Candidate pharmacological treatments for substance use disorder and suicide identified by gene co-expression network-based drug repositioning.

Patients with substance use disorders (SUD) are at high risk to die by suicide. So far, the neurobiology of the suicide-SUD association has not been elucidated. This study aimed to identify potential pharmacological targets among hub genes from brain gene co-expression networks of individuals with SUD in a suicidal and non-suicidal context. Post-mortem samples from the prefrontal cortex of 79 individuals were analyzed. Individuals were classified into the following groups: suicides with SUD (n = 28), suicides without SUD (n = 23), nonsuicides with SUD (n = 9), nonsuicides without SUD (n = 19). Gene expression profiles were evaluated with the Illumina HumanHT-12 v4 array. Co-expression networks were constructed in WGCNA using the differentially expressed genes found in the comparisons: (a) suicides with and without SUD and (b) nonsuicides with and without SUD. Hub genes were selected for drug-gene interaction testing in the DGIdb database. Among drugs interacting with hub genes in suicides we found MAOA inhibitors and dextromethorphan. In the nonsuicide individuals, we found interactions with eglumegad and antipsychotics (olanzapine, clozapine, loxapine). Modafinil was found to interact with genes in both suicides and nonsuicides. These drugs represent possible candidate treatments for patients with SUD with and without suicidal behavior and their study in each context is encouraged.

Brain Gene Expression Profiling of Individuals With Dual Diagnosis Who Died by Suicide.

Objective: Dual diagnosis (DD) is the co-occurrence of at least one substance use disorder and one or more mental disorders in a given individual. Despite this comorbidity being highly prevalent and associated with adverse clinical outcomes, its neurobiology remains unclear. Furthermore, patients with DD are at higher risk for suicidal behavior in comparison with single disorder patients. Our objective was to evaluate brain gene expression patterns in individuals with DD who died by suicide. Methods: We compared the gene expression profile in the dorsolateral prefrontal cortex of suicides with DD (n = 10) to the transcriptome of suicides with substance use disorder alone (n = 10), suicides with mood disorders (MD) alone (n = 13), and suicides without mental comorbidities (n = 5). Gene expression profiles were assessed by microarrays. In addition, we performed a brain cell type enrichment to evaluate whether the gene expression profiles could reflect differences in cell type compositions among the groups. Results: When comparing the transcriptome of suicides with DD to suicides with substance use disorder alone and suicides with MD alone, we identified 255 and 172 differentially expressed genes (DEG), respectively. The overlap of DEG between both comparisons (112 genes) highlighted the presence of common disrupted pathways in substance use disorder and MD. When comparing suicides with DD to suicides without mental comorbidities, we identified 330 DEG, mainly enriched in neurogenesis. Cell type enrichment indicated higher levels of glial markers in suicides with DD compared to the other groups. Conclusions: Suicides with DD exhibited a gene expression profile distinct from that of suicides with a single disorder, being substance use disorder or MD, and suicides without mental disorders. Our results suggest alteration in the expression of genes involved in glial specific markers, glutamatergic and GABAergic neurotransmission in suicides with DD compared to suicides with a single disorder and suicides without mental comorbidities. Alterations in the expression of synaptic genes at different levels were found in substance use disorder and MD.

Telomere Length, Oxidative Stress, Inflammation and BDNF Levels in Siblings of Patients with Bipolar Disorder: Implications for Accelerated Cellular Aging.

Background: Growing evidence supports the existence of neurobiological trait abnormalities in individuals at genetic risk for bipolar disorder. The aim of this study was to examine potential differences in brain-derived neurotrophic factor, cytokines, oxidative stress, and telomere length markers between patients with bipolar disorder, their siblings, and healthy controls. Methods: Thirty-six patients with bipolar disorder type I, 39 siblings, and 44 healthy controls were assessed. Serum levels of brain-derived neurotrophic factor, interleukin-6, interleukin-10, tumor necrosis factor-α, C-C motif chemokine 11, C-C motif chemokine 24, and 3-nitrotyrosine were measured, as were the activities of glutathione peroxidase, glutathione reductase, and glutathione S-transferase. Telomere length (T/S ratio) was measured using quantitative polymerase chain reaction. Results: Telomere length was different between the 3 groups (P = .041) with both patients and siblings showing a shorter T/S ratio compared with healthy controls. Patients showed increased levels of interleukin-6 (P = .005) and interleukin-10 (P = .002) compared with controls as well as increased levels of interleukin-6 (p = 0.014) and CCL24 (P = .016) compared with their siblings. C-C motif chemokine 11 levels were increased in siblings compared with controls (P = .015), and a similar tendency was found in patients compared with controls (P = .045). Glutathione peroxidase activity was decreased in patients compared with controls (P = .006) and siblings (P = .025). No differences were found for the other markers. Conclusions: The present results suggest that unaffected siblings may present accelerated aging features. These neurobiological findings may be considered as endophenotypic traits. Further prospective studies are warranted.

