ArticleLiterature Review

The Role of Dopamine in the Pathophysiology of Depression

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Abstract

Multiple sources of evidence support a role for diminished dopaminergic neurotransmission in major depression. The physiological alterations underlying reduced dopamine (DA) signaling could result from either diminished DA release from presynaptic neurons or impaired signal transduction, either due to changes in receptor number or function and/or altered intracellular signal processing. There are data supporting each of these mechanisms, although interpretation of previous research is confounded by issues around study population, medication status, and technological limitations. In some patients with depression, DA-related disturbances improve by treatment with antidepressants, presumably by acting on serotonergic or nor-adrenergic circuits, which then affect DA function. However, most antidepressant treatments do not directly enhance DA neurotransmission, which may contribute to residual symptoms, including impaired motivation, concentration, and pleasure. Animal models of major depression show considerable responsiveness to manipulations of DA neurotransmission. Several studies, including postmortem investigations, particularly of subjects with severe depression, have demonstrated reduced concentrations of DA metabolites both in the cerebrospinal fluid and in brain regions that mediate mood and motivation. Although the neuroimaging findings are not unequivocal, several studies support the hypothesis that major depression is associated with a state of reduced DA transmission, possibly reflected by a compensatory up-regulation of D(2) receptors. These alterations in DA signaling may underlie the findings of increased "liking" or "high" feelings reported by severely depressed subjects treated with d-amphetamine compared with the response of less severely ill and normal control subjects. The efficacy of medications that directly act on DA neurons or receptors, such as monoamine oxidase inhibitors and pramipexole, suggests that subtypes of depression stemming from a primary DA dysfunction exist. Further research on the contribution of DA to the pathophysiology of depression is justified to improve outcomes for patients with treatment-resistant and nonremitting depression.

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... The [SRX]-dopamine (SRXD) receptor had a stronger connection than the serotonin and TrkB kinase receptors due to its greater binding energy value. Given the growing evidence that DA transmission assists antidepressant therapeutic goals [60], this augmentation of transmission could have clinical implications. This is because the majority of modern antidepressants do not boost dopamine neurotransmission [60]. ...
... Given the growing evidence that DA transmission assists antidepressant therapeutic goals [60], this augmentation of transmission could have clinical implications. This is because the majority of modern antidepressants do not boost dopamine neurotransmission [60]. ...
... Figure 10 and Figure S2 show the hydrophobic, ionizability, aromatic, and hydrogen bond surfaces at the interaction location of [(SRX)(TCNQ)] and dopamine, respectively. Given the growing evidence that DA transmission assists antidepressant therapeutic goals [60], this augmentation of transmission could have clinical implications. This is because the majority of modern antidepressants do not boost dopamine neurotransmission [60]. ...
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The charge transfer interactions between the seproxetine (SRX) donor and π-electron acceptors [picric acid (PA), dinitrobenzene (DNB), p-nitrobenzoic acid (p-NBA), 2,6-dichloroquinone-4-chloroimide (DCQ), 2,6-dibromoquinone-4-chloroimide (DBQ), and 7,7′,8,8′-tetracyanoquinodi methane (TCNQ)] were studied in a liquid medium, and the solid form was isolated and characterized. The spectrophotometric analysis confirmed that the charge–transfer interactions between the electrons of the donor and acceptors were 1:1 (SRX: π-acceptor). To study the comparative interactions between SRX and the other π-electron acceptors, molecular docking calculations were performed between SRX and the charge transfer (CT) complexes against three receptors (serotonin, dopamine, and TrkB kinase receptor). According to molecular docking, the CT complex [(SRX)(TCNQ)] binds with all three receptors more efficiently than SRX alone, and [(SRX)(TCNQ)]-dopamine (CTcD) has the highest binding energy value. The results of AutoDock Vina revealed that the molecular dynamics simulation of the 100 ns run revealed that both the SRX-dopamine and CTcD complexes had a stable conformation; however, the CTcD complex was more stable. The optimized structure of the CT complexes was obtained using density functional theory (B-3LYP/6-311G++) and was compared.
... The best described reward network is the mesolimbic pathway, which starts from the ventral tegmental area and affects the nucleus accumbens of the ventral striatum, some nuclei of the terminal stria, the amygdala and the hippocampus [54]. ...
... When these connections fail, together with social isolation and other age-related risk factors, an anhedonic state occurs. This event can be interpreted as the proxy of reward system impairment [54]. ...
... We have already highlighted that a dysfunction of the dopaminergic system is an important risk factor for the development of anhedonia [54]. When there are functional impairments in the reward system the reward response (regardless of whether it is a primary reward or a non-primary reward) is ineffective. ...
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During aging, many physiological systems spontaneously change independent of the presence of chronic diseases. The reward system is not an exception and its dysfunction generally includes a reduction in dopamine and glutamate activities and the loss of neurons of the ventral tegmental area (VTA). These impairments are even more pronounced in older persons who have neurodegenerative diseases and/or are affected by cognitive and motoric frailty. All these changes may result in the occurrence of cognitive and motoric frailty and accelerated progression of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases. In particular, the loss of neurons in VTA may determine an acceleration of depressive symptoms and cognitive and motor frailty trajectory, producing an increased risk of disability and mortality. Thus, we hypothesize the existence of a loop between reward system dysfunction, depression, and neurodegenerative diseases in older persons. Longitudinal studies are needed to evaluate the determinant role of the reward system in the onset of motoric-cognitive risk syndrome.
... A link between depression and contrast sensitivity is implicated by previous studies regarding dopamine (a neurotransmitter) in the visual system. On the one hand, it is well established that depressive individuals suffer from deficits of the dopaminergic system (for reviews, Belujon & Grace, 2017;Delva & Stanwood, 2021;Dunlop & Nemeroff, 2007). On the other hand, dopamine acts within the retina (Chen et al., 2021;Ghilardi et al., 1989;Weil et al., 2016), which is regarded as the first processing stage of the visual system (for a recent review, Pokorny & Smith, 2020). ...
... By measuring the pattern electroretinogram (PERG), which mainly reflects electrophysiological activity at the level of the retina (Mafei & Fiorentini, 1981), researchers found that MDD patients had lower retinal contrast gain (Bubl et al., 2010;Bubl et al., 2012;Bubl et al., 2015;Fam et al., 2013). In the retina, dysfunction of dopamine (a neurotransmitter) for depressive individuals has been found (Dunlop & Nemeroff, 2007;Lambert et al., 2000), which might lead to the altered retinal sensitivity. In addition, melatonin (a hormone), which is associated with the treatment of depression (Tonon et al., 2021), can also modulate the retinal sensitivity (Baba et al., 2009;Gagné et al., 2009;Huang et al., 2013;Wiechmann et al., 2003). ...
