The involvement of neuroinflammation in an animal model of dementia and depression.

Alzheimer's disease (AD) and depression are inflammatory pathologies, leading to increased inflammatory response and neurotoxicity. Therefore, this study aimed to evaluate the effect of the treatment with fluoxetine and/or galantamine and/or donepezil on the levels of proinflammatory and anti-inflammatory cytokines in a mixed animal model of depression and dementia. Adult male Wistar rats underwent chronic mild stress (CMS) protocol for 40 days and were subjected to stereotaxic surgery for intra-hippocampal administration of amyloid-beta (Aꞵ) peptide or artificial cerebrospinal fluid (ACSF) to mimic the dementia animal model. On the 42nd day, animals were treated with water, galantamine, donepezil, and/or fluoxetine, orally for 17 days. On the 57th and 58th days, the Splash and Y-maze tests for behavior analysis were performed. The frontal cortex and hippocampus were used to analyze the tumor necrosis factor alfa (TNF-α), interleukin 1 beta (IL-1ꞵ), IL-6, and IL-10 levels. The results of this study show that animals subjected to CMS and administration of Aꞵ had anhedonia, cognitive impairment, increased TNF-α and IL-1ꞵ levels in the frontal cortex, and reduced IL-10 levels in the hippocampus. All treatment groups were able to reverse the cognitive impairment. Only donepezil did not decrease the TNF-α levels in the hippocampus. Fluoxetine + galantamine and fluoxetine + donepezil reversed the anhedonia. Fluoxetine reversed the anhedonia and IL-1ꞵ levels in the frontal cortex. In addition, fluoxetine + donepezil reversed the reduction of IL-10 levels in the hippocampus. The results indicate a pathophysiological interaction between AD and depression, and the association of medications in the future may be a possible therapeutic strategy to reduce inflammation, especially the fluoxetine-associated treatments.

Evidence of hypoglycemic anhedonia and modulation by bupropion in rats.

BACKGROUND: Disorders characterized by dysfunction of glucose metabolism are often comorbid with depression. The current study investigated whether a hypoglycemic state caused by 2-deoxy-d-glucose (2-DG) can result in anhedonic behaviors responsive to stimulation of monoamine activity. METHODS: In experiment 1, male Sprague-Dawley rats were tested for maintenance of intra-oral self-administration (IOSA) of a sweet solution after pre-treatment with 300 or 500 mg/kg 2-DG, a blocker of glucose metabolism. Experiment 2 determined whether exposure to an environment previously paired with the effects of 2-DG (0, 200 or 300 mg/kg) can influence IOSA, and whether 2-DG can modify taste reactivity to same sweet solution. Finally, experiment 3 examined whether 0 or 30 mg/kg bupropion, a monoamine-reuptake blocker, would attenuate the effect of 300 mg/kg 2-DG on IOSA and taste reactivity. RESULTS: It was found that 2-DG produced a sustained decrease in IOSA when animals were tested drug-free. This decrease in IOSA did not appear linked to place conditioning or to alterations in taste reactivity, and it was partially normalized by pre-treatment with bupropion. CONCLUSIONS: Taken together, these results in rats suggest that rapid hypoglycemia can induce an anhedonic state characterized by impaired consummatory responses to nutritional incentive stimuli and that can be alleviated by the antidepressant bupropion.

Ingestion of Lactobacillus intestinalis and Lactobacillus reuteri causes depression- and anhedonia-like phenotypes in antibiotic-treated mice via the vagus nerve.

