A Genetically Defined Compartmentalized Striatal Direct Pathway for Negative Reinforcement.

The striosome compartment within the dorsal striatum has been implicated in reinforcement learning and regulation of motivation, but how striosomal neurons contribute to these functions remains elusive. Here, we show that a genetically identified striosomal population, which expresses the Teashirt family zinc finger 1 (Tshz1) and belongs to the direct pathway, drives negative reinforcement and is essential for aversive learning in mice. Contrasting a "conventional" striosomal direct pathway, the Tshz1 neurons cause aversion, movement suppression, and negative reinforcement once activated, and they receive a distinct set of synaptic inputs. These neurons are predominantly excited by punishment rather than reward and represent the anticipation of punishment or the motivation for avoidance. Furthermore, inhibiting these neurons impairs punishment-based learning without affecting reward learning or movement. These results establish a major role of striosomal neurons in behaviors reinforced by punishment and moreover uncover functions of the direct pathway unaccounted for in classic models.

Consolidating the Circuit Model for Addiction.

Addiction is a disease characterized by compulsive drug seeking and consumption observed in 20-30% of users. An addicted individual will favor drug reward over natural rewards, despite major negative consequences. Mechanistic research on rodents modeling core components of the disease has identified altered synaptic transmission as the functional substrate of pathological behavior. While the initial version of a circuit model for addiction focused on early drug adaptive behaviors observed in all individuals, it fell short of accounting for the stochastic nature of the transition to compulsion. The model builds on the initial pharmacological effect common to all addictive drugs-an increase in dopamine levels in the mesolimbic system. Here, we consolidate this early model by integrating circuits underlying compulsion and negative reinforcement. We discuss the genetic and epigenetic correlates of individual vulnerability. Many recent data converge on a gain-of-function explanation for circuit remodeling, revealing blueprints for novel addiction therapies.

Aberrant reward learning, but not negative reinforcement learning, is related to depressive symptoms: an attentional perspective.

BACKGROUND: Aberrant reward functioning is implicated in depression. While attention precedes behavior and guides higher-order cognitive processes, reward learning from an attentional perspective - the effects of prior reward-learning on subsequent attention allocation - has been mainly overlooked. METHODS: The present study explored the effects of reward-based attentional learning in depression using two separate, yet complimentary, studies. In study 1, participants with high (HD) and low (LD) levels of depression symptoms were trained to divert their gaze toward one type of stimuli over another using a novel gaze-contingent music reward paradigm - music played when fixating the desired stimulus type and stopped when gazing the alternate one. Attention allocation was assessed before, during, and following training. In study 2, using negative reinforcement, the same attention allocation pattern was trained while substituting the appetitive music reward for gazing the desired stimulus type with the removal of an aversive sound (i.e. white noise). RESULTS: In study 1 both groups showed the intended shift in attention allocation during training (online reward learning), while generalization of learning at post-training was only evident among LD participants. Conversely, in study 2 both groups showed post-training generalization. Results were maintained when introducing anxiety as a covariate, and when using a more powerful sensitivity analysis. Finally, HD participants showed higher learning speed than LD participants during initial online learning, but only when using negative, not positive, reinforcement. CONCLUSIONS: Deficient generalization of learning characterizes the attentional system of HD individuals, but only when using reward-based positive reinforcement, not negative reinforcement.

Management of dairy heifers: Can operant conditioning be an effective and feasible tool to decrease stress and ease animals' close contact and handling?

