Measure Of Anhedonia Research Articles

Preference for vigorous exercise versus sedentary sucrose drinking: an animal model of anergia induced by dopamine receptor antagonism.

Motivation has activational and directional components. Mesolimbic dopamine is critical for the regulation of behavioral activation and effort-related processes in motivated behaviors. Impairing mesolimbic dopamine function leads to fatigue and anergia, but leaves intact other aspects of reinforce seeking behaviors, such as the consummatory or hedonic component. In male Swiss mice, we characterized the impact of dopamine antagonism on the selection of concurrently presented stimuli that have different vigor requirements. We analyzed running wheel activity versus sucrose solution intake, typically used as a measure of anhedonia. Results are compared with data from nonconcurrent presentation to those stimuli. In the concurrent presentation experiment, control mice preferred to spend time running compared to sucrose intake. Dopamine antagonism shifted relative reinforcer preference, reducing time spent on the running wheel, but actually increasing time-consuming sucrose. Mice increased frequency of bouts for both reinforcers, suggesting that there was fatigue in the running wheel rather than aversion. Moreover, satiation or habituation by preexposing animals to both reinforcers did not shift preferences. In the nonconcurrent experiments, haloperidol reduced running wheel but had no impact on sucrose consumption. Dopamine antagonism did not change preference for sucrose or total volume consumed. Additional correlational analyses indicated that baseline differences in sucrose consumption were independent of baseline running or novelty exploration. Thus, dopamine antagonism seems to have anergic rather than anhedonic effects, and the concurrent presentation in this setting could be useful for assessing preferences based on effort requirements.

Trajectories of state anhedonia and recent changes in anhedonia in college students: Associations with other psychiatric syndromes

BackgroundRecent works suggest recent changes in anhedonia may be specifically predictive of key elements of psychopathology. The present study aimed to identify the trajectories of state anhedonia and recent changes in anhedonia, and to investigate their associations with other psychiatric syndromes over time. MethodsA total of 859 college students were assessed at three time points. State anhedonia was assessed using the Snaith Hamilton Pleasure Scale and recent changes in anhedonia were assessed with a subscale extracted from the Symptom Check-List-90. The Latent Growth Curve Modelling analysis was used to analyze trajectories. Associations with anhedonia were investigated with logistic regression models. ResultsThree state anhedonia trajectories and two recent changes in anhedonia trajectories were identified. The decreasing trajectory was the most prevalent class in both two types of anhedonia. Depression and suicidal ideation predicted recent changes in anhedonia whereas other psychiatric syndromes predicted state anhedonia. ConclusionsThe current study highlighted the development trajectories of different measures of anhedonia. The results showed that the relationships between anhedonia and psychiatric syndromes were different according to the kind of anhedonia.

Anhedonia across borders: Transdiagnostic relevance of reward dysfunction for noninvasive brain stimulation endophenotypes.

IntroductionAnhedonia is a transdiagnostic psychopathological dimension, consisting in the impaired ability to experience pleasure. In order to further our understanding of its neural correlates and to explore its potential relevance as a predictor of treatment response, in this article we systematically reviewed studies involving anhedonia and neuromodulation interventions, across different disorders.MethodsWe included seven studies fulfilling inclusion/exclusion criteria and involving different measures of anticipatory and consummatory anhedonia, as well as different noninvasive brain stimulation interventions (transcranial magnetic stimulation and transcranial direct current stimulation). Studies not exploring hedonic measures or not involving neuromodulation intervention were excluded.ResultsAll the included studies entailed the use of rTMS protocols in one of the diverse prefrontal targets. The limited amount of studies and the heterogeneity of stimulation protocols did not allow to draw any conclusion with regard to the efficacy of rTMS in the treatment of transnosographic anhedonia. A potential for anhedonia in dissecting possible endophenotypes of different psychopathological conditions preliminarily emerged.ConclusionsAnhedonia is an underexplored condition in neuromodulation trials. It may represent a valuable transdiagnostic dimension that requires further examination in order to discover new clinical predictors for treatment response.