Impaired endoplasmic reticulum stress response in bipolar disorder: cellular evidence of illness progression.

Bipolar disorder (BD) is a severe chronic psychiatric disorder that has been associated with cellular dysfunctions related to mitochondria, neurotrophin levels, and oxidative stress. Evidence has shown that endoplasmic reticulum (ER) stress may be a common pathway of the cellular changes described in BD. In the present study we assessed unfolded protein response (UPR) and the effects of this cellular process on lymphocytes from patients with BD. We also evaluated whether the stage of chronicity of BD was associated with changes in UPR parameters. Cultured lymphocytes from 30 patients with BD and 32 age- and sex-matched controls were treated with tunicamycin, an ER stressor, for 12 or 24 h to measure levels of UPR-related proteins (GRP78, eIF2α-P, and CHOP) using flow cytometry, and for 48 h to analyse ER stress-induced cell death. In healthy controls but not in patients we found an increase in levels of GRP78, eIF2α-P, and CHOP after ER stress induction. In addition, tunicamycin-induced cell death was significantly higher in patients compared to controls. More importantly, early-stage patients did not differ from controls while the late-stage patients showed an impaired ER stress response. Thus, dysfunction in ER-related stress response may be associated with decreased cellular resilience in BD and illness progression.

Hypothalamic-pituitary-adrenal axis dysfunction and illness progression in bipolar disorder.

BACKGROUND: Impaired stress resilience and a dysfunctional hypothalamic-pituitary-adrenal (HPA) axis are suggested to play key roles in the pathophysiology of illness progression in bipolar disorder (BD), but the mechanisms leading to this dysfunction have never been elucidated. This study aimed to examine HPA axis activity and underlying molecular mechanisms in patients with BD and unaffected siblings of BD patients. METHODS: Twenty-four euthymic patients with BD, 18 siblings of BD patients, and 26 healthy controls were recruited for this study. All subjects underwent a dexamethasone suppression test followed by analyses associated with the HPA axis and the glucocorticoid receptor (GR). RESULTS: Patients with BD, particularly those at a late stage of illness, presented increased salivary post-dexamethasone cortisol levels when compared to controls (p = 0.015). Accordingly, these patients presented reduced ex vivo GR responsiveness (p = 0.008) and increased basal protein levels of FK506-binding protein 51 (FKBP51, p = 0.012), a co-chaperone known to desensitize GR, in peripheral blood mononuclear cells. Moreover, BD patients presented increased methylation at the FK506-binding protein 5 (FKBP5) gene. BD siblings presented significantly lower FKBP51 protein levels than BD patients, even though no differences were found in FKBP5 basal mRNA levels. CONCLUSIONS: Our data suggest that the epigenetic modulation of the FKBP5 gene, along with increased FKBP51 levels, is associated with the GR hyporesponsiveness seen in BD patients. Our findings are consistent with the notion that unaffected first-degree relatives of BD patients share biological factors that influence the disorder, and that such changes are more pronounced in the late stages of the illness.

Early life stress exacerbates cognitive dysfunction induced by d-amphetamine: amelioration by valproic acid.

It has been demonstrated that experiences taking place early in life have a profound influence on brain development, interacting with the genetic background and determining differences in the vulnerability to the onset of bipolar disorder when the individual is exposed to a second adverse event later in life. Here, we investigated the effects of exposure to an early adverse life event (maternal deprivation) and to a later adverse life event [D-amphetamine (AMPH)] on cognition in an animal model of mania. We have previously demonstrated that that repeated AMPH exposure produces severe and persistent cognitive impairment, which was more pronounced when the animals were maternal deprived, suggesting that the early adverse life event could be potentiating the effects of the exposure to the second adverse life event later in life. Here, we show that valproic acid ameliorated the cognitive deficits induced by AMPH, but it was not effective when the animals were exposed to both stressors: maternal deprivation and AMPH treatment.

Staging and neuroprogression in bipolar disorder.