BACKGROUND: The brain-gut-microbiota axis plays a role in the pathogenesis of stress-related disorders such as depression. In this study, we examined the effects of fecal microbiota transplantation (FMT) in mice with antibiotic-treated microbiota depletion. METHODS: The fecal microbiota was obtained from mice subjected to chronic social defeat stress (CSDS) and control (no CSDS) mice. FMT from these two groups was performed to antibiotic-treated mice. 16S rRNA analysis was performed to examine the composition of gut microbiota. Furthermore, the effects of subdiaphragmatic vagotomy in depression-like phenotypes after ingestion of microbes were examined. RESULTS: The ingestion of fecal microbiota from CSDS-susceptible mice resulted in an anhedonia-like phenotype, higher plasma levels of interleukin-6 (IL-6), and decreased expression of synaptic proteins in the prefrontal cortex (PFC) in antibiotic-treated mice but not in water-treated mice. 16S rRNA analysis suggested that two microbes (Lactobacillus intestinalis and Lactobacillus reuteri) may be responsible for the anhedonia-like phenotype in antibiotic-treated mice after FMT. Ingestion of these two microbes for 14 days led to depression- and anhedonia-like phenotypes, higher plasma IL-6 levels, and decreased expression of synaptic proteins in the PFC of antibiotic-treated mice. Interestingly, subdiaphragmatic vagotomy significantly blocked the development of behavioral abnormalities, elevation of plasma IL-6 levels, and downregulation of synaptic proteins in the PFC after ingestion of these two microbes. CONCLUSIONS: These findings suggest that microbiota depletion using an antibiotic cocktail is essential for the development of FMT-induced behavioral changes and that the vagus nerve plays a key role in behavioral abnormalities in antibiotic-treated mice after the ingestion of L. intestinalis and L. reuteri. Therefore, it is likely that the brain-gut-microbiota axis participates in the pathogenesis of depression via the vagus nerve.

Relationship Between Nicotine Intake and Reward Function in Rats With Intermittent Short Versus Long Access to Nicotine.

INTRODUCTION: Tobacco use improves mood states and smoking cessation leads to anhedonia, which contributes to relapse. Animal studies have shown that noncontingent nicotine administration enhances brain reward function and leads to dependence. However, little is known about the effects of nicotine self-administration on the state of the reward system. METHODS: To investigate the relationship between nicotine self-administration and reward function, rats were prepared with intracranial self-stimulation electrodes and intravenous catheters. The rats were trained on the intracranial self-stimulation procedure and allowed to self-administer 0.03 mg/kg/infusion of nicotine. All rats self-administered nicotine daily for 10 days (1 hour/day) and were then switched to an intermittent short access (ShA, 1 hour/day) or long access (LgA, 23 hour/day) schedule (2 days/week, 5 weeks). RESULTS: During the first 10 daily, 1-hour sessions, nicotine self-administration decreased the reward thresholds, which indicates that nicotine potentiates reward function. After switching to the intermittent LgA or ShA schedule, nicotine intake was lower in the ShA rats than the LgA rats. The LgA rats increased their nicotine intake over time and they gradually consumed a higher percentage of their nicotine during the light phase. The nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine induced a larger increase in reward thresholds (ie, anhedonia) in the LgA rats than the ShA rats. In the LgA rats, nAChR blockade with mecamylamine decreased nicotine intake for 2 hours and this was followed by a rebound increase in nicotine intake. CONCLUSIONS: A brief period of nicotine self-administration enhances reward function and a high level of nicotine intake leads to dependence. IMPLICATIONS: These animal studies indicate that there is a strong relationship between the level of nicotine intake and brain reward function. A high level of nicotine intake was more rewarding than a low level of nicotine intake and nicotine dependence was observed after long, but not short, access to nicotine. This powerful combination of nicotine reward and withdrawal makes it difficult to quit smoking. Blockade of nAChRs temporarily decreased nicotine intake, but this was followed by a large rebound increase in nicotine intake. Therefore, nAChR blockade might not decrease the use of combustible cigarettes or electronic cigarettes.

Effects of immunomodulatory drugs on depressive symptoms: A mega-analysis of randomized, placebo-controlled clinical trials in inflammatory disorders.

Activation of the innate immune system is commonly associated with depression. Immunomodulatory drugs may have efficacy for depressive symptoms that are co-morbidly associated with inflammatory disorders. We report a large-scale re-analysis by standardized procedures (mega-analysis) of patient-level data combined from 18 randomized clinical trials conducted by Janssen or GlaxoSmithKline for one of nine disorders (N = 10,743 participants). Core depressive symptoms (low mood, anhedonia) were measured by the Short Form Survey (SF-36) or the Hospital Anxiety and Depression Scale (HADS), and participants were stratified into high (N = 1921) versus low-depressive strata based on baseline ratings. Placebo-controlled change from baseline after 4-16 weeks of treatment was estimated by the standardized mean difference (SMD) over all trials and for each subgroup of trials targeting one of 7 mechanisms (IL-6, TNF-α, IL-12/23, CD20, COX2, BLγS, p38/MAPK14). Patients in the high depressive stratum showed modest but significant effects on core depressive symptoms (SMD = 0.29, 95% CI [0.12-0.45]) and related SF-36 measures of mental health and vitality. Anti-IL-6 antibodies (SMD = 0.8, 95% CI [0.20-1.41]) and an anti-IL-12/23 antibody (SMD = 0.48, 95% CI [0.26-0.70]) had larger effects on depressive symptoms than other drug classes. Adjustments for physical health outcome marginally attenuated the average treatment effect on depressive symptoms (SMD = 0.20, 95% CI: 0.06-0.35), but more strongly attenuated effects on mental health and vitality. Effects of anti-IL-12/23 remained significant and anti-IL-6 antibodies became a trend after controlling for physical response to treatment. Novel immune-therapeutics can produce antidepressant effects in depressed patients with primary inflammatory disorders that are not entirely explained by treatment-related changes in physical health.