Besides health monitoring, a regular check of dairy heifers' growth rate is desirable, but it is rarely done because procedures that require restraint and handling can be associated with substantial stress for both animals and farmers. Inexperienced heifers, especially if they are highly responsive to humans, may find restraint and handling potentially aversive. This study investigated whether training heifers of different age and responsiveness toward humans (RTH), through operant conditioning, could reduce stress in animals, ease close contact and handling, and be feasible in terms of farmers' effort. We assessed 60 Holstein heifers of 2 age classes (young, n = 29, 291 ± 39 d; old, n = 31, 346 ± 62 d) according to the avoidance distance test and classified them as confident (n = 20), neutral (n = 21), or nonconfident (n = 19). Half of the heifers of each age and RTH class were trained (n = 29), whereas the other half was not (n = 31). The trained heifers were subjected to target training for 8 sessions and positively reinforced with feed to allow being touched on the muzzle, rump, and perineum. If a heifer refused positive reinforcement, the trainer stepped back as negative reinforcement. In the last week of the experiment, the effect of training on the reaction to handling was assessed in all heifers. We measured heart rate, root mean square of successive interbeat interval differences (RMSSD), and fecal cortisol metabolites (FCMet). The presence of behavioral distress signs was recorded as well. The avoidance distance test was performed a second time 24 h after the measuring session. All of the trained heifers, regardless of RTH class, successfully accomplished the target training task in 6 sessions, each spending on average 25.3 s per session. All of the trained heifers allowed touches on the rump and perineum at the end of the fourth session. Training nonconfident heifers required more time compared with the others. Trained heifers showed higher RMSSD than nontrained heifers (14.2 vs. 16.9 ms, respectively), indicating a lower vagal tone, and thus, a slightly lower stress level than nontrained heifers. Training did not lead to differences in HR, FCMet, or presence of stress behavioral signs. Nonconfident heifers had the highest mean baseline FCMet values compared with neutral and confident heifers (38.4 vs. 30.3 vs. 29.1 ng/g, respectively). Nonconfident heifers also showed the lowest value of FCMet 12 h after the measuring session (36.7 vs. 44.6 vs. 49.7 ng/g), likely due to a decreased responsiveness of the adrenal gland to a stressor. The average avoidance distance decreased between the beginning and the end of the experiment, especially for neutral and nonconfident heifers, regardless of whether they were trained or not. These results show how using operant conditioning on some heifers not only decreased their vagal tone, but also reduced the responsiveness to humans of all the animals, trained and not trained; in the latter case, this reduction was through nonassociative learning, such as habituation.

Development and Validation of the Maternal Drinking Motives Scale (M-DMS).

BACKGROUND: Alcohol use is a gendered behavior and motherhood is a life stage which may influence drinking motives. However, there are no drinking motive scales uniquely tailored to maternal populations. This work developed a new maternal drinking motives scale (M-DMS) and determined associations between the M-DMS and alcohol-related behavior. METHODS: An online observational survey (n = 534) and online test-retest survey (n = 164) were conducted with adult, UK mothers. From the observational study, data on drinking motives was extracted to determine M-DMS items and factor loading. This was split into two data sets for exploratory and confirmatory factor analyses. Alcohol Use Disorders Identification Test (AUDIT) and Timeline Follow back data, taken from both surveys, were combined to determine the M-DMS's predictive validity. RESULTS: Following a parallel analysis and exploratory factor analysis, a two-factor model (positive reinforcement motives, negative reinforcement motives) was deemed the best fit. Probability functional analysis identified items with problematic responses. These were removed before confirmatory factor analysis (on the second dataset) demonstrated a good fit for the two-factor model. All factor loadings were significant and positive (ßs > 0.56). Reliability of the two subscales was excellent: negative reinforcement (ωT = 0.95), positive reinforcement (ωT = 0.89). Test-retest reliability was good for both negative (ICC = 0.84, 95%CI = 0.80-0.88) and positive (ICC = 0.77, 95% CI = 0.71-0.82) subscales. Both subscales predicted AUDIT and quantity of alcohol consumption (ps < 0.001). CONCLUSION: The first tailored Maternal Drinking Motives Scale (M-DMS) provides a more valid research tool for assessing psychological mechanisms of alcohol use in mothers.

Anxiety Sensitivity and Intolerance of Uncertainty: Transdiagnostic Risk Factors for Anxiety as Targets to Reduce Risk of Suicide.