Article
Subthreshold depression (StD), as a subclinical state, is highly prevalent and increases the risk for developing major depressive disorder (MDD). Although several studies have reported deficits of contrast sensitivity in MDD patients, it is unclear whether individuals with StD could demonstrate deficits of contrast sensitivity and whether the deficits could remain stable over time. Here we used a contrast discrimination task (a suprathreshold task) and a contrast detection task (a near‐threshold task) to compare contrast sensitivity of the StD group with that of matched non‐depressed controls. For each task, a spatial four‐alternative forced‐choice method and a psychophysical QUEST procedure were used to measure contrast discrimination threshold or contrast detection threshold. Participants performed an initial assessment and a follow‐up assessment 4 months later. Compared to the non‐depressed controls, individuals with StD demonstrated reduced contrast discrimination sensitivity, not only at the initial assessment but also at the follow‐up assessment, indicating a stable abnormality. Contrast discrimination thresholds at the initial assessment did not predict changes of depression symptom severity over time. For contrast detection sensitivity, there was no significant difference between the StD group and non‐depressed controls. We concluded that contrast discrimination testing might provide a trait‐dependent biomarker for depression.
... Dopamine is a neurotransmitter and its high concentration in the CNS has been linked to love and decision making, attention, increased mental activity, motivation and goal-directed behaviour [69,70]. However, a low level of dopamine or impaired dopamine function has been associated with depression in individuals [71]. Although in this study, there was no significant difference in the reduction of brain dopamine level with an increase in the concentration of atrazine exposure, the observed reduction might still suggest the potential of atrazine to induce depression in the exposed animal. ...
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No recognised study has been conducted to monitor atrazine residue in drinking water from rural agricultural areas in Nigeria and its potential health implications. In this ecotoxicological study, we monitored atrazine residue in 69 hand-dug wells (HDW), 40 boreholes (BH) and 4 major streams from all the 6 communities (Ago-Iwoye, Ijebu-Igbo, Oru, Awa, Ilaporu and Mamu) in Ijebu North Local Government Area, Southwest Nigeria. Values of atrazine obtained were further used to evaluate the non-carcinogenic risk associated with ingestion and dermal contact in adults and children as well as neurotoxicity assessment. A total of 41 HDW, 22 BH and the 4 streams were tested positive for atrazine, which was higher in HDW than BH and stream. Ago-Iwoye recorded the highest concentration of 0.08 mg/L in its HDW while the lowest concentration of 0.01 mg/L was recorded in HDW from Oru. Hazard Index values associated with ingestion and dermal for children and adults were below the acceptable limit. Atrazine at 0.01, 0.03 and 0.04 mg/L concentrations appears to trigger defence mechanisms capable of protecting the structural integrity of the brain, but significant (p < 0.05) alterations in the oxidative stress parameters, acetylcholinesterase activity, membrane-bound ATPase enzymes, neurotransmitters as well as mild degenerative changes were observed in the brain of rats exposed to atrazine at 0.08 mg/L. Atrazine at 0.01, 0.03 and 0.04 mg/L concentrations found in drinking water from Ijebu-North may not pose any threat to brain function, but concern should be raised at 0.08 mg/L.
... Other neurotransmitters mentioned are dopamine (DA), norepinephrine (NE), brain-derived neurotrophic factor (BDNF), and glutamate. (4) Some researchers suggest that depression is caused by a combination of genetic, biological, environmental, and psychological factors. Depression can happen at any age; however, it often begins in adulthood. ...
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Background: Depression, a state of low mood and aversion to activity, can affect people's thoughts, behavior, tendencies, feelings, and sense of well-being. It can either be short-term or long-term, depending on the severity of the person's condition. Risk factors include personal or family history of depression, major life changes, trauma, stress, certain physical illnesses, and medications. Objective: This study investigates the prevalence of depression among medical students at the University of Baghdad, college of medicine in Iraq, and the association between some variables and depression. Subjects and Methods: A cross-sectional study design with a convenience sampling method was conducted. A sample of 323 medical students attending the University of Baghdad, college of medicine, were included in this study between July 2019 and September 2019, regardless of their age or gender. The study included five grades according to the year 2019-2020. An online survey was conducted using Google Forms which included two sections. Section 1 included questions about participants' demographics. The second section included the PHQ-9 (Patient Health Questionnaire-9) score. Results: A total of 323 students of different demographics participated in this study. The number of males was 108 (33.4%), and the number of females was 215 (66.6%). The frequency of participants who got mild depression was the highest, i.e., 127 (39.3%), whereas 85 (26.3%) were non-depressed. Therefore, this study sample had a high prevalence of depression. On the other hand, the frequency of mild-moderate depression was 57.9%. Conclusion: The prevalence of depression among medical students at the University of Baghdad was high. Gender, having friends, having a medical condition or disease, having family issues, whether it's easy to communicate with others, encountering an event that affected them, and having a family member who suffers from a psychological condition are associated with depression among students. In contrast, age, marital status, college year, seeking help in the past, and having a part-time job have no association with depression
... Dopamine is a neurotransmitter and its high concentration in the CNS has been linked to love and decision making, attention, increased mental activity, motivation and goal-directed behaviour [69,70]. However, a low level of dopamine or impaired dopamine function has been associated with depression in individuals [71]. Although in this study, there was no significant difference in the reduction of brain dopamine level with an increase in the concentration of atrazine exposure, the observed reduction might still suggest the potential of atrazine to induce depression in the exposed animal. ...
Article
No recognised study has been conducted to monitor atrazine residue in drinking water from rural agricultural areas in Nigeria and its potential health implications. In this ecotoxicological study, we monitored atrazine residue in 69 hand-dug wells (HDW), 40 boreholes (BH) and 4 major streams from all the 6 communities (Ago-Iwoye, Ijebu-Igbo, Oru, Awa, Ilaporu and Mamu) in Ijebu North Local Government Area, Southwest Nigeria. Values of atrazine obtained were further used to evaluate the non-carcinogenic risk associated with ingestion and dermal contact in adults and children as well as neurotoxicity assessment. A total of 41 HDW, 22 BH and the 4 streams were tested positive for atrazine, which was higher in HDW than BH and stream. Ago-Iwoye recorded the highest concentration of 0.08 mg/L in its HDW while the lowest concentration of 0.01 mg/L was recorded in HDW from Oru. Hazard Index values associated with ingestion and dermal for children and adults were below the acceptable limit. Atrazine at 0.01, 0.03 and 0.04 mg/L concentrations appears to trigger defence mechanisms capable of protecting the structural integrity of the brain, but significant (p < 0.05) alterations in the oxidative stress parameters, acetylcholinesterase activity, membrane-bound ATPase enzymes, neurotransmitters as well as mild degenerative changes were observed in the brain of rats exposed to atrazine at 0.08 mg/L. Atrazine at 0.01, 0.03 and 0.04 mg/L concentrations found in drinking water from Ijebu-North may not pose any threat to brain function, but concern should be raised at 0.08 mg/L.