Brain-derived neurotrophic factor-TrkB signaling in the medial prefrontal cortex plays a role in the anhedonia-like phenotype after spared nerve injury.

Although depressive symptoms including anhedonia (i.e., loss of pleasure) frequently accompany pain, little is known about the risk factors contributing to individual differences in pain-induced anhedonia. In this study, we examined if signaling of brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-receptor-kinase B (TrkB) contribute to individual differences in the development of neuropathic pain-induced anhedonia. Rats were randomly subjected to spared nerved ligation (SNI) or sham surgery. The SNI rats were divided into two groups based on the results of a sucrose preference test. Rats with anhedonia-like phenotype displayed lower tissue levels of BDNF in the medial prefrontal cortex (mPFC) compared with rats without anhedonia-like phenotype and sham-operated rats. In contrast, tissue levels of BDNF in the nucleus accumbens (NAc) of rats with an anhedonia-like phenotype were higher compared with those of rats without anhedonia-like phenotype and sham-operated rats. Furthermore, tissue levels of BDNF in the hippocampus, L2-5 spinal cord, muscle, and liver from both rats with or without anhedonia-like phenotype were lower compared with those of sham-operated rats. A single injection of 7,8-dihydroxyflavone (10 mg/kg; TrkB agonist), but not ANA-12 (0.5 mg/kg; TrkB antagonist), ameliorated reduced sucrose preference and reduced BDNF-TrkB signaling in the mPFC in the rats with anhedonia-like phenotype. These findings suggest that reduced BDNF-TrkB signaling in the mPFC might contribute to neuropathic pain-induced anhedonia, and that TrkB agonists could be potential therapeutic drugs for pain-induced anhedonia.

mGlu2 and mGlu3 Negative Allosteric Modulators Divergently Enhance Thalamocortical Transmission and Exert Rapid Antidepressant-like Effects.

Non-selective antagonists of metabotropic glutamate receptor subtypes 2 (mGlu2) and 3 (mGlu3) exert rapid antidepressant-like effects by enhancing prefrontal cortex (PFC) glutamate transmission; however, the receptor subtype contributions and underlying mechanisms remain unclear. Here, we leveraged newly developed negative allosteric modulators (NAMs), transgenic mice, and viral-assisted optogenetics to test the hypothesis that selective inhibition of mGlu2 or mGlu3 potentiates PFC excitatory transmission and confers antidepressant efficacy in preclinical models. We found that systemic treatment with an mGlu2 or mGlu3 NAM rapidly activated biophysically unique PFC pyramidal cell ensembles. Mechanistic studies revealed that mGlu2 and mGlu3 NAMs enhance thalamocortical transmission and inhibit long-term depression by mechanistically distinct presynaptic and postsynaptic actions. Consistent with these actions, systemic treatment with either NAM decreased passive coping and reversed anhedonia in two independent chronic stress models, suggesting that both mGlu2 and mGlu3 NAMs induce antidepressant-like effects through related but divergent mechanisms of action.

Combined Fluoxetine and Metformin Treatment Potentiates Antidepressant Efficacy Increasing IGF2 Expression in the Dorsal Hippocampus.