PURPOSE OF REVIEW: Suicide has a profound impact on individuals, families, and society. One prominent, if understudied, risk factor for suicide is anxiety. More than 70% of people with at least one suicide attempt meet diagnostic criteria for an anxiety disorder. There are several limitations to exploring the associations between anxiety and suicide using diagnosis-based classification systems. A better approach would be to consider transdiagnostic risk factors for anxiety. RECENT FINDINGS: Through a negative reinforcement model of suicide, anxiety sensitivity (AS) and intolerance of uncertainty (IU) appear to exacerbate the experience of unpleasant anxiety sensations and likely contribute to chronic suicide risk as well as acute suicidal acts. Although more research is needed to clarify the mechanisms through which AS and IU confer risk, brief interventions may offer an ideal suicide prevention strategy for anxious people.

Behavioral reinforcement of pathological exercise in anorexia nervosa.

Pathological exercise in anorexia nervosa (AN) is a harmful behavior associated with a chronic course and poor prognosis. To date, no comprehensive theoretical model exists to describe pathological exercise in the context of AN, and as such, few treatments are effective at promoting direct and sustained pathological exercise extinction. Using a framework put forth by Wise & Koob (2014), debating the relative importance of positive and negative reinforcement in substance use, we present three hypotheses of behavioral reinforcement of exercise, encompassing biological, psychological, and environmental influences. Specifically, we argue that exercise is positively reinforced through receipt of biological and behavioral rewards, negatively reinforced through avoidance of aversive emotions, and that these two systems work in tandem over time to engrain pathological exercise as a habit. We then present suggestions for testing each of these hypotheses as future directions for the field.

Activation of trace amine-associated receptor 1 attenuates nicotine withdrawal-related effects.

Nicotine addiction is a leading avoidable brain disorder globally. Although nicotine induces a modest reinforcing effect, which is important for the initial drug use, the transition from nicotine use to nicotine addiction involves the mechanisms responsible for the negative consequences of drug abstinence. Recent study suggested that trace amine-associated receptor 1 (TAAR1) is a promising pharmacological target for the modulation of positive reinforcing effects of nicotine. However, whether TAAR1 plays a part in the negative reinforcement of nicotine withdrawal remains to be determined. Here, using a long-access (LA) self-administration model, we investigated whether LA rats show increased nicotine intake and withdrawal symptoms in comparison with saline and ShA rats and then tested the effect of TAAR1 partial agonist RO5263397 on nicotine withdrawal effects. We found that rats from long-access group showed significant abstinence-induced anxiety-like behaviour, mechanic hypersensitivity, increased number of precipitated withdrawal signs and higher motivation for the drug, while rats from short-access did not differ from saline group. TAAR1 partial agonist RO5263397 significantly reduced the physical and motivational withdrawal effects of nicotine in LA rats, as reflected by increased time spent on the open arm in the elevated plus maze (EPM) test, normalized paw withdrawal threshold, decreased withdrawal signs and motivation to self-administer nicotine. This study indicates that activation of TAAR1 attenuates the negative-reinforcing effects of nicotine withdrawal and further suggests TAAR1 as a promising target to treat nicotine addiction.

Dissociating brain systems that respond to contingency and valence during monetary loss avoidance in adolescence.

Negative reinforcement processes allow individuals to avoid negative and/or harmful outcomes. They depend on the brain's ability to differentiate; (i) contingency from non-contingency, separately from (ii) judgements about positive and negative valence. Thirty-three males (8-18 years) performed a cued reaction-time task during fMRI scanning to differentiate the brain's responses to contingency and valence during loss avoidance. In two conditions, cues indicated no -contingency between participants' responses and monetary loss - (1) CERTAIN LOSS (negative valence) of €0.20, €1 or €5 or (2) CERTAIN LOSS AVOIDANCE (positive valence). In a third condition, cues indicated a contingency between short reaction times and avoidance of monetary loss. As expected participants had shorter reaction times in this latter condition where CONDITIONAL LOSS AVOIDANCE cues activated salience and motor-response-preparation brain networks - independent of the relative valence of the contrast (CERTAIN LOSS or CERTAIN LOSS AVOIDANCE). Effects of valence were seen toward the session's end where CERTAIN LOSS AVOIDANCE cues activated ventral striatum, medial-orbitofrontal cortex and medial-temporal areas more than CERTAIN LOSS. CONDITIONAL LOSS AVOIDANCE trials with feedback indicating "success" activated ventral striatum more than "failure feedback". The findings support the hypothesis that brain networks controlling contingency and valence processes during negative reinforcement are dissociable.

