METHODS: Shortly after the first COVID-19 wave (July-October 2020) n = 39, semi-structured telephone interviews were conducted with PCP in practices and at Corona contact points (CCP) in Baden-Wuerttemberg (Germany). Qualitative content analysis was applied, and the evolved categories were related to in a framework for resilience. RESULTS: Primary care had an overall strong ability to adapt and show resilience, albeit with wide variance in speed and scope of the responses. When coping with uncertainty, the reasons given by PCPs in favor of opening a CCP mainly involved intrinsic motivation and self-initiative; the reasons against doing so were i.e. the lack of personal protective equipment, problems with space, and worries about organizational burden. A strong association existed between the establishment of a CCP and the use of resources (i.e. existing networks, personal protective equipment, exercising an office of professional political function). Our study predominantly found adaptive aspects for measures taken at medical practices and transformative aspects for setting up outpatient infection centers. PCPs played an important role in the coordination process (i.e. actively transferring knowledge, integration in crisis management teams, inclusion in regional strategic efforts) reaching a high level in the dimensions knowledge and legitimacy. The dimension interdependence repeatedly came into focus (i.e. working with stakeholders to open CCP, interacting among different types of primary care facilities, intersectoral interfaces). A need for regional capacity planning was visible at the time of the interviews. CONCLUSIONS: The results can be used for practical and research-based institutional and capacity planning, for developing resilience in primary care and for augmentation by perspectives from other stakeholders in the primary health care system.

SMART: An Open-Source Extension of WholeBrain for Intact Mouse Brain Registration and Segmentation.

Mapping immediate early gene (IEG) expression across intact mouse brains allows for unbiased identification of brain-wide activity patterns underlying complex behaviors. Accurate registration of sample brains to a common anatomic reference is critical for precise assignment of IEG-positive ("active") neurons to known brain regions of interest (ROIs). While existing automated voxel-based registration methods provide a high-throughput solution, they require substantial computing power, can be difficult to implement and fail when brains are damaged or only partially imaged. Additionally, it is challenging to cross-validate these approaches or compare them to any preexisting literature based on serial coronal sectioning. Here, we present the open-source R package SMART (Semi-Manual Alignment to Reference Templates) that extends the WholeBrain R package framework to automated segmentation and semi-automated registration of intact mouse brain light-sheet fluorescence microscopy (LSFM) datasets. The SMART package was created for novice programmers and introduces a streamlined pipeline for aligning, registering, and segmenting LSFM volumetric datasets across the anterior-posterior (AP) axis, using a simple "choice game" and interactive menus. SMART provides the flexibility to register whole brains, partial brains or discrete user-chosen images, and is fully compatible with traditional sectioned coronal slice-based analyses. We demonstrate SMART's core functions using example datasets and provide step-by-step video tutorials for installation and implementation of the package. We also present a modified iDISCO+ tissue clearing procedure for uniform immunohistochemical labeling of the activity marker Fos across intact mouse brains. The SMART pipeline, in conjunction with the modified iDISCO+ Fos procedure, is ideally suited for examination and orthogonal cross-validation of brain-wide neuronal activation datasets.

Utilization of dental services and health literacy by older seniors during the COVID-19 pandemic.

BACKGROUND: This study aimed to investigate the utilization of dental services by older seniors during the COVID-19 pandemic and to evaluate their ability of finding, understanding, and using information on COVID-19. METHODS: At the end of February 2021, a survey addressing demographic characteristics of the participants, (pain-associated) utilization of dental services, worries regarding a potential COVID-19 infection, the individual use of protective masks, and difficulties regarding the access to information on COVID-19 (by using the modified European Health Literacy Questionnaire [HLS-EU-Q16]) was developed. It was sent to all patients of the Dental Clinic of University of Leipzig who were either 75, 80, or 85 years old (n = 1228). Participation was voluntarily and anonymously; questionnaires had to be returned within six weeks, no reminders were sent. RESULTS: Of the 439 replies (response rate 35.7%), twelve were excluded from data extraction due to disinterest, dementia, or lack of age information. Of the older seniors, 81.5% (n = 348) had utilized at least one dental examination and 54.2% of the dentulous patients (n = 199) had attended at least one dental hygiene appointment within the past year. Up to 55.8% of all participants said it was "difficult" or "very difficult" to find, understand, and use information on COVID-19, especially when judging reliability of information presented in the media, which was especially true for seniors with assigned care levels presenting odds ratios up to 5.30. CONCLUSIONS: The investigation revealed a frequent utilization of dental services by older seniors during the COVID-19 pandemic. However, the older seniors encountered difficulties finding, using, and understanding information about COVID-19.