... The dopamine system plays an important role in the pathogenesis of depression, and efficacy of dopamine receptor ligands in the treatment of human depression have been reported [29]. Dopamine receptors are grouped into two families: D1-like receptors (D1-and D5-receptors) and D2-like receptors (D2-, D3-, and D4-receptors). ...
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Antidepressants target a variety of proteins in the central nervous system (CNS), the most important belonging to the family of G-protein coupled receptors and the family of neurotransmitter transporters. The increasing number of crystallographic structures of these proteins have significantly contributed to the knowledge of their mechanism of action, as well as to the design of new drugs. Several computational approaches such as molecular docking, molecular dynamics, and virtual screening are useful for elucidating the mechanism of drug action and are important for drug design. This review is a survey of molecular targets for antidepressants in the CNS and computer based strategies to discover novel compounds with antidepressant activity.
... However, the physiological mechanisms of a relationship between stress and self-care behavior are not fully understood. It is believed that a possible mechanism to explain this relationship is the neural reward circuits, since the self-cleansing behavior induces endocrine and neural responses even under stress-free conditions (Dunlop and Nemeroff 2007;Shiota et al. 2016). Accordingly, a study by Van Erp et al. (1994) demonstrated that self-cleaning time is correlated with plasma levels of the adrenocorticotropic hormone (responsible for stimulating the release of cortisol), suggesting that this behavior is linked to the neuroendocrine response to stress. ...
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Rationale Depression is often associated with memory impairment, a clinical feature of Alzheimer’s disease (AD), but no effective treatment is available. 7-Chloro-4-(phenylselanyl) quinoline (4-PSQ) has been studied in experimental models of diseases that affect the central nervous system. Objectives The pharmacological activity of 4-PSQ in depressive-like behavior associated with memory impairment induced by acute restraint stress (ARS) in male Swiss mice was evaluated. Methods ARS is an unavoidable stress model that was applied for a period of 240 min. Ten minutes after ARS, animals were intragastrically treated with canola oil (10 ml/kg) or 4-PSQ (10 mg/kg) or positive controls (paroxetine or donepezil) (10 mg/kg). Then, after 30 min, mice were submitted to behavioral tests. Corticosterone levels were evaluated in plasma and oxidative stress parameters; monoamine oxidase (MAO)-A and MAO -B isoform activity; mRNA expression levels of kappa nuclear factor B (NF-κB); interleukin (IL)-1β, IL-18, and IL-33; phosphatidylinositol-se-kinase (PI3K); protein kinase B (AKT2), as well as acetylcholinesterase activity were evaluated in the prefrontal cortex and hippocampus. Results 4-PSQ attenuated the depressive-like behavior, self-care, and memory impairment caused by ARS. Based on the evidence, we believe that effects of 4-PSQ may be associated, at least in part, with the attenuation of HPA axis activation, attenuation of alterations in the monoaminergic system, modulation of oxidative stress, reestablishment of AChE activity, modulation of the PI3K/AKT2 pathway, and reduction of neuroinflammation. Conclusions These results suggested that 4-PSQ exhibited an antidepressant-like effect and attenuated the memory impairment induced by ARS, and it is a promising molecule to treat these comorbidities.
... Major depressive disorder (item 9 in Table 3) is negatively associated with P/P. The former is related to low dopamine levels 18 , while excess dopamine transmission is theorized to be a mechanism in P/P 2 . ...
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Background: There are presently very few genetic studies for PANS (Pediatric Acute-Onset Neuropsychiatric Syndrome) or PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections). More work in genetic associations for PANS and PANDAS (P/P) is needed to increase understanding of these debilitating childhood disorders that have a range of presentations. Objective: This work represents a novel approach that aims to determine genetic associations between P/P and other diseases, disorders and traits (hereafter referred to as phenotypes). Methods: Consumer genetic data (23andMe, AncestryDNA) for 155 patients with P/P were obtained from consenting parents over a period from 2018 to 2020. An analysis plan for this work was registered at Open Science Framework, additional genotypes imputed using Impute.me, and polygenic risk scores for 1,702 phenotypes calculated for each of the 155 P/P patients. Results: One-sample t-tests performed across the 155 individual risk scores revealed that P/P is statistically significantly associated with 21 different groups of Single Nucleotide Polymorphisms (SNPs) that are in turn associated with 21 phenotypes. Some of the 21 phenotypes (see Table 3) are previously known to be related to or associated with P/P: a group of SNPs associated with Tourette’s Syndrome, and another group associated with Autism Spectrum Disorder or Schizophrenia, and a third associated with “feeling nervous” yielded t-tests with p values of 1.2x10-5, 1.2x10-11 and 1.0x10-5 respectively for association with the P/P data. This validated our analysis methodology. Our analysis also revealed novel genetic associations such as between P/P and plasma anti-thyroglobulin levels (p=1.3x10-7), between P/P and triglycerides (p=5.6x10-6), and between P/P and Lewy body disease (p=7.8x10-6), inviting further investigation into the underlying etiology of P/P. Conclusion: P/P is associated with many phenotypes not previously recognized as being connected to P/P. Further work on these connections can lead to better understanding of P/P.
... Several studies report that 74 a decreased dopaminergic activity, e.g., by dopaminergic antagonists, can slow down the 75 internal clock leading to an underestimation of timing intervals, and increasing levels of 76 dopamine, e.g., by dopaminergic agonists, speeds up the internal clock [9,72,79]. 77 Furthermore, studies involving patients suffering from psychiatric disorders involving 78 dopaminergic disbalance, such as schizophrenia [45,62] and depression [8,19], 79 demonstrate altered performance in time discrimination tasks compared to healthy 80 subjects [71]. A meta-analysis published by Thoenes and Oberfeld in 2015 shows a 81 significantly reduced speed of the perceived flow of time in depressive subjects 82 compared to non-depressive subjects [79]. ...