The role of matrix metalloproteinase-9 in negative reinforcement learning and plasticity in alcohol dependence.

A role for matrix metalloproteinases (MMPs) in plasticity-dependent learning has been established. MMPs degrade the extracellular matrix (ECM) when synaptic reorganization is warranted. Previously, we showed that escalation of alcohol self-administration is a learned plasticity-dependent process that requires an intact MMP system. To identify the MMP subtypes within specific brain regions that are associated with plasticity underlying the negative reinforcing effects of alcohol (as measured by escalated alcohol self-administration) during acute withdrawal in alcohol dependence, male Wistar rats were trained to self-administer alcohol in an operant paradigm, subjected to one month of intermittent alcohol vapor exposure to induce alcohol dependence and then allowed to self-administer alcohol during repeated acute withdrawal self-administration sessions. Subsequently, rat brains were extracted after initial or stable escalated alcohol self-administration phases of acute withdrawal and analyzed by immunoblot to detect MMP-2, -3, and -9 levels in the anterior cingulate cortex (ACC), bed nucleus of the stria terminalis, central amygdala (CeA), hippocampus, and nucleus accumbens (NAc). The results showed that MMP-9 expression in the CeA and NAc of alcohol-dependent rats was increased, however, MMP-9 expression in the ACC was decreased during negative reinforcement learning. Subsequently, the importance of plasticity mediated by MMP-9 in escalated alcohol self-administration during acute withdrawal was functionally assessed through site-specific intra-CeA MMP-9 inhibition during repeated acute withdrawal self-administration sessions. MMP-9 inhibition prevented acute withdrawal-induced escalation of alcohol self-administration in a manner that was not confounded by locomotor effects or a permanent inability to learn about the negative reinforcing effects of alcohol.

Modeling the Distinct Negative-Reinforcement Mechanisms Associated with Alcohol Misuse and Unhealthy Snacking.

BACKGROUND: Negative personality characteristics have been implicated in promoting overconsumption of both alcohol and food. Furthermore, positive motivations (enhancement) and negative motivations (coping) may mediate the association between personality and alcohol or food (over)consumption. OBJECTIVES: This study hypothesized that i.) drinking to cope and ii.) eating to cope would mediate the association between hopelessness/anxiety sensitivity and hazardous drinking/unhealthy snacking, respectively, and iii.) eating and drinking to cope would represent separate strategies. METHODS: Participants were recruited via opportunity sampling through university schemes, social media, email and web page advertisements. Questionnaires included the Alcohol Use Disorders Identification Test, Substance Use Risk Profile Scale, Modified Drinking Motives Questionnaire Short Form, Palatable Eating Motives Scale and Snack/Meal Food Intake Measure. RESULTS: Participants were 198 undergraduates, weight-related research volunteers and the public (83% female; 90% university educated). The hypothesized structural model fit the data well. As predicted, there were significant indirect associations between negative personality characteristics, hazardous drinking and unhealthy snacking via coping; specifically, individuals higher in anxiety sensitivity/hopelessness used food or alcohol to cope which, in turn, significantly predicted unhealthy snacking, and hazardous drinking, respectively. Importantly, drinking and eating to cope represented outcome-specific strategies, indicated by no significant association between eating to cope and hazardous drinking, or between drinking to cope and snacking. CONCLUSIONS: This study demonstrates that coping motivations are critical to the relationship between negative personality characteristics and unhealthy behaviors and highlights the distinct negative-reinforcement pathways associated with hazardous drinking and unhealthy snacking in majority university-educated females from the UK.