[Prevalence of temporomandibular disorders in seniors-Symptom-related analyses in younger and older seniors]. / Prävalenz kraniomandibulärer Dysfunktionen bei Senioren ­ symptombezogene Analysen bei jüngeren und älteren Senioren.

BACKGROUND: Temporomandibular disorders (TMD) are common in the general population even in old age. Information on the prevalence of TMD in older people is sparse. OBJECTIVE: To present prevalence values for symptoms and signs of TMD in old people according to the research diagnostic criteria for temporomandibular disorders (RDC/TMD). To compare prevalence values between the age groups of 60-74 years (younger seniors) and ≥ 75 years (older seniors). MATERIAL AND METHODS: Subjects of the interdisciplinary longitudinal study of adult development (ILSE), a representative sample of old people in Germany, were examined between 2014-2016. Subjects of the urban area of Leipzig were chosen to examine symptoms and signs of TMD. RESULTS: The most prevalent symptom was orofacial pain (13.0%) in the aged participants (n = 192). Temporomandibular joint (TMJ) sounds were the most prevalent sign with values up to 35.5%. Gender comparisons revealed higher prevalence values for the symptom headache/migraine as well as for the signs TMJ sounds (especially clicking sounds) and limited mouth opening in females. Regarding age groups, significant differences were only observed for self-reported headache/migraine. CONCLUSION: Orofacial pain was reported by 13.0% of the subjects and TMJ sounds were observed in every third participant. Similar prevalence values for TMD symptoms and signs in younger and older seniors were found.

Incubation of palatable food craving is associated with brain-wide neuronal activation in mice.

Studies using rodent models have shown that relapse to drug or food seeking increases progressively during abstinence, a behavioral phenomenon termed "incubation of craving." Mechanistic studies of incubation of craving have focused on specific neurobiological targets within preselected brain areas. Recent methodological advances in whole-brain immunohistochemistry, clearing, and imaging now allow unbiased brain-wide cellular resolution mapping of regions and circuits engaged during learned behaviors. However, these whole-brain imaging approaches were developed for mouse brains, while incubation of drug craving has primarily been studied in rats, and incubation of food craving has not been demonstrated in mice. Here, we established a mouse model of incubation of palatable food craving and examined food reward seeking after 1, 15, and 60 abstinence days. We then used the neuronal activity marker Fos with intact-brain mapping procedures to identify corresponding patterns of brain-wide activation. Relapse to food seeking was significantly higher after 60 abstinence days than after 1 or 15 days. Using unbiased ClearMap analysis, we identified increased activation of multiple brain regions, particularly corticostriatal structures, following 60 but not 1 or 15 abstinence days. We used orthogonal SMART2 analysis to confirm these findings within corticostriatal and thalamocortical subvolumes and applied expert-guided registration to investigate subdivision and layer-specific activation patterns. Overall, we 1) identified brain-wide activity patterns during incubation of food seeking using complementary analytical approaches and 2) provide a single-cell resolution whole-brain atlas that can be used to identify functional networks and global architecture underlying the incubation of food craving.

Older Seniors during the COVID-19 Pandemic-Social Support and Oral Health-Related Quality of Life.