An increasing number of studies show that selective serotonin reuptake inhibitors (SSRIs) exert their therapeutic action, at least in part, by amplifying the influence of the living environment on mood. As a consequence, when administered in a favorable environment, SSRIs lead to a reduction of symptoms, but in stressful conditions, they show limited efficacy. Therefore, novel therapeutic approaches able to neutralize the influence of the stressful environment on treatment are needed. The aim of our study was to test whether, in a mouse model of depression, the combined administration of SSRI fluoxetine and metformin, a drug able to improve the metabolic profile, counteracts the limited efficacy of fluoxetine alone when administered in stressful conditions. Indeed, metabolic alterations are associated to both the onset of major depression and the antidepressant efficacy. To this goal, adult C57BL/6 male mice were exposed to stress for 6 weeks; the first two weeks was aimed at generating a mouse model of depression. During the remaining 4 weeks, mice received one of the following treatments: vehicle, fluoxetine, metformin, or a combination of fluoxetine and metformin. We measured liking- and wanting-type anhedonia as behavioral phenotypes of depression and assessed the expression levels of selected genes involved in major depressive disorder and antidepressant response in the dorsal and ventral hippocampus, which are differently involved in the depressive symptomatology. The combined treatment was more effective than fluoxetine alone in ameliorating the depressive phenotype after one week of treatment. This was associated to an increase in IGF2 mRNA expression and enhanced long-term potentiation, specifically in the dorsal hippocampus, at the end of treatment. Overall, the present results show that, when administered in stressful conditions, the combined fluoxetine and metformin treatment may represent a more effective approach than fluoxetine alone in a short term. Finally, our findings highlight the relevance of polypharmacological strategy as effective interventions to increase the efficacy of the antidepressant drugs currently available.

Fractionating Blunted Reward Processing Characteristic of Anhedonia by Over-Activating Primate Subgenual Anterior Cingulate Cortex.

Anhedonia is a core symptom of depression, but the underlying neurobiological mechanisms are unknown. Correlative neuroimaging studies implicate dysfunction within ventromedial prefrontal cortex, but the causal roles of specific subregions remain unidentified. We addressed these issues by combining intracerebral microinfusions with cardiovascular and behavioral monitoring in marmoset monkeys to show that over-activation of primate subgenual anterior cingulate cortex (sgACC, area 25) blunts appetitive anticipatory, but not consummatory, arousal, whereas manipulations of adjacent perigenual ACC (pgACC, area 32) have no effect. sgACC/25 over-activation also reduces the willingness to work for reward. 18F-FDG PET imaging reveals over-activation induced metabolic changes in circuits involved in reward processing and interoception. Ketamine treatment ameliorates the blunted anticipatory arousal and reverses associated metabolic changes. These results demonstrate a causal role for primate sgACC/25 over-activity in selective aspects of impaired reward processing translationally relevant to anhedonia, and ketamine's modulation of an affective network to exert its action.

Differential effects of chronic 17ß-oestradiol treatment on rat behaviours relevant to depression.

Sex differences are a prominent feature of the pathophysiology of psychiatric disorders, such as major depressive disorder, which affects women at a higher incidence than men. Research suggests that the most potent endogenous oestrogen, 17ß-oestradiol, may have therapeutic potential in treating depression. However, preclinical studies have produced mixed results, likely as a result of various methodological factors such as treatment duration. The present study aimed to investigate the effects of ovariectomy and chronic 17ß-oestradiol treatment via a s.c. silastic implant on behaviours relevant to depression in adult female Sprague-Dawley rats. Rats were assessed in the forced swim test, saccharin preference test and novel object recognition memory test, as well as for possible confounding behaviours, including locomotion and anxiety (open field test) and motivation and anxiety (novelty suppressed feeding test). Treatment effects were verified using body and uterus weight, as well as serum concentrations of 17ß-oestradiol, progesterone and testosterone. Compared to ovariectomised rats, chronic 17ß-oestradiol treatment enhanced saccharin preference and novel object recognition performance. There were no group differences in passive or active coping behaviour when assayed using the forced swim test. Taken together, these results support an antidepressant-like action of oestrogens but highlight that the beneficial effects of chronic 17ß-oestradiol treatment may be related to specific depression-related symptoms, particularly anhedonia and memory.

Fish oil ameliorates sickness behavior induced by lipopolysaccharide in aged mice through the modulation of kynurenine pathway.