The impact of PTSD clusters on cannabis use in a racially diverse trauma-exposed sample: An analysis from ecological momentary assessment.

BACKGROUND: Accumulating evidence indicates a link between post-traumatic stress disorder (PTSD) and cannabis use and suggests that this link may vary as a function of the PTSD symptom cluster type. Consistent with negative reinforcement models of substance use, individuals with elevated Cluster D (Hyperarousal) symptoms may be more likely to use cannabis in response to elevated state anxiety and experience decreases in state anxiety after using cannabis. OBJECTIVES: We aimed to test hypotheses that the interaction of Cluster D and state anxiety would be related to subsequent cannabis use and that those with elevated Cluster D symptoms who used cannabis would report the greatest decreases in state anxiety. To test the specificity, we tested whether Clusters B (re-experiencing) and C (avoidance) showed similar relationships. METHODS: The present study used ecological momentary assessment to examine cannabis use among 87 cannabis-using individuals with PTSD symptoms (64.4% male, 56.3% non-Hispanic Caucasian). State anxiety and cannabis use were assessed over the two-week period via signal contingent (six random prompts per day), interval contingent (each bedtime), and event contingent (cannabis use episodes) assessments. RESULTS: Consistent with negative reinforcement models, participants with clinically significant Cluster D symptoms with elevated state anxiety had a greater likelihood of subsequent cannabis use and cannabis use resulted in less subsequent anxiety. The negative reinforcement hypothesis was only partially supported for those with Cluster B and C symptoms. CONCLUSIONS: The results suggest that negative reinforcement models may be especially relevant to understanding cannabis use among those with clinically elevated Cluster D symptoms.

Dopaminergic Contributions to Vocal Learning.

Although the brain relies on auditory information to calibrate vocal behavior, the neural substrates of vocal learning remain unclear. Here we demonstrate that lesions of the dopaminergic inputs to a basal ganglia nucleus in a songbird species (Bengalese finches, Lonchura striata var. domestica) greatly reduced the magnitude of vocal learning driven by disruptive auditory feedback in a negative reinforcement task. These lesions produced no measureable effects on the quality of vocal performance or the amount of song produced. Our results suggest that dopaminergic inputs to the basal ganglia selectively mediate reinforcement-driven vocal plasticity. In contrast, dopaminergic lesions produced no measurable effects on the birds' ability to restore song acoustics to baseline following the cessation of reinforcement training, suggesting that different forms of vocal plasticity may use different neural mechanisms. SIGNIFICANCE STATEMENT: During skill learning, the brain relies on sensory feedback to improve motor performance. However, the neural basis of sensorimotor learning is poorly understood. Here, we investigate the role of the neurotransmitter dopamine in regulating vocal learning in the Bengalese finch, a songbird with an extremely precise singing behavior that can nevertheless be reshaped dramatically by auditory feedback. Our findings show that reduction of dopamine inputs to a region of the songbird basal ganglia greatly impairs vocal learning but has no detectable effect on vocal performance. These results suggest a specific role for dopamine in regulating vocal plasticity.

Active avoidance requires a serial basal amygdala to nucleus accumbens shell circuit.

Freezing is a species-typical defensive reaction to conditioned threats. While the neural circuitry of aversive Pavlovian behavior has been extensively studied, less is known about the circuitry underlying more active responses to danger. Here we show that the flow of information between the basal amygdala (BA) and the nucleus accumbens (NAcc) is necessary for signaled active avoidance behavior. Rats trained to avoid shock by shuttling during an auditory conditioned stimulus showed increased expression of the activity-dependent protein c-Fos in the NAcc, specifically the shell subregion (NAccSh). Silencing neural activity in the NAccSh, but not in the adjacent NAcc core, disrupted avoidance behavior. Disconnection of the BA and the NAccSh was just as effective at disrupting avoidance behavior as bilateral NAccSh inactivations, suggesting learned avoidance behavior requires an intact BA-NAccSh circuit. Together, these data highlight an essential role for the amygdalar projection to the ventral striatum in aversively motivated actions.