The apparently progressive nature of a considerable proportion of cases of bipolar disorder (BD) has been acknowledged in recently proposed clinical staging models. This has been part of an attempt to facilitate and refine diagnosis, treatment selection, and establish a prognosis. The study of the progressive nature of some cases of BD has given raise to the hypothesis of neuroprogression, which postulates that different stages of BD are associated with distinct neurobiological underpinnings. Given that BD may be intimately associated with chronic stress response and coping mechanisms over the course of illness, we propose that cellular resilience mechanisms may play a key role in the neuroprogression in BD. In the present study, we review neuroanatomical evidence of the progression that occurs in many cases of BD, as well as cellular resilience mechanisms and peripheral biomarkers associated with distinct stages of this disorder. In summary, cellular resilience mechanisms seem to be less efficient at later stages of BD, especially mitochondrial and endoplasmic reticulum-related responses to stress. These insights may help in developing staging models of BD, with a special emphasis on the search for biomarkers associated with illness progression.

Telomeres: the role of shortening and senescence in major depressive disorder and its therapeutic implications.

Major depressive disorder (MDD) is one of the most prevalent and debilitating psychiatric disorders, with a large number of patients not showing an effective therapeutic response to available treatments. Several biopsychosocial factors, such as stress in childhood and throughout life, and factors related to biological aging, may increase the susceptibility to MDD development. Included in critical biological processes related to aging and underlying biological mechanisms associated with MDD is the shortening of telomeres and changes in telomerase activity. This comprehensive review discusses studies that assessed the length of telomeres or telomerase activity and function in peripheral blood cells and brain tissues of MDD individuals. Also, results from in vitro protocols and animal models of stress and depressive-like behaviors were included. We also expand our discussion to include the role of telomere biology as it relates to other relevant biological mechanisms, such as the hypothalamic-pituitary-adrenal (HPA) axis, oxidative stress, inflammation, genetics, and epigenetic changes. In the text and the discussion, conflicting results in the literature were observed, especially considering the size of telomeres in the central nervous system, on which there are different protocols with divergent results in the literature. Finally, the context of this review is considering cell signaling, transcription factors, and neurotransmission, which are involved in MDD and can be underlying to senescence, telomere shortening, and telomerase functions.

Total and mitochondrial nitrosative stress, decreased brain-derived neurotrophic factor (BDNF) levels and glutamate uptake, and evidence of endoplasmic reticulum stress in the hippocampus of vitamin A-treated rats.

Vitamin A supplementation has caused concern among public health researchers due to its ability in decreasing life quality from acute toxicological effects to increasing mortality rates among vitamin supplement users. For example, it was described cognitive decline (i.e. irritability, anxiety, and depression) in patients subjected to long-term vitamin A therapy, as occurs in cancer treatment. However, the mechanism by which vitamin A affects mammalian cognition is not completely understood. Then, we performed the present work to investigate the effects of vitamin A supplementation at clinical doses (1,000-9,000 IU/kg day(-1)) for 28 days on rat hippocampal nitrosative stress levels (both total and mitochondrial), bioenergetics states, brain-derived neurotrophic factor (BDNF), alpha- and beta-synucleins, BiP and dopamine receptor 2 (D2 receptor) contents, and glutamate uptake. We observed mitochondrial impairment regarding respiratory chain function: increased complex I-III, but decreased complex IV enzyme activity. Also, decreased BDNF levels were observed in vitamin A-treated rats. The present data demonstrates, at least in part, that mitochondrial dysfunction and decreased BDNF and D2 receptors levels, as well as decreased glutamate uptake may take an important role in the mechanism behind the previously reported cognitive disturbances associated to vitamin A supplementation.

Sex differences in brain gene expression among suicide completers.

BACKGROUND: Suicide rates vary substantially by sex. Suicides committed by males significantly outnumber female suicides. Disparities in community and social factors provide a partial explanation for this phenomenon. Thus, the evaluation of sex differences at a biological level might contribute to the elucidation of the factors involved in this imbalance. The aim of the present study was to evaluate sex-specific gene expression patterns in the suicidal brain. METHODS: postmortem samples from the dorsolateral prefrontal cortex (DLPFC) of 75 Latino individuals were analyzed. We considered the following groups: i) male suicides (n = 38), ii) female suicides (n = 10), iii) male controls (n = 20), and iv) female controls (n = 7). Gene expression profiles were evaluated by microarrays. Differentially expressed genes among the groups were identified with a linear model. Similarities and differences in the gene sets between the sexes were identified. RESULTS: Differentially expressed genes were identified between suicides and controls of each sex: 1,729 genes in females and 1,997 genes in males. Female-exclusive suicide genes were related to cell proliferation and immune response. Meanwhile, male-exclusive suicide genes were associated to DNA binding and ribonucleic protein complex. Sex-independent suicide genes showed enrichment in mitochondrial and vesicular functions. LIMITATIONS: Relatively small sample size. Our diagnosis approach was limited to information found on coroner's records. The analysis was limited to a single brain area (DLPFC) and we used microarrays. CONCLUSION: Previously unexplored sex differences in the brain gene expression of suicide completers were identified, providing valuable foundation for the evaluation of sex-specific factors in suicide.