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Coordinated movements, speech and other actions are impossible without precise timing. Realistic computational models of interval timing in the mammalian brain are expected to provide key insights into the underlying mechanisms of timing. Existing computational models of time perception have only been partially replicating experimental observations, such as the linear increase of time, the dopaminergic modulation of this increase, and the scalar property, i.e., the linear increase of the standard deviation of temporal estimates. In this work, we incorporate the state-dependent computational model, which encodes time in the dynamic evolution of network states without the need for a specific network structure into a biologically plausible prefrontal cortex (PFC) model based on in vivo and in vitro recordings of rodents. Specifically, we stimulated 1000 neurons in the beginning and in the end of a range of different time intervals, extracted states of neurons and trained the readout layer based on these states using least squares to predict the respective inter stimulus interval. We show that the naturally occurring heterogeneity in cellular and synaptic parameters in the PFC is sufficient to encode time over several hundreds of milliseconds. The readout faithfully represents the duration between two stimuli applied to the superficial layers of the network, thus fulfilling the requirement of a linear encoding of time. A simulated activation of the D2 dopamine receptor leads to an overestimation and an inactivation to an underestimation of time, in line with experimental results. Furthermore, we show that the scalar property holds true for intervals of several hundred milliseconds, and provide a mechanistic explanation for the origin of the scalar property as well as its deviations. We conclude that this model can represent durations up to 750 ms in a biophysically plausible setting, compatible with experimental findings in this regime.
... e depletion of monoamine neurotransmitters is the pathophysiological basis of depression [87]. Decreased dopaminergic transmission may contribute to blunted reward processing and repaired reward learning, which are features of depression [88][89][90]. e antidepressant effects of dopamine agonists may depend on the ventrostriatal dopamine and reward function [91]. mTOR signaling, as a downstream intracellular signal, is associated with antidepressant effects [92,93]. ...
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Objective: We aimed to investigate the mechanisms underlying the effects of the Cyperi Rhizoma-Chuanxiong Rhizoma herb pair (CCHP) against depression using a network pharmacology approach. Methods: A network pharmacology approach, including screening of active compounds, target prediction, construction of a protein-protein interaction (PPI) network, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, and molecular docking, molecular dynamics (MD) simulations, and molecular mechanics Poisson-Boltzmann surface area (MMPBSA), were used to explore the mechanisms of CCHP against depression. Results: Twenty-six active compounds and 315 and 207 targets of CCHP and depression, respectively, were identified. The PPI network suggested that AKT1, IL-6, TP53, DRD2, MAPK1, NR3C1, TNF, etc., were core targets. GO enrichment analyses showed that positive regulation of transcription from RNA polymerase II promoter, plasma membrane, and protein binding were of great significance. Neuroactive ligand-receptor interaction, PI3K-Akt signaling pathway, dopaminergic synapse, and mTOR signaling pathway were important pathways. Molecular docking results revealed good binding affinities for the core compounds and core targets. MD simulations and MMPBSA validated that quercetin can stably bind to 6hhi. Conclusions: The effects of CCHP against depression involve multiple components, targets, and pathways, and these findings will promote further research on and clinical application of CCHP.
... Zhou et al. reported that transplantation of fecal microbiota, from normal mice to antibiotic-pretreated PD mice increased dopamine levels in the recipient PD mice, suggesting that gut microbiota contributed to the neuroprotection for PD [21]. There are evidences that dopamine plays an important role in anxiety and depression [22,23]. Based on this, we speculate that FMT treatment could contributed to the neuroprotection and alleviate the anxiety-and depression-like behaviors of patients by regulating the dopamine levels. ...
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Background Anxiety and depression are complications in Irritable bowel syndrome (IBS) patients. In this study, we recruited 18 IBS patients with mild-modest anxiety and depression behaviors, and after the screening, we defined the FMT treatment group (n = 9) and the control group (n = 9). The IBS symptom severity scale (IBS-SSS), Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Rating Scale (HAM-D), Irritable Bowel Syndrome Quality of Life (IBS-QOL) and Bristol stool scale (BSS) were evaluated one week before FMT (baseline), one-week-, one-month-, two-month-, and three-month-following FMT. Meanwhile, we determined the SCFAs in the patient’s feces and serum and continued the metagenomic analysis of the microorganisms in the patient’s feces. Results The results showed that the patient’s anxiety and depression behavior gradually improved with FMT treatment. Moreover, the illness and quality of life had also been relieved significantly. The content of isovaleric acid and valeric acid was significantly reduced in the FMT group compared to the Col group. Metagenomic analysis showed that FMT treatment decreased the abundance of Faecalibacterium, Eubacterium and Escherichia . From KEGG functional analysis, we confirmed that the top five abundant pathways were “bacterial chemotaxis, “flagellar assembly”, “glycine, serine and threonine metabolism”, “apoptosis”, and “bacterial invasion of epithelial cells”. Conclusions FMT treatment can effectively alleviate the anxiety and depression behaviors of IBS-D patients and reduce the IBS-SSS score, indicating that FMT can improve patients’ symptoms. The high throughput sequencing results show that Bifidobacterium and Escherichia play the most critical role in the formation and recovery of IBS-D patients. The GC/MS data indicated that faeces isovaleric acid and valeric acid might be more suitable as a metabolic indicator of IBS-D remission. Trial registration ChiCTR, ChiCTR1900024924, Registered 3 August 2019, https://www.chictr.org.cn/showproj.aspx?proj=41676 .
... Meanwhile, it is important to note that differential, or even opposite, modulations of the dopaminergic mesolimbic and mesocortical pathways have been already reported, including in the context of depression [99,100]. Actually, confirming the differential impact of saffron on DA neurotransmission according to the pathway should be particularly interesting considering their preferential involvement in different depressive symptoms, the mesolimbic pathway being for example particularly critical to those related to reward processing and motivation [12,100,101]. Interestingly, we also reported that DRD1 protein levels measured in the STR and FCx, two brain areas where this receptor is highly expressed [98], are lower in stressed mice receiving saffron than in their untreated counterparts. ...