Learning context modulates aversive taste strength in honey bees.

The capacity of honey bees (Apis mellifera) to detect bitter substances is controversial because they ingest without reluctance different kinds of bitter solutions in the laboratory, whereas free-flying bees avoid them in visual discrimination tasks. Here, we asked whether the gustatory perception of bees changes with the behavioral context so that tastes that are less effective as negative reinforcements in a given context become more effective in a different context. We trained bees to discriminate an odorant paired with 1 mol l(-1) sucrose solution from another odorant paired with either distilled water, 3 mol l(-1) NaCl or 60 mmol l(-1) quinine. Training was either Pavlovian [olfactory conditioning of the proboscis extension reflex (PER) in harnessed bees], or mainly operant (olfactory conditioning of free-walking bees in a Y-maze). PER-trained and maze-trained bees were subsequently tested both in their original context and in the alternative context. Whereas PER-trained bees transferred their choice to the Y-maze situation, Y-maze-trained bees did not respond with a PER to odors when subsequently harnessed. In both conditioning protocols, NaCl and distilled water were the strongest and the weakest aversive reinforcement, respectively. A significant variation was found for quinine, which had an intermediate aversive effect in PER conditioning but a more powerful effect in the Y-maze, similar to that of NaCl. These results thus show that the aversive strength of quinine varies with the learning context, and reveal the plasticity of the bee's gustatory system. We discuss the experimental constraints of both learning contexts and focus on stress as a key modulator of taste in the honey bee. Further explorations of bee taste are proposed to understand the physiology of taste modulation in bees.

Eating and inflicting pain out of boredom.

In the present study it was investigated whether boredom promotes eating and if so, whether this effect likely reflects an increased drive for rewarding stimulation (positive reinforcement) or more plainly the drive to escape boredom (negative reinforcement). In the latter case, the valence of the stimulation should not matter and people might even be willing to look for negative stimulation, for instance to hurt oneself, just to escape boredom. In two parallel experiments, it was tested whether induced boredom promotes the consumption of chocolate (Experiment 1) and whether participants likewise are more inclined to self-administer electrocutaneous stimuli (Experiment 2). In both experiments, a total of 30 participants attended two separate sessions watching a documentary for 1 h (neutral condition) and a monotonous repetition of a single clip from the same documentary for 1 h (boring condition), in balanced order. During Experiment 1, participants had free access to M&Ms and during Experiment 2 participants could freely self-administer brief electrical shocks. It was found that participants ate more M&Ms when bored but also that they more readily self-administered electrical shocks when bored. It is concluded that eating when bored is not driven by an increased desire for satisfying incentive stimulation, but mainly by the drive to escape monotony.

One-Year Test-Retest Reliability of the Maryland Resource for the Behavioral Utilization of the Reinforcement of Negative Stimuli (MRBURNS).

The Maryland Resource for the Behavioral Utilization of the Reinforcement of Negative Stimuli (MRBURNS) is a novel behavioral task designed to measure individual differences in negative reinforcement-based risk taking propensity. Performance on the MRBURNS has been linked with alcohol-related problems and negative reinforcement-based drinking motives, as well as symptoms of anxiety and depression; however, it is unclear if performance on the task represents a stable measure of negative reinforcement-based risk taking over time. As such, the current study aimed to examine the test-retest reliability of the MRBURNS over a period of one year. Results indicate that the correlation between year 1 and year 2 risk behavior (average number of pumps) on the MRBURNS was .43 across all trials. With the one year test-retest reliability of the MRBURNS established, the MRBURNS may be a useful approach to measuring the relative contribution of negative reinforcement-based risk taking in the development of risky behaviors over time, and may be used to monitor the effects of novel interventions that aim to reduce negative reinforcement based risk taking in the real world.

Does hangover influence the time to next drink? An investigation using ecological momentary assessment.