Maltreatment subtypes, depressed mood, and anhedonia: A longitudinal study with adolescents.

Maltreatment exposure is a robust predictor of adolescent depression. Yet despite this well-documented association, few studies have simultaneously examined how maltreatment subtypes relate to qualitatively distinct depressive symptoms. The present multiwave longitudinal study addressed this gap in the literature by examining how different maltreatment subtypes independently impact depressed mood and anhedonia over time in a diverse adolescent sample. Adolescents (N = 673, Mage = 14.83, SDage = 0.66, 57.1% female, 32.8% Hispanic, 30.4% Caucasian, 25.0% African American) completed self-report inventories for child-maltreatment and annual self-report measures of depressed mood and anhedonia over the course of 6 years. We used latent-growth-curve modeling to test how maltreatment exposure predicted anhedonia and depressed mood, and whether these relations differed as a function of sex and/or race/ethnicity. Overall, both emotional abuse (p < .001) and neglect (p = .002) predicted levels of depressed mood over time, whereas only emotional neglect predicted levels (p < .001) and trajectories (p = .001) of anhedonia. Physical and sexual abuse did not predict depressive symptoms after accounting for emotional abuse and neglect (ns). These findings were largely invariant across sex and race. Findings suggest that the consequences of emotional neglect may be especially problematic in adolescence because of its impact on both depressed mood and anhedonia, and that emotional abuse's association with depression is best explained via symptoms of depressed mood. These findings are congruent with recent findings that more "silent types" of maltreatment uniquely predict depression, and that abuse and neglect experiences confer distinct profiles of risk for psychological distress. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Higher depression severity mediates the association of assault military sexual trauma and sexual function in partnered female service members/veterans

Background: Military sexual trauma (MST), and assault as opposed to harassment-only MST in particular, is associated with lower sexual function among female service members/veterans (SM/Vs). Recent research revealed that higher posttraumatic stress disorder (PTSD) symptom clusters of anhedonia and dysphoric arousal mediated the association of assault MST and sexual function. Such clusters represent the depressive symptoms of PTSD, and theories of sexual function suggest that depression worsens sexual function. The impact of depression on the association of MST and sexual function has yet to be tested. Method: Using path analysis, the study examined whether depression severity mediated the association of MST and sexual function after accounting for demographics and mediators of PTSD-related anhedonia and dysphoric arousal. Female SM/Vs (N = 697) completed measures of MST (history, severity), depression, PTSD-related anhedonia and dysphoric arousal, sexual function, and a demographic inventory. Results: One hundred twenty-two (17.50%) indicated that they did not experience MST, 336 (48.21%) reported that they experienced harassment-only MST, and 239 (34.29%) reported assault MST. Fit indices evidenced strong model fit, χ2(12, N = 697)=18.85, p=.09, CFI=1.00, TLI=0.99, SRMR=0.02, and RMSEA=0.03. The indirect effect of depression severity was significant (p<.001). Limitations: Use of cross-sectional data in a convenience sample of female SM/Vs. Conclusions: Even after accounting for established covariates and mediators of assault MST and sexual function, depression accounted for a significant amount of variance in this association. Treatment of poor sexual function must address depressive symptoms. As medications for depression can exacerbate sexual issues, psychotherapy may be the most effective treatment strategy.

Parsing metabolic heterogeneity in mood disorders: A hypothesis-driven cluster analysis of glucose and insulin abnormalities.