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Depressive disorders are a major public health concern. Despite currently available treatment options, their prevalence steadily increases, and a high rate of therapeutic failure is often reported, together with important antidepressant-related side effects. This highlights the need to improve existing therapeutic strategies, including by using nutritional interventions. In that context, saffron recently received particular attention for its beneficial effects on mood, although the underlying mechanisms are poorly understood. This study investigated in mice the impact of a saffron extract (Safr’Inside™; 6.25 mg/kg, per os) on acute restraint stress (ARS)-induced depressive-like behavior and related neurobiological alterations, by focusing on hypothalamic–pituitary–adrenal axis, inflammation-related metabolic pathways, and monoaminergic systems, all known to be altered by stress and involved in depressive disorder pathophysiology. When given before stress onset, Safr’Inside administration attenuated ARS-induced depressive-like behavior in the forced swim test. Importantly, it concomitantly reversed several stress-induced monoamine dysregulations and modulated the expression of key enzymes of the kynurenine pathway, likely reducing kynurenine-related neurotoxicity. These results show that saffron pretreatment prevents the development of stress-induced depressive symptoms and improves our understanding about the underlying mechanisms, which is a central issue to validate the therapeutic relevance of nutritional interventions with saffron in depressed patients.
... The thalamic reticular nucleus (TRN) is largely composed of GABAergic neurons that express parvalbumin, and the reduction of these neurons in the TRN of psychiatric patients has been suggested to induce attentional, cognitive, and emotional deficits [81]. Moreover, CEWAS highlighted a CNS gene set related to dopaminergic neuron morphology for schizophrenia, which aligns with the dopamine hypothesis [82], and genes found by CEWAS for depression are highly expressed in the ventral tegmental area, which is one of the main dopaminergic areas in the brain with projections to amygdala and hippocampus for emotion and reward processing as discussed, and reduced dopamine has been linked to depressed symptoms [83]. ...
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The majority of genetic variants detected in genome wide association studies (GWAS) exert their effects on phenotypes through gene regulation. Motivated by this observation, we propose a multi-omic integration method that models the cascading effects of genetic variants from epigenome to transcriptome and eventually to the phenome in identifying target genes influenced by risk alleles. This cascading epigenomic analysis for GWAS, which we refer to as CEWAS, comprises two types of models: one for linking cis genetic effects to epigenomic variation and another for linking cis epigenomic variation to gene expression. Applying these models in cascade to GWAS summary statistics generates gene level statistics that reflect genetically-driven epigenomic effects. We show on sixteen brain-related GWAS that CEWAS provides higher gene detection rate than related methods, and finds disease relevant genes and gene sets that point toward less explored biological processes. CEWAS thus presents a novel means for exploring the regulatory landscape of GWAS variants in uncovering disease mechanisms.
... Mood and anxiety disorders such as major depressive disorder and generalized anxiety disorder are highly comorbid with HIV (Beer et al., 2019;Camara et al., 2020;Nanni et al., 2015;Remien et al., 2019;Wang et al., 2018). As dysregulation of biogenic amine signaling has been implicated in the etiology of these disorders (Dunlop and Nemeroff, 2007;Lin et al., 2014;Mann, 2013;Mann and Currier, 2007), defining changes in biogenic amine levels may suggest mechanisms by which HIV infection could drive comorbid neuropsychiatric conditions. As deprenyl is a monoamine oxidase inhibitor, it should prevent monoamine oxidase from metabolizing dopamine into its metabolite 3,4-Dihydroxyphenylaceticacid (DOPAC). ...
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In the era of antiretroviral therapy, inflammation is currently a central factor in a growing number of HIV-associated comorbidities, such as cardiovascular disease, cognitive impairment, and neuropsychiatric disorders. This highlights the value of developing therapeutics that both reduce HIV-associated inflammation and treat associated co-morbidities. Previous research on monoamine oxidase inhibitors (MAOIs) suggests that this class of drugs has anti-inflammatory properties in addition to neuropsychiatric effects. Therefore, we examined the impact of the deprenyl, an MAOI, on SIV-associated inflammation during acute SIV infection using the rhesus macaque model of HIV infection. Our results show that deprenyl decreased both peripheral and CNS inflammation but had no effect on viral load in either the periphery or CNS. These data show that the MAOI deprenyl has broad anti-inflammatory effects when given during the acute stage of SIV infection, suggesting that repurposing this drug could provide a beneficial adjuvant for antiretroviral therapy.
... In addition to our findings showing overall associations between the transdiagnostic effect and sensory-fugal microstructural gradients, we observed associations to the spatial distribution of different neurotransmitter systems derived from in vivo neuroimaging. Notably, associations were seen both to serotonin (5-HT1a and 5-HT1b) and dopamine receptors and transporters (DAT/D1 and D2), two important markers of mental health and targets for pharmacological treatments [100][101][102][103][104][105][106][107][108]. In both cases (i.e. ...
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A bstract It is increasingly recognized that multiple psychiatric conditions are underpinned by shared neural pathways, affecting similar brain systems. Here, we assessed i) shared dimensions of alterations in cortical morphology across six major psychiatric conditions (autism spectrum disorder, attention deficit/hyperactivity disorder, major depression, obsessive-compulsive disorder, bipolar disorder, schizophrenia) and ii) carried out a multiscale neural contextualization, by cross-referencing shared anomalies against cortical myeloarchitecture and cytoarchitecture, as well as connectome and neurotransmitter organization. Pooling disease-related effects on MRI-based cortical thickness measures across six ENIGMA working groups, including a total of 28,546 participants (12,876 patients and 15,670 controls), we computed a shared disease dimension on cortical morphology using principal component analysis that described a sensory-fugal pattern with paralimbic regions showing the most consistent abnormalities across conditions. The shared disease dimension was closely related to cortical gradients of microstructure and intrinsic connectivity, as well as neurotransmitter systems, specifically serotonin and dopamine. Our findings embed the shared effects of major psychiatric conditions on brain structure in multiple scales of brain organization and may provide novel insights into neural mechanisms into transdiagnostic vulnerability.
... Considering the dopamine-dependent regulation of the receptive field sizes in the retina (48) and the assumption of a disturbed dopamine homeostasis in MDD (49,50), check size specific PERG alterations in MDD patients seem convincing. Particularly, dopamine is known for its modulatory role in the light adaptation of the retina, favoring daylight vision with high acuity, a mechanism provided by the decoupling of horizontal cells in the retina, thereby shrinking the antagonistic surround structures of the receptive fields (48). ...