The coronavirus disease (COVID-19) has greatly affected all parts of private life and led to social distancing and self-isolation. Limited social support for older or frail people might have led to decreased oral health and its related quality of life. The current study aimed to investigate the social support of older seniors and self-perceived oral health-related quality of life (OHRQoL) over the course of the COVID-19 pandemic. Questionnaires were sent to all patients of the Dental Clinic of the University of Leipzig (Germany) aged 75, 80, or 85 years (n = 1228) at the end of February 2021. Besides demographic characteristics and care level, an adapted German version of the ENRICHD Social Support Inventory (ESSI-D) and the German Oral Health Impact Profile-14 (OHIP-14) were included. The response rate was 35.7% (n = 439). Twelve replies were not included in the data analysis as participants had either no interest, were cognitively impaired, or did not match the required age group. Analysis of ESSI-D revealed low social support for 13.2% (n = 53/403) of the seniors. No statistically significant impact of assigned care level on low social support was identified. Seniors with an assigned care level (CLyes) presented higher OHIP-14 sum scores (CLno/CLyes 6.43/10.12; p < 0.001). This was also true for six of the seven OHIP-14 domains, except for functional limitation. Regarding seniors with an assigned care level, a weak positive correlation was identified for sum scores of the ESSI-D and the OHIP-14 (r = 0.29). Despite the COVID-19 pandemic, older seniors reported high self-perceived social support. As seniors with an assigned care level revealed more impaired OHRQoL and a correlation with lower social support, special attention should be given to this vulnerable and frail group in times of a pandemic. When restrictions may minimize access to dental treatment and might negatively influence the oral health of older seniors, health care programs should offer more individual options for dental/medical appointments.

Inactivation of the infralimbic cortex decreases discriminative stimulus-controlled relapse to cocaine seeking in rats.

Persistent susceptibility to cue-induced relapse is a cardinal feature of addiction. Discriminative stimuli (DSs) are one type of drug-associated cue that signal drug availability (DS+) or unavailability (DS-) and control drug seeking prior to relapse. We previously established a trial-based procedure in rats to isolate DSs from context, conditioned stimuli, and other drug-associated cues during cocaine self-administration and demonstrated DS-controlled cocaine seeking up to 300 abstinence days. The behavioral and neural mechanisms underlying trial-based DS-control of drug seeking have rarely been investigated. Here we show that following discrimination training in our trial-based procedure, the DS+ and DS- independently control the expression and suppression of cocaine seeking during abstinence. Using microinjections of GABAA + GABAB receptor agonists (muscimol + baclofen) in medial prefrontal cortex, we report that infralimbic, but not prelimbic, subregion of medial prefrontal cortex is critical to persistent DS-controlled relapse to cocaine seeking after prolonged abstinence, but not DS-guided discriminated cocaine seeking or DS-controlled cocaine self-admininstration. Finally, using ex vivo whole-cell recordings from pyramidal neurons in the medial prefrontal cortex, we demonstrate that the disruption of DS-controlled cocaine seeking following infralimbic cortex microinjections of muscimol+baclofen is likely a result of suppression of synaptic transmission in the region via a presynaptic mechanism of action.

Perception of Old Age in German Undergraduate Dental Students-A Comparison of Two Cohorts 10 Years Apart.

Previous studies revealed that students' willingness to provide dental services for older patients is mainly influenced by their individual perception of elders rather than their knowledge about old age. The aim of this study was to estimate students' perception of old and young age as well as their hopes and fears associated with old age and to compare two cohorts that participated in the study 10 years apart. Data were obtained from a questionnaire completed by two cohorts of undergraduate dental students from 2006 to 2008 (T1, n = 207) and 2016 to 2018 (T2, n = 135). Participants were asked to define the ages that they consider a man or woman to be old and young. Moreover, they had to specify their fears and hopes associated with old age. Reported thresholds for old age differed significantly between T1 and T2. In contrast to T1 students, T2 students defined a person to be old at a higher age and barely differentiated between the old ages of men and women. Furthermore, T2 students presented more fears related to aging than T1 students, e.g., psychological problems or loss of independence. The perception of age appears to be a multifactorial process and significantly changed between students of T1 and T2. Fears of dental students regarding old age should be addressed in, e.g., gerodontological curricula, to foster positive experiences in interaction with older people and highlight the important and rewarding aspects of gerodontology.

Considerations for the Prosthetic Dental Treatment of Geriatric Patients in Germany.

Demographic changes in the industrialized countries require that dentists adapt to the growing and heterogeneous group of elderly patients and develop concepts for the dental care of fit, frail, and dependent old and very old people. In general, dental care for old and very old people should be based on their individual everyday life. As a result of demographic changes, improved oral hygiene at home, and the establishment of professional teeth and denture cleaning, tooth loss occurs increasingly in higher ages, which implies that first extensive prosthetic rehabilitation with fixed or/and removable dental prostheses is shifting to a higher average age than ever before. This phenomenon requires that the individual diseases, potential multimorbidity and polypharmacy, and associated limitations are taken into consideration. Against this background, the current survey aims to summarize epidemiological trends associated with tooth loss, using Germany as a highly representative country for demographic changes as an example. Furthermore, the current narrative summary outlines general principles that should be followed in dental care, treatment of geriatric patients, and outlines current therapeutic options in prosthetic dentistry.