Metabolically based distinctions for disturbances in glucose and insulin may provide meaningful insights both clinically and mechanistically. Data were derived from 352 subjects of previously completed clinical studies with a mood disorder (MD) (bipolar disorder: n=179, major depressive disorder: n=173) and 218 healthy controls from the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy. We conducted a factor analysis to replicate a priori dissociable factors informed by glucose and insulin levels and indices of insulin resistance and beta-cell function: elevated insulin and insulin resistance ("insulin-IR"), and increased fasting glucose and reduced insulin secretion ("glucotoxicity"). Cluster analyses were conducted, separately in men and women, to evaluate the clinical relevance of subtyping individuals with MDs using insulin-IR and glucotoxicity (GT) factor scores. Factors insulin-IR and GT explained 92.64% and 92.09% of the variance in men and women respectively. Three clusters were replicated in men and women separately: metabolically healthy (MH), high GT, and insulin-resistant (IR). After adjusting for age, gender, study cohort, MD diagnosis, and antipsychotics use, body mass index (BMI) and mean arterial pressure were higher in IR- vs GT- or MH-clustered individuals; GT-clustered individuals had more metabolic syndrome components and higher C-reactive protein. Glucotoxic-clustered subjects reported greater impairments in cognitive function and global functioning when compared to MH- or IR-clustered subjects. Using simple, cost-effective, and accessible measures, we identified stable, gender-convergent, subgroups of individuals that significantly diverged on measures of cognitive dysfunction, self-reported anhedonia, functional disability, BMI, and blood pressure.

Diminished Anticipatory and Consummatory Pleasure in Dysphoria: Evidence From an Experience Sampling Study.

Anhedonia, the experience of diminished pleasure, is a core feature of major depressive disorder and is often present long before the diagnosis of depression. Most previous studies have investigated anhedonia with self-report measures of trait anhedonia or with behavioral paradigms using laboratory stimuli, and the real-time characteristics of hedonic processing in subclinical depression remain under-investigated. We used the experience sampling method to evaluate momentary experience of hedonic feelings in the context of daily life. Dysphoric (n = 49) and non-dysphoric (n = 51) college students completed assessments of their current positive affect (PA), as well as state anticipatory and consummatory pleasure, 3 or 4 times a day every day for 2 weeks. The results showed that dysphoric individuals reported less state anticipatory and consummatory pleasure compared with non-dysphoric individuals. Moreover, significant time-lagged associations between anticipatory pleasure and follow-up consummatory pleasure were found in the whole sample, after adjustment for current PA. The current findings thus hold considerable promise in advancing our understanding of anhedonia as well as the important role of state anticipatory pleasure in relation to depression.

N-Methyl-D-aspartate receptor antagonist d-methadone produces rapid, mTORC1-dependent antidepressant effects.

Currently available antidepressants have a delayed onset and limited efficacy, highlighting the need for new, rapid and more efficacious agents. Ketamine, an NMDA receptor antagonist, has emerged as a new rapid-acting antidepressant, effective even in treatment resistant patients. However, ketamine induces undesired psychotomimetic and dissociative side effects that limit its clinical use. The d-stereoisomer of methadone (dextromethadone; REL-1017) is a noncompetitive NMDA receptor antagonist with an apparently favorable safety and tolerability profile. The current study examined the rapid and sustained antidepressant actions of d-methadone in several behavioral paradigms, as well as on mTORC1 signaling and synaptic changes in the medial prefrontal cortex (mPFC). A single dose of d-methadone promoted rapid and sustained antidepressant responses in the novelty-suppressed feeding test (NSFT), a measure of anxiety, and in the female urine sniffing test (FUST), a measure of motivation and reward. D-methadone also produced a rapid reversal of the sucrose preference deficit, a measure of anhedonia, in rats exposed to chronic unpredictable stress. D-methadone increased phospho-p70S6 kinase, a downstream target of mTORC1 in the mPFC, and intra-mPFC infusion of the selective mTORC1 inhibitor rapamycin blocked the antidepressant actions of d-methadone in the FUST and NSFT. D-methadone administration also increased levels of the synaptic proteins, PSD95, GluA1, and Synapsin 1 and enhanced synaptic function in the mPFC. Studies in primary cortical cultures show that d-methadone also increases BDNF release, as well as phospho-p70S6 kinase. These findings indicate that d-methadone induces rapid antidepressant actions through mTORC1-mediated synaptic plasticity in the mPFC similar to ketamine.

Cortical 5-hydroxytryptamine 1A receptor biased agonist, NLX-101, displays rapid-acting antidepressant-like properties in the rat chronic mild stress model.