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Background: The retina has gained increasing attention in non-ophthalmological research in recent years. The pattern electroretinogram (PERG), a method to evaluate retinal ganglion cell function, has been used to identify objective correlates of the essentially subjective state of depression. A reduction in the PERG contrast gain was demonstrated in patients with depression compared to healthy controls with normalization after remission. PERG responses are not only modulated by stimulus contrast, but also by check size and stimulation frequency. Therefore, the rationale was to evaluate potentially more feasible procedures for PERG recordings in daily diagnostics in psychiatry. Methods: Twenty-four participants (12 patients with major depression (MDD) and 12 age- and sex-matched healthy controls) were examined in this pilot study. We investigated PERG amplitudes for two steady-state pattern reversal frequencies (12.5/18.75 rps) and four sizes of a checkerboard stimulus (0.8°, 1.6°, 3.2°, and 16°) to optimize the PERG recordings in MDD patients. Results: Smaller PERG amplitudes in MDD patients were observed for all parameters, whereby the extent of the reduction appeared to be stimulus-specific. The most pronounced decline in the PERG of MDD patients was observed at the higher stimulation frequency and the finest pattern, whilst responses for the largest check size were less affected. Following the PERG ratio protocol for early glaucoma, where similar stimulus dependent modulations have been reported, we calculated PERG ratios (0.8°/16°) for all participants. At the higher frequency (18.75 rps), significantly reduced ratios were observed in MDD patients. Conclusion: The “normalization” of the PERG responses—via building a ratio—appears to be a very promising approach with regard to the development of an objective biomarker of the depressive state, facilitating inter-individual assessments of PERG recordings in patients with psychiatric disorders.
... One of the most frequent and clinically signifi cant neuropsychiatric disorders in PD is depres sion, which occurs on average in 35% of patients [8,10]. The DA ergic system and, specifically, D2 receptors, are believed to play an important role not only in the fundamental mechanisms of manifestation of the depression symptoms, but also in the formation of the temporal structure of depressive states [11,12]. Among the characteris tic depression symptoms in PD, anhedonia (loss of ability to experience and strive for pleasure) occurs in an average of 45.7% of PD cases and can correlate with other signs of depression (apathy, increased anxiety, decreased performance) [8]. ...
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Abstract—Parkinson’s disease (PD) is a neurodegenerative disorder mainly diagnosed in elderly patients, which is now considered incurable. To date, there are no effective neuroprotectors suitable to treat PD patients. We have previously demonstrated that U133 therapy, which induces the synthesis of Hsp70 and Hsp40 heat shock proteins in the brain, prevents the development of neurodegeneration in the nigrostriatal system and eliminates sleep disorders in an animal model of PD. In the present study, we assessed the antidepressant properties of preventive U133 therapy, as well as its neuroprotective effect on monoaminergic emotiogenic brain structures in a preclinical model of PD in aged (20�month�old) Wistar rats, created by intranasal administration of the proteasome inhibitor lactacystin. It was found that intraperitoneal U133 administration in aged animals led to a delayed (after 3–7 days) elevation of the Hsp70 (HSPA1) level in the midbrain ventral tegmental area and locus coeruleus. Preventive U133 therapy eliminated the manifestations of depression�like behavior in the form of anhedonia, which develops during the preclinical stage of PD in aged rats. It was established that the antidepressant�like effect of the chaperone inducer U133 is due to the ability of the Hsp70 chaperone to attenuate neurodegeneration and neuroinflammation in the dopaminergic mesolimbic reward system and locus coeruleus noradrenergic system. The data obtained may serve as a fundamental basis for the development of a novel chaperone inducer�based molecular technology for preventive therapy of polyetiological PD and concomitant anhedonia. DOI: 10.1134/S0022093021050148
... In this review, although most studies excluded individuals with psychiatric diseases (e.g., major depression symptoms, post-traumatic stress disorder) and people who had a history of childhood abuse, other studies included these individuals [52,61,63,66,85]. Because individuals with depression and post-traumatic stress disorder usually have diminished dopamine function [87,88], and those with childhood abuse usually have elevated dopamine function [89], the inclusion of people with these comorbidities may bias the results. ...
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Objective Binge eating, a core diagnostic symptom in binge eating disorder and bulimia nervosa, increases the risk of multiple physiological and psychiatric disorders. The neurotransmitter dopamine is involved in food craving, decision making, executive functioning, and impulsivity personality trait; all of which contribute to the development and maintenance of binge eating. The objective of this paper is to review the associations of dopamine levels/activities, dopamine regulator (e.g., dopamine transporter, degrading enzymes) levels/activities, and dopamine receptor availability/affinity with binge eating. Methods A literature search was conducted in PubMed and PsycINFO to obtain human and animal studies published since 2010. Results A total of 31 studies (25 human, six animal) were included. Among the human studies, there were 12 case–control studies, eight randomized controlled trials, and five cross-sectional studies. Studies used neuroimaging (e.g., positron emission tomography), genetic, and pharmacological (e.g., dopamine transporter inhibitor) techniques to describe or compare dopamine levels/activities, dopamine transporter levels/activities, dopamine degrading enzyme (e.g., catechol-O-methyltransferase) levels/activities, and dopamine receptor (e.g., D1, D2) availability/affinity among participants with and without binge eating. Most human and animal studies supported an altered dopaminergic state in binge eating (26/31, 83.9%); however, results were divergent regarding whether the altered state was hyperdopaminergic (9/26, 34.6%) or hypodopaminergic (17/26, 65.4%). The mixed findings may be partially explained by the variability in sample characteristics, study design, diagnosis criteria, and neuroimaging/genetic/pharmacological techniques used. However, it is possible that instead of being mutually exclusive, the hyperdopaminergic and hypodopaminergic state may co-exist, but in different stages of binge eating or in different individual genotypes. Conclusions For future studies to clarify the inconsistent findings, a homogenous sample that controls for confounders that may influence dopamine levels (e.g., psychiatric diseases) is preferable. Longitudinal studies are needed to evaluate whether the hyper- and hypo-dopaminergic states co-exist in different stages of binge eating or co-exist in individual phenotypes. Plain Language Summary Binge eating is characterized by eating a large amount of food in a short time and a feeling of difficulty to stop while eating. Binge eating is the defining symptom of binge eating disorder and bulimia nervosa, both of which are associated with serious health consequences. Studies have identified several psychological risk factors of binge eating, including a strong desire for food, impaired cognitive skills, and distinct personality traits (e.g., quick action without careful thinking). However, the physiological markers of binge eating remain unclear. Dopamine is a neurotransmitter that is heavily involved in feeding behavior, human motivation, cognitive ability, and personality. Therefore, dopamine is believed to play a critical role in binge eating. This review synthesized study findings related to the levels and activities of dopamine, dopamine regulators, and dopamine receptors in the context of binge eating. The primary finding is that most studies that used neuroimaging, genetic, or drug techniques found an altered dopaminergic state related to binge eating. However, the literature is inconsistent concerning the direction of the alteration. Considering the mixed findings and the limitations in study design, future studies, especially those that include repeated measurements, are needed to clarify the role of dopamine in binge eating.