BACKGROUND: Measures of hangover are associated with current and future problematic alcohol use. At present, it is not known whether these associations reflect any direct influence of hangover events on near-term drinking behaviors. The current study aimed to determine whether hangover following a drinking episode influences time to next drink (TTND) and, if so, to determine the direction of this effect and identify any moderating personal or contextual factors. METHODS: Community-recruited, frequent drinkers oversampled for current smoking (N = 386) carried electronic diaries for 21 days, reporting on drinking behaviors and other experiences. Survival analysis was used to model data from 2,276 drinking episodes, including 463 episodes that were followed by self-reported hangover in morning diary entries. RESULTS: When tested as the sole predictor in a survival model, hangover was associated with increased TTND. The median survival time was approximately 6 hours longer after episodes with hangovers compared to those without. In a multivariate model, hangover was only significant in the presence of interaction effects involving craving at the end of the index drinking episode and the occurrence of financial stressors. Additional predictors of TTND in the final multivariate model included age, lifetime alcohol use disorder diagnosis, typical drinking frequency, day of the week, and morning reports of craving, negative affect, and stressors after the index episode. There was no association between morning reports of hangover and contemporaneous diary ratings of likelihood of drinking later the same day. CONCLUSIONS: The findings suggest that hangover has, at best, a modest or inconsistent influence on the timing of subsequent alcohol use among frequent drinkers.

Neuropeptide YY(2)R blockade in the central amygdala reduces anxiety-like behavior but not alcohol drinking in alcohol-dependent rats.

Electrophysiological data suggest a dual role of Y2 receptors (Y2 Rs) as autoreceptors regulating neuropeptide Y release and heteroceptors regulating gamma-aminobutyric acid release in the central amygdala (CeA). Here, we report that neither systemic (JNJ-31020028) nor intra-CeA (BIIE0246) Y2 R antagonism altered operant alcohol responding by alcohol-dependent or non-dependent rats. Conversely, BIIE0246 in the CeA reduced anxiety-like behavior in alcohol-dependent and alcohol-naïve rats. The finding that Y2 R antagonism reduces anxiety-like behavior but not alcohol drinking suggests that these two effects may occur via different functions of the Y2 R (e.g. autoreceptor versus heteroceptor function).

Associations between sleep health, negative reinforcement learning, and alcohol use among South Florida college students with elevated internalizing symptoms.

Negative reinforcement is proposed to mediate associations between sleep and alcohol use, especially among people with depression and/or anxiety symptoms. Worse sleep (e.g., shorter duration, less efficiency, more irregular timing) exacerbates negative emotions, which alcohol may temporarily relieve. Not yet examined, we propose sleep indirectly impacts early stages of alcohol use via differences in negative reinforcement learning (NRL), since sleep impacts emotion, reward response, and learning. The current study aimed to replicate associations between sleep and alcohol use, test associations with NRL, and examine indirect associations between sleep health and alcohol use via NRL among 60 underage college students (ages 18-20 years, 77% female) varying in depression and anxiety symptoms. Participants wore Fitbit smartwatches and completed daily diaries measuring sleep and substance use for ∼14 days before completing two computer tasks assessing social (SNRL) and monetary (MNRL) negative reinforcement learning. Robust generalized linear models tested direct associations within the proposed model. SNRL performance was positively associated with alcohol use, but no other associations were observed. Statistical mediation models failed to indicate indirect effects of sleep on alcohol use via SNRL or MNRL performance. Post-hoc exploratory models examining depression and anxiety symptoms as moderators of direct associations indicated several interactions. Positive associations between sleep timing variability and alcohol use were weakened at higher anxiety symptom severity and stronger at higher depression symptom severity. The positive association between SNRL performance and alcohol use was also stronger at higher depression symptom severity. Among students with elevated depression symptoms, variable sleep timing and stronger SNRL performance were independently associated with more alcohol use, but indirect effects were not supported. Future research should replicate findings, confirm causality of interactions, and examine sleep timing and behavioral responses to negative social stimuli as targets for improving alcohol-related outcomes among underage college students with elevated depressive symptoms.