NLX-101 (also known as F15599) is a highly selective and efficacious 'biased' agonist at cortical 5-hydroxytryptamine 1A (5-HT1A) heteroreceptors. In rodents, it possesses marked antidepressant-like activity, potently and completely abolishing immobility in the forced swim test (FST) with extended duration of action. We investigated the antidepressant-like activity of NLX-101 using the rat chronic mild stress (CMS) model of depression, considered to have a higher translational potential than the FST, as it possesses construct, face and predictive validity. The effects of CMS and repeated NLX-101 treatment were tested using sucrose consumption (a measure of anhedonia), novel object recognition (NOR; a measure of working memory) and elevated plus maze (EPM; a measure of anxiety) tests. NLX-101 reversed the CMS-induced decrease of sucrose intake on day 1 of testing, with full reversal observed at the dose of 0.16 mg/kg and a less pronounced but still significant effect at 0.04 mg/kg, both given twice a day intraperitoneally. The effects of NLX-101 were maintained over the 2 week treatment period and persisted for four weeks following cessation of treatment. In the NOR test, both doses of NLX-101 rescued the deficit in discrimination index caused by CMS, without any effect on locomotor activity. However, NLX-101 had no effect on the reduction of open-arms entries produced by CMS in the EPM model. In control, non-stressed rats, NLX-101 produced non-significant effects in all three models. NLX-101 displayed efficacious activity in the CMS test, with more rapid (1 day) antidepressant-like effects than pharmacological compounds tested previously under the same experimental conditions. These observations suggest that biased agonist targeting of cortical 5-HT1A receptors constitutes a promising strategy to achieve rapid-acting and sustained antidepressant effects.

Resting-State Quantitative Electroencephalography Demonstrates Differential Connectivity in Adolescents with Major Depressive Disorder.

Background: Biomarkers for psychiatric disorders in children and adolescents are urgently needed. This cross-sectional pilot study investigated quantitative electroencephalogram (qEEG), a promising intermediate biomarker, in pediatric patients with major depressive disorder (MDD) compared with healthy controls (HCs). We hypothesized that youth with MDD would have increased coherence (connectivity) and absolute alpha power in the frontal cortex compared with HC. Methods: qEEG was obtained in adolescents aged 14-17 years with MDD (n = 25) and age- and gender-matched HCs (n = 14). The primary outcome was overall coherence on qEEG in the four frequency bands (alpha, beta, theta, and delta). Other outcomes included frontal-only coherence, overall and frontal-only qEEG power, and clinician-rated measures of anhedonia and anxiety. Results: Average coherence in the theta band was significantly lower in MDD patients versus HCs, and also lower in frontal cortex among MDD patients. Seven node pairs were significantly different or trending toward significance between MDD and HC; all had lower coherence in MDD patients. Average frontal delta power was significantly higher in MDD versus HCs. Conclusions: Brain connectivity measured by qEEG differs significantly between adolescents with MDD and HCs. Compared with HCs, youth with MDD showed decreased connectivity, yet no differences in power in any frequency bands. In the frontal cortex, youth with MDD showed decreased resting connectivity in the alpha and theta frequency bands. Impaired development of a resting-state brain network (e.g., default mode network) in adolescents with MDD may represent an intermediate phenotype that can be assessed with qEEG.

Anhedonia in adolescents at ultra-high risk (UHR) of psychosis: findings from a 1-year longitudinal study.

Previous findings suggested deficits in pleasure experience in schizophrenia, but little is known in psychosis risk prodrome, especially in adolescence. Aim of this study was (1) to assess anhedonia in distinct help-seeking subgroups of adolescents identified through the ultra-high risk (UHR) criteria, (2) to explore any association of anhedonia with other psychopathological aspects in the UHR group, and (3) to monitor longitudinally the stability of anhedonia in UHR individuals across 1-year follow-up period. 123 participants (13-18years) completed the Comprehensive Assessment of At-Risk Mental States (CAARMS), the Beck Depression Inventory-II, the Schizotypal Personality Questionnaire-Brief version, the Brief-O-LIFE questionnaire (BOL), and the Brief version of the World Health Organization Quality of Life scale (WHOQOL-BREF). Two different indexes of anhedonia were used: CAARMS "Anhedonia" item 4.3 and BOL "Introvertive Anhedonia" subscale scores. No difference in anhedonia levels between UHR and First Episode Psychosis (FEP) groups was found. UHR adolescents showed higher CAARMS and BOL anhedonia scores than non-UHR/FEP. After 1-year follow-up period, UHR adolescents had a significant decrease in severity only in CAARMS anhedonia subscores. In UHR subgroup, CAARMS anhedonia measures showed significant correlations with impaired role functioning and negative symptoms, while BOL anhedonia was significantly correlated with specific schizotypal personality traits concerning interpersonal deficits. Anhedonia is prominent in the psychosis prodrome, also in adolescence. Its severity is not statistically different from that of FEP adolescents and is related to more severe functioning impairment and a worse quality of life.