Discriminative stimuli are sufficient for incubation of cocaine craving.

In abstinent drug addicts, cues formerly associated with drug-taking experiences gain relapse-inducing potency ('incubate') over time. Animal models of incubation may help develop treatments to prevent relapse, but these models have ubiquitously focused on the role of conditioned stimuli (CSs) signaling drug delivery. Discriminative stimuli (DSs) are unique in that they exert stimulus-control over both drug taking and drug seeking behavior and are difficult to extinguish. For this reason, incubation of the excitatory effects of DSs that signal drug availability, not yet examined in preclinical studies, could be relevant to relapse prevention. We trained rats to self-administer cocaine (or palatable food) under DS control, then investigated DS-controlled incubation of craving, in the absence of drug-paired CSs. DS-controlled cocaine (but not palatable food) seeking incubated over 60 days of abstinence and persisted up to 300 days. Understanding the neural mechanisms of this DS-controlled incubation holds promise for drug relapse treatments.

Trial-based Discrimination Procedure for Studying Drug Relapse in Rats.

In abstinent drug addicts, cues formerly associated with drug-taking experiences gain relapse-inducing potency ('incubate') over time. Animal models of incubation may help in developing treatments for relapse prevention. However, these models have primarily focused on the role of conditioned stimuli (CSs) signaling drug delivery and not on discriminative stimuli (DSs), which signal drug availability and are also known to play a major role in drug relapse. We recently showed that DS-controlled cocaine seeking in rats also incubates during abstinence and persists up to 300 days. We used a trial-based procedure to train male and female rats to discriminate between two light cues: one light cue (DS+) signaled the availability of cocaine reward and the second light cue (DS-) signaled the absence of reward. Rats learned to press a central retractable lever during trials in which the DS+ cue was presented and to suppress responding when the DS- cue was presented. Here, we provide a detailed protocol for the behavioral procedure used in our study. The trial-based design of this behavior lends itself well to time-locked in vivo recording and manipulation approaches that can be used to identify neurobiological mechanisms underlying the contributions of DSs to drug relapse.

Maladaptive Decision Making in Adults with a History of Adolescent Alcohol use, in a Preclinical Model, Is Attributable to the Compromised Assignment of Incentive Value during Stimulus-Reward Learning.

According to recent WHO reports, alcohol remains the number one substance used and abused by adolescents, despite public health efforts to curb its use. Adolescence is a critical period of biological maturation where brain development, particularly the mesocorticolimbic dopamine system, undergoes substantial remodeling. These circuits are implicated in complex decision making, incentive learning and reinforcement during substance use and abuse. An appealing theoretical approach has been to suggest that alcohol alters the normal development of these processes to promote deficits in reinforcement learning and decision making, which together make individuals vulnerable to developing substance use disorders in adulthood. Previously we have used a preclinical model of voluntary alcohol intake in rats to show that use in adolescence promotes risky decision making in adulthood that is mirrored by selective perturbations in dopamine network dynamics. Further, we have demonstrated that incentive learning processes in adulthood are also altered by adolescent alcohol use, again mirrored by changes in cue-evoked dopamine signaling. Indeed, we have proposed that these two processes, risk-based decision making and incentive learning, are fundamentally linked through dysfunction of midbrain circuitry where inputs to the dopamine system are disrupted by adolescent alcohol use. Here, we test the behavioral predictions of this model in rats and present the findings in the context of the prevailing literature with reference to the long-term consequences of early-life substance use on the vulnerability to develop substance use disorders. We utilize an impulsive choice task to assess the selectivity of alcohol's effect on decision-making profiles and conditioned reinforcement to parse out the effect of incentive value attribution, one mechanism of incentive learning. Finally, we use the differential reinforcement of low rates of responding (DRL) task to examine the degree to which behavioral disinhibition may contribute to an overall decision-making profile. The findings presented here support the proposition that early life alcohol use selectively alters risk-based choice behavior through modulation of incentive learning processes, both of which may be inexorably linked through perturbations in mesolimbic circuitry and may serve as fundamental vulnerabilities to the development of substance use disorders.