Sickness behavior is an expression of a central motivational state triggered by activation of the immune system, being considered a strategy of the organism to fight infection. Sickness behavior is induced by peripheral administration of lipopolysaccharide (LPS). LPS can increase the levels of proinflammatory cytokines, which induce the activation of the kynurenine pathway (KP) and behavioral alterations. Previous studies have shown that omega-3 (n-3) polyunsaturated fatty acid (PUFA) has anti-inflammatory properties. Because of this, the purpose of the present study was to evaluate the protective effect of fish oil (FO) supplementation against LPS-induced sickness behavior in aged mice with respect to anhedonia, locomotor activity and body weight. Moreover, we evaluated the ability of FO treatment on the regulation of neuroinflammation (levels of interleukin-1ß, interleukin-6, tumor factor necrosis-α and interferon-γ), KP biomarkers (levels of tryptophan, kynurenine, kynurenic acid, 3-hydroxykynurenine and quinolinic acid and activities of indoleamine-2,3-dioxygenase, kynurenine monooxygenase and kynurenine aminotransferase) and serotonergic system (levels of serotonin and 5-hydroxyindoleactic acid) in the hippocampus, striatum and prefrontal cortex of LPS-treated mice. We found that FO prevented the LPS-mediated body weight loss, anhedonic behavior, reduction of locomotor activity, up-regulation of the proinflammatory cytokines and serotoninergic alterations. We also found that FO was effective in modulating the KP biomarkers, inhibiting or attenuating KP dysregulation induced by LPS. Together, our results indicated that FO may have beneficial effects on LPS induced sickness-behavior in aged mice either by modulating central inflammation, KP and serotonergic signaling (indirectly effect) or by fatty acids incorporation into neuronal membranes (direct effect).

TNFα-dependent anhedonia and upregulation of hippocampal serotonin transporter activity in a mouse model of collagen-induced arthritis.

The serotonin transporter (SERT) facilitates high affinity reuptake of 5-HT from the extracellular fluid and dysregulation of transporter function has been implicated in a range of mood disorders including depression. Recent studies have linked immune system activation to depression as well as to altered serotonin transporter activity. Advancing previous studies, which have mainly focussed on acute effects of immune system activation, in this study we used collagen-induced arthritis (CIA) in mice as a model of chronic inflammatory disease, to investigate the effect of prolonged inflammation on brain SERT function and behaviour. We found that 5-6 weeks after immunisation, CIA mice display anhedonia, a core depression-like behaviour. Behavioural symptoms are temporally correlated with a region-specific upregulation of SERT activity in the hippocampus, which occurs at a post-translational level and is independent of SERT trafficking. Kinetic analysis of 5-HT uptake revealed that the elevation of transporter activity is due to an increase in 5-HT transport capacity (Vmax) with no change in apparent Km values, suggesting that different regulatory mechanisms govern SERT modulation under chronic versus acute inflammatory conditions. Protein expression of tumour necrosis factor receptor 1 (TNFR1) was specifically upregulated in the hippocampus of CIA mice, indicating altered TNFα signalling. Anti-TNFα treatment using etanercept not only diminished joint inflammation, but also prevented the development of anhedonia and the upregulation of SERT activity in the hippocampus, suggesting a key role for TNFα signalling in brain function regulation in this disease model. Our study provides novel insight into molecular mechanisms underlying mood symptoms in chronic inflammatory diseases, with particular relevance to rheumatoid arthritis.

The Gender-Biased Effects of Intranasal MPTP Administration on Anhedonic- and Depressive-Like Behaviors in C57BL/6 Mice: the Role of Neurotrophic Factors.

Depression is a highly prevalent and debilitating non-motor symptom observed during the early stages of Parkinson's disease (PD). Although PD prevalence is higher in men, the depressive symptoms in PD are more common in women. Therefore, the aim of this study was to investigate the development of anhedonic- and depressive-like behaviors in male and female mice and the potential mechanisms related to depressive symptoms in an experimental model of PD. Young adult male and female C57BL/6 mice (3 months old) received a single intranasal (i.n.) administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and were submitted to a battery of behavioral tasks (sucrose consumption, splash test, tail suspension, forced swimming and open field tests) to assess their emotional and motor profiles. Considering the role of sexual hormones in emotional behaviors, the same protocol of i.n. MPTP administration and the splash, tail suspension, and open field tests were conducted in ovariectomized (OVX) and aged C57BL/6 female (20 months old) mice. We also investigated the immunocontent of neurotrophins (BDNF, GDNF, and VEGF) in the hippocampus and prefrontal cortex by western blot. I.n.  MPTP administration induced more pronounced anhedonic- and selective depressive-like behaviors in female adult mice, also observed in OVX and aged female mice, with the absence of motor impairments. Furthermore, MPTP induced a more pronounced depletion of neurotrophins in the prefrontal cortex and hippocampus in female than male mice. This study provides new evidence of increased susceptibility of female mice to anhedonic- and depressive-like behaviors following i.n. MPTP administration. The observed gender-related effects of MPTP on emotional parameters seem to be linked to increased depletion of neurotrophins (particularly BDNF and GDNF) in the hippocampus and prefrontal cortex of female mice.