Mapping anticipatory anhedonia: an fMRI study.

Anhedonia-broadly defined as loss of interest and/or an inability to experience pleasure-is an important feature of several psychiatric disorders. Research into the clinical presentation and neurobiology of this symptom has identified components related to motivation, learning, anticipation, and experience of pleasure as important constructs that inform therapeutic interventions. The experimental study of anhedonia is largely based on incentive processing paradigms, most often with monetary rewards, though studies have also used pleasantness ratings of various stimuli. However, linking an individual's own system of reinforcers and ability to enjoy them with anhedonia and neural activity remains comparatively under-explored. A previous study of participants with major depressive disorder (MDD) and healthy controls found that activity word ratings correlated with measures of anhedonia, depression, and motivation. The present study collected functional magnetic resonance imaging (fMRI) images in healthy controls while they rated activity words and pictures showing activities in order to identify networks differentially responsive to subjective decisions about the appetitive value of activities. The study sought to measure individually-relevant hedonic capacity as demonstrated by correlations between task measures and anticipatory anhedonia ratings. Ratings of potential pleasure were associated with neural activity in areas previously identified as relevant to pleasure and reward processing, such as anterior and posterior cingulate, middle frontal areas, and dorsal and ventral striatum. Although the study included only healthy controls, the results demonstrate a link between anhedonia measures, behavior, and brain responses and also test a paradigm that could be used to study anhedonia in clinical populations.

Impact of Pharmacological Manipulation of the κ-Opioid Receptor System on Self-grooming and Anhedonic-like Behaviors in Male Mice.

The kappa (κ) opioid receptor/dynorphin system modulates depression-like states and anhedonia, as well adaptations to stress and exposure to drugs of abuse. Several relatively short-acting small molecule κ-receptor antagonists have been synthesized, and their behavioral profile has been examined under some conditions. The hypothesis of this study is that pharmacological manipulations of the κ-receptor system will result in changes in ethologically relevant anhedonic-like behaviors in mice. Adult male C57BL/6j mice (n = 6-8) were examined for self-grooming behavior in the splash test (in which robust self-grooming is elicited by spraying the dorsum of the mouse with a sucrose solution). The κ-agonist salvinorin A (0.56-1.8 mg/kg) produced dose-dependent decreases in self-grooming, a marker of anhedonia. The selectivity, potency, and duration of action of two relatively short-acting κ-antagonists, LY2444296 [(S)-3-fluoro-4-(4-((2-(3-fluorophenyl) pyrrolidin-1-yl)methyl)phenoxy)benzamide] and LY2795050 [3-chloro-4-(4-(((2S)-2-pyridin-3-ylpyrrolidin-1-yl)methyl) phenoxy)benzamide], were studied for their effectiveness in preventing grooming deficits caused by salvinorin A (1.8 mg/kg). κ-selective doses of both LY2444296 (0.032-1 mg/kg) and LY2795050 (0.032-0.32 mg/kg) dose- and time-dependently prevented the grooming deficits caused by salvinorin A (1.8 m/kg). We also found that a κ-selective dose of each of these antagonists decreased immobility in the forced swim test, a common test of anti-anhedonia effects. This study shows that the κ-receptor system is involved in an ethologically relevant measure of anhedonia, and that κ-selective doses of these antagonists can produce effects consistent with rapid anti-anhedonia. SIGNIFICANCE STATEMENT: Activation of the κ-opioid receptor system results in grooming deficits in mice, an ethologically relevant marker of anhedonia. Shorter acting κ-antagonists are able to cause effects consistent with rapid antianhedonia.