... Marijuana use frequency has been associated with anhedonia and anxious arousal symptoms 20 , but studies exploring the association with co-use and among adolescents are lacking. THC (tetrahydrocannabinol) and nicotine both trigger dopamine release, low levels of which are related to anhedonia 21,22 . Dopamine has also been associated with anxiety as it is released into the brain regions associated with anxiety 23 , including the amygdala 24 . ...
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Introduction: Young people with depression and/or anxiety may self-medicate with tobacco or tobacco with marijuana to reduce their symptoms. This study sought to differentiate between the use of tobacco products as intended and tobacco products modified to accommodate marijuana, and to explore their relationships with symptoms of depression and anxiety among youth and young adults. Methods: The study is a secondary analysis of Wave 9 (Spring 2019) data from the Texas Adolescent Tobacco and Marketing Surveillance (TATAMS) (n=2439, N=274030). Anxiety and major depressive symptoms were measured by GAD-7 and PHQ-9, respectively. Results: The odds of reporting current use of e-cigarettes without marijuana (adjusted prevalence odds ratio, APOR=2.34; 95% CI: 1.30-4.21, p=0.005) and current use of combustible tobacco without marijuana (APOR=2.99; 95% CI: 1.26-7.09, p=0.014) were significantly higher among those who reported depression/anxiety comorbidity compared to those who reported no symptoms of major depressive symptoms (MDS), anxiety or comorbidity. The odds of reporting ever use of e-cigarettes with marijuana (APOR=3.68; 95% CI: 1.69- 8.00, p=0.001), current use of e-cigarettes with marijuana (APOR=2.76; 95% CI: 1.28-5.97, p=0.01) and ever use of combustible tobacco with marijuana (APOR=3.99; 95% CI: 1.66-9.58, p=0.002) were significantly higher among those reporting only MDS compared to those who reported no symptoms of MDS, anxiety or comorbidity. Conclusions: The study findings can have implications for intervention planning, as interventions need to address marijuana and nicotine use in tobacco products and address anxiety and depression.
... 9,10 Anhedonia is generally resistant to common first-line antidepressant options (such as SSRIs and serotonin-norepinephrine reuptake inhibitors), owing to their inadequate effect on dopamine transmission. 30 Anhedonia can therefore persist in individuals with MDD who have experienced improvement in other symptoms and may continue to affect quality of life. 31,32 Multiple pharmacological treatment approaches for anhedonia have been investigated over the years; certain monoaminergic antidepressants, glutamatergic agents, psychedelics, and stimulants have all shown some degree of efficacy in improving anhedonia, although these results are preliminary. ...
Article
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Aim: Anhedonia in major depressive disorder may be resistant to first-line antidepressants. We examined the effect of vortioxetine, a multimodal antidepressant, on anhedonia-like symptoms in Japanese patients with major depressive disorder. Methods: This was a post hoc analysis of an 8-week, randomized, double-blind, placebo-controlled, phase 3 study of vortioxetine (10 mg or 20 mg) in Japanese patients aged 20-75 years with recurrent major depressive disorder and a Montgomery-Åsberg Depression Rating Scale (MADRS) total score of at least 26. The primary outcome was the mean change from baseline to week 8 in anhedonia-like symptoms as measured by MADRS anhedonia factor score, composed of: Q1, apparent sadness; Q2, reported sadness; Q6, concentration; Q7, lassitude; and Q8, inability to feel. Mean change in MADRS total score and anhedonia factor score were compared among treatment groups, with data categorized by median baseline anhedonia factor score (0-17 or ≥18). Results: Data were available for 489 patients. The least-squares mean difference in MADRS anhedonia factor score change from baseline to week 8 versus placebo was -1.34 for vortioxetine 10 mg (P = 0.0300) and -1.77 for vortioxetine 20 mg (P = 0.0044). The least-squares mean difference between vortioxetine and placebo in MADRS total score change from baseline to week 8 was -3.11 (10 mg dose) and -3.37 (20 mg dose) for patients with a higher baseline anhedonia factor score (≥18), and -2.08 (10 mg) and -2.61 (20 mg) for patients with a lower baseline score (0-17). Conclusion: This post hoc analysis suggests that vortioxetine may have therapeutic potential in patients with anhedonia-like symptoms of major depressive disorder. ClinicalTrials.gov identifier for primary study: NCT02389816.
... According to the dopamine theory, postulated by Randrup et al. (1975) [157], depression could be the result of a decreased dopaminergic function. In support of this view, both decreased dopamine cerebrospinal cord fluid levels [157][158][159] and DA turnover were found in patients suffering from depression [157,160], and many common antidepressant drugs such as dopamine agonists and dopamine reuptake inhibitors showed antidepressant activity [157,[161][162][163]. ...
Article
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Among mental diseases, major depressive disorder (MDD) and anxiety deserve a special place due to their high prevalence and their negative impact both on society and patients suffering from these disorders. Consequently, the development of novel strategies designed to treat them quickly and efficiently, without or at least having limited side effects, is considered a highly important goal. Growing evidence indicates that emerging properties are developed on recognition, trafficking, and signaling of G-protein coupled receptors (GPCRs) upon their heteromerization with other types of GPCRs, receptor tyrosine kinases, and ionotropic receptors such as N-methyl-D-aspartate (NMDA) receptors. Therefore, to develop new treatments for MDD and anxiety, it will be important to identify the most vulnerable heteroreceptor complexes involved in MDD and anxiety. This review focuses on how GPCRs, especially serotonin, dopamine, galanin, and opioid heteroreceptor complexes, modulate synaptic and volume transmission in the limbic networks of the brain. We attempt to provide information showing how these emerging concepts can contribute to finding new ways to treat both MDD and anxiety disorders.
... HVA is the final excretion product of dopamine and reflects dopamine levels in the brain. 61 GABA GABA is the major inhibitory neurotransmitter in the CNS suggested to play a vital role in the control of stress and depression. GABA deficiency has repeatedly been observed in patients with depression. ...