Antidepressant-like actions by silencing of neuronal ELAV-like RNA-binding proteins HuB and HuC in a model of depression in male mice.

Currently available antidepressant drugs often fail to achieve full remission and patients might evolve to treatment resistance, showing the need to achieve a better therapy of depressive disorders. Increasing evidence supports that post-transcriptional regulation of gene expression is important in neuronal development and survival and a relevant role is played by RNA binding proteins (RBP). To explore new therapeutic strategies, we investigated the role of the neuron-specific ELAV-like RBP (HuB, HuC, HuD) in a mouse model of depression. In this study, a 4-week unpredictable chronic mild stress (UCMS) protocol was applied to mice to induce a depressive-like phenotype. In the last 2 weeks of the UCMS regimen, silencing of HuB, HuC or HuD was performed by using specific antisense oligonucleotides (aODN). Treatment of UCMS-exposed mice with anti-HuB and anti-HuC aODN improved both anhedonia and behavioural despair, used as measures of depressive-like behaviour, without modifying the response of stressed mice to an anxiety-inducing environment. On the contrary, HuD silencing promoted an anxiolytic-like behaviour in UCMS-exposed mice without improving depressive-like behaviours. The antidepressant-like phenotype of anti-HuB and anti-HuC mice was not shown concurrently with the promotion of adult hippocampal neurogenesis in the dentate gyrus, and no increase in the BDNF and CREB content was detected. Conversely, in the CA3 hippocampal region, projection area of newly born neurons, HuB and HuC silencing increased the number of BrdU/NeuN positive cells. These results give the first indication of a role of nELAV in the modulation of emotional states in a mouse model of depression.

Chronic Swimming Exercise Ameliorates Low-Soybean-Oil Diet-Induced Spatial Memory Impairment by Enhancing BDNF-Mediated Synaptic Potentiation in Developing Spontaneously Hypertensive Rats.

Exercise and low-fat diets are common lifestyle modifications used for the treatment of hypertension besides drug therapy. However, unrestrained low-fat diets may result in deficiencies of low-unsaturated fatty acids and carry contingent risks of delaying neurodevelopment. While aerobic exercise shows positive neuroprotective effects, it is still unclear whether exercise could alleviate the impairment of neurodevelopment that may be induced by certain low-fat diets. In this research, developing spontaneously hypertensive rats (SHR) were treated with chronic swimming exercise and/or a low-soybean-oil diet for 6 weeks. We found that performance in the Morris water maze was reduced and long-term potentiation in the hippocampus was suppressed by the diet, while a combination treatment of exercise and diet alleviated the impairment induced by the specific low-fat diet. Moreover, the combination treatment effectively increased the expression of brain-derived neurotrophic factor (BDNF) and N-methyl-D-aspartic acid receptor (NMDAR), which were both down-regulated by the low-soybean-oil diet in the hippocampus of developing SHR. These findings suggest that chronic swimming exercise can ameliorate the low-soybean-oil diet-induced learning and memory impairment in developing SHR through the up-regulation of BDNF and NMDAR expression.

Aripiprazole relieves motivational anhedonia in rats.