Brain-derived neurotrophic factor gene val66met polymorphism and executive functioning in patients with bipolar disorder.

OBJECTIVE: In the present study, we investigate the association between the val66met polymorphism of the brain-derived neurotrophic factor (BNDF) and the performance on the Wisconsin Card Sorting Test in a sample of Caucasian Brazilian patients with bipolar disorder. METHOD: Sixty-four patients with bipolar disorder were assessed and their performance on the Wisconsin Card Sorting Test was compared with the allele frequency and genotype of the val66met polymorphism of the brain-derived neurotrophic factor. RESULTS: The percentage of non-perseverative errors was significantly higher among patients with the val/val genotype. There was no association between (BNDF) genotype frequency and other Wisconsin Card Sorting Test domains. CONCLUSION: Our results did not replicate previous descriptions of an association between a worse cognitive performance and the presence of the met allele of the val66met brain-derived neurotrophic factor gene polymorphism.

Peripheral blood microRNA levels in females with cocaine use disorder.

BACKGROUND: There is growing emphasis in the field of psychiatry on the need to identify candidate biomarkers to aid in diagnosis and clinical management of addictive disorders. MicroRNAs (miRNAs) are small nucleotide sequences with the ability to regulate gene expression at the transcriptomic level. However, the role of miRNAs as potential biomarkers for addiction is still underexplored. Based on translational and clinical findings, we compared the expression levels of microRNA-124 (miR-124), microRNA-181 (miR-181), and microRNA-212 (miR-212) between a group of females with cocaine use disorder (CUD; n = 30) and a group of healthy female controls (HC; n = 20). METHODS: Blood expression levels of miR-124, miR-181, and miR-212 in the HC and CUD group were determined by qPCR, using two miRNAs as endogenous controls (miR-24 and miR-126). Substance use behavior was assessed by self-report using the Addiction Severity Index (ASI-6) and depressive symptoms severity was measured using the Beck Depressive Inventory (BDI-II). Urine screen test was performed to detect cocaine metabolites. RESULTS: Mir-124 and miR-181 were upregulated in the CUD group (p > 0.01). Furthermore, increased cognitive/affective depression symptoms were identified among a CUD subgroup with the higher miR-181 expression levels (p > 0.05). No significant difference in expression levels was found for miR-212. CONCLUSIONS: MiR-124 and miR-181 show promise as biomarkers for CUD when assessed in the peripheral blood. Further investigation is needed to elucidate the molecular mechanisms underlying these associations and to validate target genes regulated by these miRNAs.

Brain Gene Expression Pattern of Subjects with Completed Suicide and Comorbid Substance Use Disorder.

BACKGROUND/AIM: Although individuals with substance use disorder (SUD) are at high risk of committing suicide, most studies of postmortem gene expression exclude subjects with SUD due to the potential confounding effect of drugs in the transcriptome. Thus, little is known about the gene expression profile in suicides with SUD. The identification of altered biological processes in suicides with SUD is crucial in the comprehension of the interaction between both pathologies. METHODS: We evaluated the gene expression profile in the dorsolateral prefrontal area of suicides and nonsuicides with and without SUD by microarrays. RESULTS: We identified 222 differentially expressed genes, predominately enriched in cell proliferation in the comparison between suicides with and without SUD. When comparing the transcriptome of suicides with SUD to nonsuicides with SUD, we identified 550 differentially expressed genes, mainly enriched in oxidative phosphorylation. Differentially expressed genes (1,417) between suicides and nonsuicides without SUD were detected. Most of them were related to mitochondrial function. CONCLUSION: Interaction between suicide and SUD seems to influence the expression of genes involved in glial proliferation and glutamatergic neurotransmission. These results highlight, for the first time, that suicides with SUD have a gene expression profile distinct from that of subjects with only one of these disorders.

High Exploratory Phenotype Rats Exposed to Environmental Stressors Present Memory Deficits Accompanied by Immune-Inflammatory/Oxidative Alterations: Relevance to the Relationship Between Temperament and Mood Disorders.

