Role of dopamine neurons in familiarity.

Dopamine neurons signal the salience of environmental stimuli and influence learning, although it is less clear if these neurons also determine the salience of memories. Ventral tegmental area (VTA) dopamine neurons increase their firing in the presence of new objects and reduce it upon repeated, inconsequential exposures, marking the shift from novelty to familiarity. This study investigates how dopamine neuron activity during repeated familiar object exposure affects an animal's preference for new objects in a subsequent novel object recognition (NOR) test. We hypothesize that a single familiarization session will not sufficiently lower dopamine activity, such that the memory of a familiar object remains salient, leading to equal exploration of familiar and novel objects and weaker NOR discrimination. In contrast, multiple familiarization sessions likely suppress dopamine activity more effectively, reducing the salience of the familiar object and enhancing subsequent novelty discrimination. Our experiments in mice indicated that multiple familiarization sessions reduce VTA dopamine neuron activation, as measured by c-Fos expression, and enhance novelty discrimination compared with a single familiarization session. Dopamine neurons that show responsiveness to novelty were primarily located in the paranigral nucleus of the VTA and expressed vesicular glutamate transporter 2 transcripts, marking them as dopamine-glutamate neurons. Chemogenetic inhibition of dopamine neurons during a single session paralleled the effects of multiple sessions, improving NOR. These findings suggest that a critical role of dopamine neurons during the transition from novelty to familiarity is to modulate the salience of an object's memory.

Food restriction induces synaptic incorporation of calcium-permeable AMPA receptors in nucleus accumbens.

Chronic food restriction potentiates behavioral and cellular responses to drugs of abuse and D-1 dopamine receptor agonists administered systemically or locally in the nucleus accumbens (NAc). However, the alterations in NAc synaptic transmission underlying these effects are incompletely understood. AMPA receptor trafficking is a major mechanism for regulating synaptic strength, and previous studies have shown that both sucrose and d-amphetamine rapidly alter the abundance of AMPA receptor subunits in the NAc postsynaptic density (PSD) in a manner that differs between food-restricted and ad libitum fed rats. In this study we examined whether food restriction, in the absence of reward stimulus challenge, alters AMPAR subunit abundance in the NAc PSD. Food restriction was found to increase surface expression and, specifically, PSD abundance, of GluA1 but not GluA2, suggesting synaptic incorporation of GluA2-lacking Ca2+-permeable AMPARs (CP-AMPARs). Naspm, an antagonist of CP-AMPARs, decreased the amplitude of evoked EPSCs in NAc shell, and blocked the enhanced locomotor response to local microinjection of the D-1 receptor agonist, SKF-82958, in food-restricted, but not ad libitum fed, subjects. Although microinjection of the D-2 receptor agonist, quinpirole, also induced greater locomotor activation in food-restricted than ad libitum fed rats, this effect was not decreased by Naspm. Taken together, the present findings are consistent with the synaptic incorporation of CP-AMPARs in D-1 receptor-expressing medium spiny neurons in NAc as a mechanistic underpinning of the enhanced responsiveness of food-restricted rats to natural rewards and drugs of abuse.

Role of Dopamine Neurons in Familiarity.

Dopamine neurons signal the salience of environmental stimuli, influencing learning and motivation. However, research has not yet identified whether dopamine neurons also modulate the salience of memory content. Dopamine neuron activity in the ventral tegmental area (VTA) increases in response to novel objects and diminishes as objects become familiar through repeated presentations. We proposed that the declined rate of dopamine neuron activity during familiarization affects the salience of a familiar object's memory. This, in turn, influences the degree to which an animal distinguishes between familiar and novel objects in a subsequent novel object recognition (NOR) test. As such, a single familiarization session may not sufficiently reduce dopamine activity, allowing the memory of a familiar object to maintain its salience and potentially attenuating NOR. In contrast, multiple familiarization sessions could lead to more pronounced dopamine activity suppression, strengthening NOR. Our data in mice reveals that, compared to a single session, multiple sessions result in decreased VTA dopamine neuron activation, as indicated by c-Fos measurements, and enhanced novelty discrimination. Critically, when VTA dopamine neurons are chemogenetically inhibited during a single familiarization session, NOR improves, mirroring the effects of multiple familiarization sessions. In summary, our findings highlight the pivotal function of dopamine neurons in familiarity and suggest a role in modulating the salience of memory content.