BACKGROUND: Anhedonia is considered a relevant feature in depression and psychosis, characterized by poor treatment outcome, and associated with deficits in mesolimbic dopaminergic responsiveness. Clinical studies suggest the potential utility of aripiprazole as adjunctive therapy for resistant depression. Since aripiprazole can stabilize the dopaminergic system, in search of tailored therapeutic strategies for reward dysfunctions, we investigated whether the drug restored motivation toward positive stimuli in a rat model. METHODS: Anhedonia is modeled in non food-deprived 9-week old male Sprague-Dawley rats by exposing them to a chronic unavoidable stress protocol, consisting in repeated exposure to tail-shock or restrain, which disrupts the motivation to acquire a reward-directed behavior and the competence to escape aversive stimuli. We evaluated whether long-term aripiprazole administration (1mg/kg/day, i.p.) restored in chronically stressed rats, a) the disrupted dopaminergic response to sucrose consumption measuring DARPP-32 phosphorylation levels in the nucleus accumbens shell by immunoblotting; b) the motivation to operate in a sucrose self-administration protocol. RESULTS: Long-term aripiprazole administration restored DARPP-32 phosphorylation changes in response to sucrose and reinstated the motivational drive to acquire the reward in the progressive ratio task. However, it did not restore reactivity to aversive stimuli. LIMITATIONS: The results obtained in our model may not fully translate to the clinic, as anhedonia is a complex construct in patients, where motivational aspects represent a central but not unique feature. CONCLUSIONS: This study demonstrates that aripiprazole relieved motivational anhedonia in a stress-induced model and warrants further studies to ascertain whether this activity is clinically relevant for antipsychotic or adjunctive antidepressant treatments.

Anhedonia at experimental models of chronic stress and its correction.

INTRODUCTION: Different types of chronic stress lead to neurotic and depressive disorders. Key symptoms of these disorders are anhedonia and correction of which will indicate the efficacy of proposed therapy. The aim of the paper is to investigate the influence of amide 2-hydroxy-N-naftalen-1-il-2-(2-oxo-1,2-dihidro-indole-3-iliden) and ethyl ether 4-[2-hydroxy-2-(2-oxo-1,2-dihidro-indole-3-iliden)-acetamin]-butyric acid on anhedonia after the experimental neurosis and chronic moderate stress in rats. MATERIALS AND METHODS: It was studied the influence of therapeutic and preventive administration of substances 18 and E-38 in the dosage of 12mg/kg during chronic mild stress "conflict of afferent activation" during 30 days and depression-like behavior chronic mild stress that modeled 8 weeks. Results of investigation: Experimental neurosis caused decrease of number of comings to drinking-bowl, decrease of total number of drank sucrose and decrease of the percent of drank water with sugar in comparison with intact animals. Analogical but more significant changes were noticed during depression-like behavior. The use of amide 2-oxoindolin-3-glyoxylic acid based on neurosis counters effectively the development of anhedonia. Substance 18 increased the number of comings to drinking-bowl with sucrose and increased the amount of the number of drank water with sucrose in comparison with control pathology without correction. The substance possibly assists in use of solution with sucrose among water and does not compromise reference-preparation such as diazepam. The administration of ethyl ether of 2-oxoindolin-3-glyoxylic acid at chronic mild stress possibly increased the number of comings to the drinking-bowl and increased the number of drank sucrose in comparison with control pathology and it was more effective than imipramine and countered anhedonia. CONCLUSIONS: It was indicated that during 30 day experimental neurosis and 8 week depression-like behavior cause the development of anhedonia. Therapeutic use of amide 2-hydroxy-N-naftalen-1-il-2-(2-oxo-1,2-dihidro-indole-3-iliden) and ethyl ether 4-[2-hydroxy-2-(2-oxo-1,2-dihidro-indole-3-iliden)-acetamin]-butyric acid corrected effectively anhedonia after experimental neurosis and chronic mild stress in rats.

Assessment of nicotine withdrawal-induced changes in sucrose preference in mice.

Anhedonia, induced by nicotine withdrawal, may serve as an important affective sign that reinforces tobacco use and smoking relapse rates in humans. Animal models provide a way to investigate the underlying neurobiological factors involved in the decrease in responding for positive affective stimuli during nicotine withdrawal and may aid in drug development for nicotine dependence. Thus, we explored the use of the sucrose preference test to measure nicotine withdrawal-induced reduction in response for positive affective stimuli in mice. C57BL/6J and knockout (KO) mice were chronically exposed to different doses of nicotine through surgically implanted subcutaneous osmotic minipumps for 14days and underwent spontaneous nicotine withdrawal on day 15. A sucrose preference time course was performed and the results were compared to another well-established affective sign of nicotine withdrawal, the reduction in time spent in light side, using the Light Dark Box test. Subsequently, our results demonstrated a time-dependent and dose-related reduction in sucrose preference in nicotine withdrawn male C57BL/6J mice, indicative of a decrease in responding for positive affective stimuli. Furthermore, the sucrose preference reduction during nicotine withdrawal was consistent with decrease in time spent in the light side of the Light Dark Box test. We also found the reduction for positive affective stimuli and time spent in the light side was not present in nicotine withdrawn ß2 and α6 KO mice, suggesting that these nicotinic subunits are involved in the affective signs of nicotine withdrawal. Thus, this report highlights the potential utility of the sucrose preference test as a useful measure of the decrease in responding for positive affective stimuli during spontaneous nicotine withdrawal.