Sleeping through anything: The effects of unpredictable disruptions on mouse sleep, healing, and affect.

Many aspects of the laboratory environment are not tailored to the needs of rodents, which may cause stress. Unpredictable stressors can cause ulcers, prolonged pituitary-adrenal activation, and anhedonia. Similarly, pain has been demonstrated to slow wound healing, and mice experiencing pain exhibit altered behavior. However it is unknown how husbandry, which occurs when the mice are inactive, and lack of analgesia, specifically in a punch biopsy procedure, effects animal physiology, behavior, and welfare, particularly as it relates to sleep fragmentation. We hypothesized that sleep fragmentation, induced by unpredictable husbandry and lack of pain management will slow wound healing. Two main treatments were tested in a factorial design in C57BL/6 mice of both sexes (64 mice total); 1) analgesia (carprofen and saline) and 2) sleep disruptions (random and predictable). Mice were singly housed in a non-invasive sleep monitoring apparatus on arrival (Day -4). Disruption treatments were applied from Day -3 to 2. All mice received a punch biopsy surgery (Day 0) with topical lidocaine gel and their analgesic treatment prior to recovery, and on Days 1 and 2. Nesting behavior was assessed daily and a sugar cereal consumption test, as a measure of anhedonia, was conducted on Days -1 to 2. On Day 3, mice were euthanized and wound tissue and adrenal glands were collected. We found that the disruption predictability had no effect on mouse sleep, wound healing, or adrenal cortex:medulla ratio. It’s possible that the disruption period was not long enough to induce chronic stress. However, male mice who received analgesia slept more than their female counterparts; this may be related to sex differences in pain perception. Overall, it does not appear that the predictability of disturbance effects sleep fragmentation or stress responses, indicating that husbandry activities do not need to occur at set predictable times to improve welfare.

Sex-Dependent Ketamine Addiction-Like Behavior Profile Following Exposure to Chronic Mild Stress

Background Ketamine has rapid antidepressant effects and shows great promise as a novel treatment for depression, but its limitations including its abuse potential are poorly understood. Given that the prevalence of depression is twice as high in women as in men and that depression and substance use disorders are highly comorbid, we hypothesized that a sex-specific responsivity to behavioral assays that characterize addiction-like behavior may arise in rats with prior exposure to chronic stress and therapeutically relevant ketamine. Methods Male and female rats that underwent chronic mild stress were treated with four 1.47 mg/kg intravenous ketamine infusions once every fourth day and underwent operant self-administration of 0.5 mg/kg/infusion ketamine. Measures of anhedonia (or lack of pleasure, a signature feature of depression), anxiety-induced neophagia, motivation to obtain ketamine, and craving were assessed using the sucrose intake test, novelty-suppressed feeding test, progressive ratio schedule of reinforcement, and incubation of craving following abstinence, respectively. Finally, dendritic spine density in the nucleus accumbens core was measured. Results Ketamine infusions reduced anxiety-induced neophagia in both male rats and female rats but had no effect on measures of anhedonia. Female rats with prior exposure to chronic mild stress had greater motivation to obtain ketamine compared to nonstressed female rats, an effect not observed in male rats. Additionally, female rats who received antidepressant ketamine infusions had a higher threshold for displaying ketamine addiction-like behavior than saline-treated female rats as well as increased thin spine density in the nucleus accumbens core. These effects were not observed in male rats. Conclusion This study shows that repeated low-dose ketamine does not increase abuse potential of subsequent ketamine. It also highlights an important female-specific effect of stress to increase ketamine addiction-like behavior, which requires further investigation for clinical populations.