A randomized clinical trial of strengths-based case management to link emergency department patients to opioid use disorder treatment.

BACKGROUND: Despite the existence of effective pharmacotherapies, rates of opioid use disorder and opioid overdose deaths have continued to increase. Emergency department (ED) visits provide an important opportunity to engage in treatment patients with untreated opioid use disorder (OUD). Case management implemented in other settings is effective in linking those with opioid and other drug use disorders to longer-term treatment, but research has not established its efficacy in the ED. Here we report the results of a trial of Strengths-Based Case Management (SBCM) for people with untreated OUD who are identified during ED visits, with the primary goal of linking them to pharmacologic treatment. METHODS: The study identified patients with untreated OUD during a treatment episode at a large urban ED. The study randomly assigned three hundred participants in 1:1 ratio to receive SBCM or screening, assessment, and referral (SAR) to OUD treatment. Those assigned to SBCM received up to six sessions of SBCM with the primary goal of linkage to treatment. Primary outcomes were initiation of treatment and engagement in pharmacotherapy for OUD. The study defined a "successful outcome" for opioid use as a 3-month urine negative for illicit opioids and no more than 2 days of self-reported opioid misuse in the 4 weeks prior to the 3-month interview. RESULTS: Rates of treatment initiation were not significantly different in the SBCM and SAR groups (57.4% vs. 49.7%, respectively, p > 0.05), nor did engagement in pharmacotherapy differ significantly between groups (p > 0.05). During the 90 days following the index ED visit, SBCM and SAR participants engaged in pharmacotherapy for a mean of 21.8% (SD = 35.1%) versus 17.7% (SD = 31.0%) of days, respectively. Likewise, no significant difference occurred between groups in rates of "successful opioid use outcome" as defined a priori (p > 0.05), although self-reported opioid use over the entire 6-month follow-up period was lower in the SBCM group (10.8 vs. 13.4 days/month, p = 0.042). CONCLUSIONS: SBCM-ED did not improve OUD treatment initiation and engagement in this ED study. Although these findings do not necessarily generalize to all EDs, other approaches, such as direct referral or initiation of treatment in the ED, have considerable empirical support, and should be implemented where they are feasible.

Implementation of strength-based case management for opioid-dependent patients presenting in medical emergency departments: rationale and study design of a randomized trial.

BACKGROUND: As the USA grapples with an opioid epidemic, medical emergency departments (EDs) have become a critical setting for intervening with opioid-dependent patients. Brief interventions designed to bridge the gap from acute ED care to longer-term treatment have shown limited efficacy for this population. Strength-based case management (SBCM) has shown strong effects on treatment linkage among patients with substance use disorders in other healthcare settings. This study aimed to investigate whether SBCM is an effective model for linking opioid-dependent ED patients with addiction treatment and pharmacotherapy. Here, we describe the implementation and challenges of adapting SBCM for the ED (SBCM-ED). Study rationale, design, and baseline characteristics are also described. METHODS: This study compared the effects of SBCM-ED to screening, assessment, and referral alone (SAR) on treatment linkage, substance use, and functioning. We recruited participants from a public hospital in NYC. Working alliance between case managers and participants and the feasibility of SBCM implementation were evaluated. Baseline data from the randomized sample were analyzed for group equivalency. Outcomes analyses are forthcoming. RESULTS: Three hundred adult participants meeting DSM-IV criteria for opioid dependence were randomly assigned to either SBCM, in which they received a maximum of six case management sessions within 90 days of enrollment, or SAR, in which they received a comprehensive referral list and pamphlet outlining drug use consequences. No significant differences were found between groups at baseline on demographic or substance use characteristics. All SAR participants and 92.6% of SBCM-ED participants initiated their assigned intervention. Over half of SBCM-ED first sessions occurred in the ED on the day of enrollment. Case managers developed a strong working alliance with SBCM-ED participants after just one session. CONCLUSION: Interventions that exceed SBIRT were accepted by an opioid-dependent patient population seen in an urban medical ED. At the time of study funding, this trial was one of the first to focus specifically on this population in this challenging setting. The successful implementation of SBCM demonstrates its adaptability to the ED and may serve as a potential model for EDs seeking to adopt an intervention that overcomes the barrier between the ED encounter and more intensive treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT02586896 . Registered on 27 October 2015.