Striatal dopamine D2/3 receptor-mediated neurotransmission in major depression: Implications for anhedonia, anxiety and treatment response.

Dopamine (DA) neurotransmission within the brain's reward circuit has been implicated in the pathophysiology of depression and in both, cognitive and pharmacological mechanisms of treatment response. Still, a direct relationship between measures of DA neurotransmission and reward-related deficits in patients with depression has not been demonstrated. To gain insight into the symptom-specific alterations in the DA system in patients with depression, we used positron emission tomography (PET) and the D2/3 receptor-selective radiotracer [11C]raclopride in twenty-three non-smoking un-medicated Major Depressive Disorder (MDD) patients and sixteen healthy controls (HC). We investigated the relationship between D2/3 receptor availability and baseline measures of depression severity, anxiety, anhedonia, and cognitive and pharmacological mechanisms of treatment response. We found that, compared to controls, patients with depression showed greater D2/3 receptor availability in several striatal regions, including the bilateral ventral pallidum/nucleus accumbens (vPAL/NAc), and the right ventral caudate and putamen. In the depressed sample, D2/3 receptor availability in the caudal portion of the ventral striatum (NAc/vPAL) correlated with higher anxiety symptoms, whereas D2/3 receptor availability in the rostral area of the ventral striatum correlated negatively with the severity of motivational anhedonia. Finally, MDD non-remitters showed greater baseline anxiety, greater D2/3 availability in the NAc/vPAL, and greater placebo-induced DA release in the bilateral NAc. Our results demonstrate abnormally high D2/3 receptor availability in the ventral striatum of patients with MDD, which seem to be associated with comorbid anxiety symptoms and lack of response to antidepressants.

Systemic N-terminal fragments of adrenocorticotropin reduce inflammation- and stress-induced anhedonia in rats.

Emerging evidence implicates impaired self-regulation of the hypothalamic-pituitary-adrenal (HPA) axis and inflammation as important and closely related components of the pathophysiology of major depression. Antidepressants show anti-inflammatory effects and are suggested to enhance glucocorticoid feedback inhibition of the HPA axis. HPA axis activity is also negatively self-regulated by the adrenocorticotropic hormone (ACTH), a potent anti-inflammatory peptide activating five subtypes of melanocortin receptors (MCRs). There are indications that ACTH-mediated feedback can be activated by noncorticotropic N-terminal ACTH fragments such as a potent anti-inflammatory MC1/3/4/5R agonist α-melanocyte-stimulating hormone (α-MSH), corresponding to ACTH(1-13), and a MC3/5R agonist ACTH(4-10). We investigated whether intraperitoneal administration of rats with these peptides affects anhedonia, which is a core symptom of depression. Inflammation-related anhedonia was induced by a single intraperitoneal administration of a low dose (0.025mg/kg) of lipopolysaccharide (LPS). Stress-related anhedonia was induced by the chronic unpredictable stress (CUS) procedure. The sucrose preference test was used to detect anhedonia. We found that ACTH(4-10) pretreatment decreased LPS-induced increase in serum corticosterone and tumor necrosis factor (TNF)-α, and a MC3/4R antagonist SHU9119 blocked this effect. Both α-MSH and ACTH(4-10) alleviated LPS-induced anhedonia. In the CUS model, these peptides reduced anhedonia and normalized body weight gain. The data indicate that systemic α-MSH and ACTH(4-10) produce an antidepressant-like effect on anhedonia induced by stress or inflammation, the stimuli that trigger the release of ACTH and α-MSH into the bloodstream. The results suggest a counterbalancing role of circulating melanocortins in depression and point to a new approach for antidepressant treatment.