Low-exploratory (LE) and high-exploratory (HE) rodents mimic human depressive and hyperthymic temperaments, respectively. Mood disorders (MD) may be developed by the exposure of these temperaments to environmental stress (ES). Psychiatric symptoms severity in MD patients is related to the magnitude of memory impairment. Thus, we aimed at studying the consequences of the exposure of LE and HE male Wistar rats, during periadolescence, to a combination of ES, namely, paradoxical sleep deprivation (PSD) and unpredictable stress (US), on anxiety-related behavior in the plus maze test, working (WM) and declarative memory (DM) performance. We also evaluated hippocampal immune-inflammatory/oxidative, as consequences of ES, and prevention of ES-induced alterations by the mood-stabilizing drugs, lithium and valproate. Medium exploratory (ME) control rats were used for comparisons with HE- and LE-control rats. We observed that HE-controls presented increased anxiolytic behavior that was significantly increased by ES exposure, whereas LE-controls presented increased anxiety-like behavior relative to ME-controls. Lithium and valproate prevented anxiolytic alterations in HE+ES rats. HE+ES- and LE+ES-rats presented WM and DM deficits. Valproate and lithium prevented WM deficits in LE-PSD+US rats. Lithium prevented DM impairment in HE+ES-rats. Hippocampal levels of reduced glutathione (GSH) increased four-fold in HE+ES-rats, being prevented by valproate and lithium. All groups of LE+ES-rats presented increased levels of GSH in relation to controls. Increments in lipid peroxidation in LE+ES- and HE+ES-rats were prevented by valproate in HE+ES-rats and by both drugs in LE+ES-rats. Nitrite levels were increased in HE+ES- and LE+ES-rats (five-fold increase), which was prevented by both drugs in LE+ES-rats. HE+ES-rats presented a two-fold increase in the inducible nitric oxide synthase (iNOS) expression that was prevented by lithium. HE+ES-rats showed increased hippocampal and plasma levels of interleukin (IL)-1ß and IL-4. Indoleamine 2, 3-dioxygenase 1 (IDO1) was increased in HE+ES- and LE+ES-rats, while tryptophan 2,3-dioxygenase (TDO2) was increased only in HE+ES-rats. Altogether, our results showed that LE- and HE-rats exposed to ES present distinct anxiety-related behavior and similar memory deficits. Furthermore, HE+ES-rats presented more brain and plasma inflammatory alterations that were partially prevented by the mood-stabilizing drugs. These alterations in HE+ES-rats may possibly be related to the development of mood symptoms.

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.

IL-6, TNF-α, IL-10, and nutritional status in pediatric patients with biliary atresia.

OBJECTIVES: The objective of the present study is to evaluate whether IL-6, TNF-α, IL-10 are associated with nutritional status in patients with cirrhosis secondary to biliary atresia and compare to healthy controls. METHODS: The parameters used for nutritional assessment were the standard deviation scores of height-for-age and of triceps skinfold thickness-for-age. The severity of cirrhosis was evaluated using the Child-Pugh score and PELD/MELD. Serum cytokines were measured using Cytometric Bead Array flow cytometry. RESULTS: IL-6, TNF-α, and IL-10 were significantly higher in the cirrhosis group when compared with the control group (2.4 vs. 0.24 (p<0.001), 0.21 vs. 0.14 (p=0.007), and 0.65 vs. 0.36 (p=0.004), respectively. IL-6 and IL-10 were positively correlated with disease severity (0.450 [p=0.001] and 0.410; [p=0.002], respectively). TNF-α did not show a significant correlation with disease severity (0.100; p=0.478). Regarding nutritional evaluation, IL-6 was negatively correlated with the standard deviation score of height-for-age (-0.493; p<0.001) and of triceps skinfold thickness-for-age (-0.503; p<0.001), respectively. IL-10 exhibited a negative correlation with the standard deviation score of height-for-age (-0.476; p<0.001) and the standard deviation score of triceps skinfold thickness-for-age (-0.388; p=0.004). TNF-α did not show any significance in both anthropometric parameters (-0.083 (p=0.555) and -0.161 (p=0.253). CONCLUSION: The authors suggest that, in patients with cirrhosis secondary to biliary atresia, IL-6 could be used as a possible supporting biomarker of deficient nutritional status and elevated IL-10 levels could be used as a possible early-stage supporting biomarker of deteriorating nutritional status.