Amygdalar hyperactivation in response to safety signal in anxiety trait and generalised anxiety disorder

Although Parkinson's disease (PD) is characterized by progressive neurodegeneration of multiple neurotransmitter systems, 6-hydroxydopamine (6-OHDA) as a model substance is mainly used to selectively damage the nigrostriatal dopaminergic neurons and induce parkinsonian-like motor disturbances in rats. We hypothesized that high doses of this neurotoxin affecting other monoaminergic systems may also evoke the depressive-like behavior.The impact of 6-OHDA (8, 12, 16 μg/4 μl) administered unilaterally into the medial forebrain bundle on the sucrose solution intake (a measure of anhedonia) and on the tissue levels of noradrenaline (NA), dopamine (DA) and serotonin (5-HT) in the striatum (STR), substantia nigra (SN), prefrontal cortex (PFC) and hippocampus (HIP) was examined in rats pretreated or non-pretreated with desipramine.The highest dose of 6-OHDA reduced the preference for 3% sucrose solution both in rats without and with desipramine pretreatment. All used doses of 6-OHDA dramatically decreased DA content in the studied brain structures on the ipsilateral side. NA levels were severely decreased in the ipsilateral STR, HIP and PFC of rats non-pretreated with desipramine and to a much lesser extent in those pretreated with desipramine. In the SN, moderate decreases in NA level were found both in rats pretreated and non-pretreated with desipramine. Higher doses of 6-OHDA reduced 5-HT content in the ipsilateral STR, HIP and PFC, but not in the SN, only in rats non-pretreated with desipramine.Administration of the highest dose of 6-OHDA without desipramine pretreatment evoked neurochemical and behavioral changes resembling the advanced PD with coexisting depression.

Anti-cytokine agents for anhedonia: targeting inflammation and the immune system to treat dimensional disturbances in depression.

The etiology of mood disorders is mechanistically heterogeneous, underscoring the need for a dimensional approach to identify and develop targeted treatments in psychiatry. Accumulating evidence implicates inflammation as an important contributor to the pathophysiology of depression and presents the immune system as a viable therapeutic target that may be more proximate to the pathogenic nexus of brain-based disorders in specific subpopulations. Anhedonia is a transdiagnostic (e.g. Parkinson's disease, diabetes mellitus, rheumatic diseases), yet specific, and clinically relevant symptom dimension subserved by well-characterized neurobiological and neurophysiological substrates of the positive valence systems (PVS). Brain circuits, nodes, and networks, as well as cellular and molecular pathways (e.g. dopaminergic transmission; excitotoxicity; synaptic plasticity), subserving anhedonia are preferentially affected by inflammatory processes. To our knowledge, no published randomized, controlled clinical trial in populations with mood disorders has, to date, primarily sought to determine the effects of an anti-inflammatory agent on PVS functions or pathophysiology. Three ongoing clinical trials aim to investigate the effects of anti-TNF-alpha biologic infliximab on measures of anhedonia [ClinicalTrials.gov identifier: NCT02363738], motivational behavior and circuitry [ClinicalTrials.gov identifier: NCT03006393], and glutamatergic changes in the basal ganglia [ClinicalTrials.gov identifier: NCT03004443] in clinical populations with unipolar or bipolar depression. Positive results would further instantiate the relevance of inflammatory processes and the immune system in the pathophysiology of mood disorders and provide the impetus to develop scalable treatments targeting inflammation and the immune system to mitigate transdiagnostic, dimensional disturbances in brain-based disorders.

Anhedonia in cocaine use disorder is associated with inflammatory gene expression.