The FKBP5 polymorphism rs1360780 is associated with lower weight loss after bariatric surgery: 26 months of follow-up.

BACKGROUND: Bariatric surgery is the most effective treatment choice for severe obesity. Recent literature indicates that FK506-binding protein 51 (FKBP51) could play a role in energy homeostasis, influencing adipogenesis and weight. OBJECTIVE: To evaluate if the presence of the T allele of the FKBP5 SNP rs1360780, associated with increased FKBP51 expression, could influence weight loss after bariatric surgery. SETTING: Hospital de Clínicas de Porto Alegre, Brazil. METHODS: Forty-two patients awaiting bariatric surgery were included, and the presence of the FKBP5 rs1360780 polymorphism was evaluated. During the postoperative period, a 26-month follow-up of weight loss was performed (n = 42, 36, 35, 35, and 30, from the first to fifth postoperative evaluation, respectively; loss to follow-up: 28.6%). RESULTS: Carriers of the T allele presented significantly lower weight loss compared with patients with the C/C genotype after the 12th to 14th month follow-up period. Differences in weight loss between genotypes ranged from 14.2% to 19.9% of excess weight loss (P = .045 and .004, respectively) and from 7.6% to 9.0% of total weight loss (P = .002 for both comparisons). Furthermore, carriers of the T allele also presented an earlier cessation of weight loss after surgery. CONCLUSION: The presence of the T allele of the FKBP5 SNP rs1360780 was associated with weight loss after bariatric surgery. Bariatric surgery can interact with genes involved in metabolic regulation, leading to different weight loss outcomes.

Role of P2X7 Receptor in an Animal Model of Mania Induced by D-Amphetamine.

The objective of this study was to explore the association between the P2X7 purinergic receptor (P2X7R) and neuroinflammation using a preclinical model of acute bipolar mania. We analyzed the modulatory effects of P2X7R agonist (3'-O-(4-benzoyl)benzoyl-adenosine 5'-triphosphate, BzATP) and antagonists (brilliant blue, BBG and 3-[[5-(2,3 dichlorophenyl)-1H-tetrazol-1-yl]methyl]pyridine hydrochloride, A438079) on assessments related to behavior (locomotor activity), neuroinflammation (interleukin-1 beta, IL-1ß; tumor necrosis factor alpha, TNF-α; and interleukin- 6, IL-6), oxidative stress (thiobarbituric acid reactive substances, TBARS) and neuroplasticity (brain-derived neurotrophic factor, BDNF) markers in a pharmacological model of mania induced by acute and chronic treatment with D-amphetamine (AMPH) (2 mg/kg) in mice. An apparent lack of responsiveness to AMPH was observed in terms of the locomotor activity in animals with blocked P2X7R or with genetic deletion of P2X7R in knockout (P2X7R(-/-)) mice. Likewise, P2X7R participated in the AMPH-induced increase of the proinflammatory and excitotoxic environment, as demonstrated by the reversal of IL-1ß, TNF-α, and TBARS levels caused by P2X7R blocking. Our results support the hypothesis that P2X7R plays a role in the neuroinflammation induced by AMPH in a preclinical model of mania, which could explain the altered behavior. The present data suggest that P2X7R may be a therapeutic target related to the neuroinflammation reported in bipolar disorder.

Ethanol during adolescence decreased the BDNF levels in the hippocampus in adult male Wistar rats, but did not alter aggressive and anxiety-like behaviors.

OBJECTIVE: To investigate the effects of ethanol exposure in adolescent rats during adulthood by assesssing aggression and anxiety-like behaviors and measuring the levels of inflammatory markers. METHODS: Groups of male Wistar rats (mean weight 81.4 g, n = 36) were housed in groups of four until postnatal day (PND) 60. From PNDs 30 to 46, rats received one of three treatments: 3 g/kg of ethanol (15% w/v, orally, n = 16), 1.5 g/kg of ethanol (12.5% w/v, PO, n = 12), or water (n = 12) every 48 hours. Animals were assessed for aggressive behavior (resident x intruder test) and anxiety-like behaviors (elevated plus maze) during adulthood. RESULTS: Animals that received low doses of alcohol showed reduced levels of brain-derived neurotrophic factor (BDNF) in the hippocampus as compared to the control group. No significant difference was found in prefrontal cortex. CONCLUSIONS: Intermittent exposure to alcohol during adolescence is associated with lower levels of BDNF in the hippocampus, probably due the episodic administration of alcohol, but alcohol use did not alter the level agression toward a male intruder or anxiety-like behaviors during the adult phase.