Treatments for Cocaine Use Disorder (CUD) are variably effective, and there are no FDA-approved medications. One approach to developing new treatments for CUD may be to investigate and target poor prognostic signs. One such sign is anhedonia (i.e. a loss of pleasure or interest in non-drug rewards), which predicts worse outcomes in existing CUD treatments. Inflammation is thought to underlie anhedonia in many other disorders, but the relationship between anhedonia and inflammation has not been investigated in CUD. Therefore, we assessed peripheral genome-wide gene expression in n = 48 individuals with CUD with high (n = 24) vs. low (n = 24) levels of anhedonia, defined by a median split of self-reported anhedonia. Our hypothesis was that individuals with high anhedonia would show differential gene expression in inflammatory pathways. No individual genes were significantly different between the low and high anhedonia groups when using t-tests with a stringent false discovery rate correction (FDR-corrected p < 0.05). However, an exploratory analysis identified 166 loci where t-tests suggested group differences at a nominal p < 0.05. We used DAVID, a bioinformatics tool that provides functional interpretations of complex lists of genes, to examine representation of this gene list in known pathways. It confirmed that mechanisms related to immunity were the top significant associations with anhedonia in the sample. Further, the two top differentially expressed genes in our sample, IRF1 and GBP5, both have primary inflammation and immune functions, and were significantly negatively correlated with total scores on our self-report of anhedonia across all 48 subjects. These results suggest that prioritizing development of anti-inflammatory medications for CUD may pay dividends, particularly in combination with treatment-matching strategies using either phenotypic measures of anhedonia or biomarkers of inflammatory gene expression to individualize treatment.

A Dissociation of the Acute Effects of Bupropion on Positive Emotional Processing and Reward Processing in Healthy Volunteers.

Background: Previous research indicates that antidepressants can restore the balance between negative and positive emotional processing early in treatment, indicating a role of this effect in later mood improvement. However, less is known about the effect of antidepressants on reward processing despite the potential relevance to the treatment of anhedonia. In this study, we investigated the effects of an acute dose of the atypical antidepressant (dual dopamine and noradrenaline reuptake inhibitor) bupropion on behavioral measures of emotional and reward processing in healthy volunteers.Methods: Forty healthy participants were randomly allocated to double-blind intervention with either an acute dose of bupropion or placebo prior to performing the Emotional Test Battery (ETB) and a probabilistic instrumental learning task.Results: Acute bupropion significantly increased the recognition of ambiguous faces as happy, decreased response bias toward sad faces and reduced attentional vigilance for fearful faces compared to placebo. Bupropion also reduced negative bias compared to placebo in the emotional recognition memory task (EMEM). There was no evidence that bupropion enhanced reward processing or learning. Instead, bupropion was associated with reduced likelihood to choose high-probability wins and increased score on a subjective measure of anhedonia.Conclusions: Whilst acute bupropion decreases negative and increases positive emotional processing, it has an adverse effect on reward processing. There seems to be a dissociation of the acute effects of bupropion on positive emotional processing and reward processing, which may have clinical implications for anhedonia early in treatment.

Possible New Symptoms of Tobacco Withdrawal II: Anhedonia-A Systematic Review.

When animals undergo nicotine deprivation, rewards become less rewarding (ie, anhedonia occurs). We searched for tests of whether anhedonia occurs in abstinent smokers. The major inclusion criterion was a within-participants comparison of behavioral measures of reward sensitivity or self-reported anhedonia during smoking versus during abstinence among daily smokers. A computerized search of PubMed, PsychInfo, and Cochrane databases and other methods located 13 studies. All but one were laboratory studies. The number of studies and participants were small and the results mixed. In terms of anticipatory anhedonia (ie, wanting a reward), abstinence appeared to decrease willingness to work for immediately available rewards, but did not appear to influence how much adding rewards to a task increased responding. Abstinence also appeared to produce small increases in self-reported anticipatory anhedonia. In terms of consummatory anhedonia (ie, liking a reward), self-report measures found anhedonia decreased pleasure from rewards in some but not all tests. In terms of learning (ie, learning to choose a more frequent reward), abstinence did not reliably decrease allocating responding to high versus low frequency reward options. Although results were mixed, abstinence appears to increase anticipatory anhedonia. It is unclear if abstinence increases consummatory or reward learning-based anhedonia. Further studies of anhedonia in clinical settings are needed (1) to estimate the reliability and clinical significance of anhedonia as a symptom of tobacco withdrawal, (2) to assess if effects represent withdrawal versus offset processes, and (3) to assess if anhedonia interferes with the ability to stop smoking. Anticipatory anhedonia appears to be a symptom of tobacco withdrawal and should be added to tobacco withdrawal checklists and diagnostic criteria. Further study of consummatory and learning-based anhedonia is warranted.