Article
Importance: Depression has been associated with alterations in neurotransmitters, hormones, and inflammatory and neurodegenerative biomarkers, and biomarkers quantified in the cerebrospinal fluid (CSF) are more likely to reflect ongoing biochemical changes within the brain. However, a comprehensive overview of CSF biomarkers is lacking and could contribute to the pathophysiological understanding of depression. Objective: To investigate differences in quantified CSF biomarkers in patients with unipolar depression compared with healthy control individuals. Data sources: PubMed, EMBASE, PsycINFO, Cochrane Library, Web of Science, and ClinicalTrials.gov were searched for eligible trials from database inception to August 25, 2021. Study selection: All studies investigating CSF biomarkers in individuals 18 years and older with unipolar depression and healthy control individuals were included. One author screened titles and abstracts, and 2 independent reviewers examined full-text reports. Studies that did not include healthy control individuals or included control individuals with recent hospital contacts or admissions that might affect CSF biomarker concentrations were excluded. Data extraction and synthesis: Data extraction and quality assessment were performed by 2 reviewers following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines. Meta-analyses were performed using standardized mean differences (SMDs) calculated with random-effects models. A third investigator was consulted if the 2 reviewers reached different decisions or when in doubt. Main outcomes and measures: Quantifiable CSF biomarkers. Results: A total of 167 studies met eligibility criteria, and 97 had available data and were included in the meta-analysis. These 97 studies comprised 165 biomarkers, 42 of which were quantified in 2 or more studies. CSF levels of interleukin 6 (7 studies; SMD, 0.35; 95% CI, 0.12 to 0.59; I2 = 16%), total protein (5 studies; SMD, 0.53; 95% CI, 0.35 to 0.72; I2 = 0%), and cortisol (2 studies; SMD, 1.23; 95% CI, 0.89 to 1.57; I2 = 0%) were higher in patients with unipolar depression compared with healthy control individuals, whereas homovanillic acid (17 studies; SMD, -0.26; 95% CI, -0.39 to -0.14; I2 = 11%), γ-aminobutyric acid (4 studies; SMD, -0.50; 95% CI, -0.92 to -0.08; I2 = 55%), somatostatin (5 studies; SMD, -1.49; 95% CI, -2.53 to -0.45; I2 = 91%), brain-derived neurotrophic factor (3 studies; SMD, -0.58; 95% CI, -0.97 to -0.19; I2 = 0%), amyloid-β 40 (3 studies; SMD, -0.80; 95% CI, -1.14 to -0.46; I2 = 0%), and transthyretin (2 studies; SMD, -0.82; 95% CI, -1.37 to -0.27; I2 = 0%) were lower. The remaining 33 biomarkers had nonsignificant results. Conclusions and relevance: The findings of this systematic review and meta-analysis point toward a dysregulated dopaminergic system, a compromised inhibitory system, hypothalamic-pituitary-adrenal axis hyperactivity, increased neuroinflammation and blood-brain barrier permeability, and impaired neuroplasticity as important factors in depression pathophysiology.
... Nevertheless, the decreases in response and remission rates after the second ADM might be related to a selection process of patients that are non-responsive to all types of mono-aminergic ADM. 23 This could explain the slight advantage of between-class over within-class switches after a first ADM, 17 24 25 but it remains to be shown empirically whether this selection effect is indeed applicable to increasing levels of TRD. Hypothetically, treatments targeting different pathways might provide better efficacy in these cases. ...
Article
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Introduction For major depression, a one-size-fits-all treatment does not exist. Patients enter a ‘trial-and-change’ algorithm in which effective therapies are subsequently applied. Unfortunately, an empirically based order of treatments has not yet been determined. There is a magnitude of different treatment strategies while clinical trials only compare a small number of these. Network meta-analyses (NMA) might offer a solution, but so far have been limited in scope and did not account for possible differences in population characteristics that arise with increasing levels of treatment-resistance, potentially violating the transitivity assumption. We; therefore, present a protocol for a systematic review and NMA aiming at summarising and ranking treatments for treatment-resistant depression (TRD) while covering a broad range of therapeutic options and accounting for possible differences in population characteristics at increasing levels of treatment-resistance. Methods and analysis Randomised controlled trials will be included that compared next-step pharmacological, neuromodulation or psychological treatments for treatment-resistant depression (TRD; ie, failure to respond to ≥1 adequate antidepressant drug trial(s) in the current episode) to each other or to a control condition. Primary outcomes will be the proportion of patients who responded to (efficacy) and dropped out of (acceptability) the allocated treatment. A random effects NMA will be conducted, synthesising the evidence for each outcome and determining the differential efficacy of treatments. Heterogeneity in treatment nodes will be reduced by considering alternative geometries of the network structure and by conducting a meta-regression examining different levels of TRD. Local and global methods will be applied to evaluate consistency. The Cochrane Risk of Bias 2 tool, Confidence in Network Meta-Analysis and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework will be used to assess risk of bias and certainty. Ethics and dissemination This review does not require ethical approval.
... ). Moreover, several lines of evidence suggest deficits in dopamine and other monoamines might underlie symptom domains central to depression(anhedonia, motivation, concentration, etc.) (Belujon & Grace, 2017;Dunlop & Nemeroff, 2007;Hamon & Blier, 2013). Thus, by normalizing DA and/or NE levels in key brain regions, psychostimulants might enable plasticity in mood or cognition-related circuits that are therapeutically modulated by rTMS. ...
Article
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Background Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for major depressive disorder (MDD). Psychostimulant medication use may be associated with improved rTMS outcomes, but a detailed understanding of these relationships is lacking. Methods We compared MDD subjects taking psychostimulants (n = 37) with those not taking one of these medications (n = 53) during a course of 30 rTMS treatments. Changes in the 30‐item Inventory of Depressive Symptomatology Self Report (IDS‐SR30) subscale scores were examined at treatment 30. We also subdivided subjects into three categories based on drug mechanism and looked at IDS‐SR30 total score after treatments 10, 20, and 30. Results Subjects taking psychostimulants had a significantly greater overall clinical improvement than those not taking these medications at treatment 30. The psychostimulant group also improved significantly more than the control group in “sleep” and “mood/cognition,” but not “anxiety/arousal” IDS‐SR30 subscales. No differences were detected among individual drug categories, which may reflect the limited sample size for individual medications. There was a negative dose–response relationship for the lisdexamfetamine/dextroamphetamine group, in which lower doses were associated with better clinical outcome. Conclusions Psychostimulant medications may enhance clinical efficacy of rTMS for MDD by preferentially impacting specific symptom domains. For some psychostimulants, these effects may be dose‐dependent. Prospective clinical trials are needed to guide psychostimulant augmentation of brain stimulation therapies.
... Au niveau du cortex préfrontal, où l'expression du DAT est très faible, la recapture est réalisée par des neurones noradrénergiques et par le transporteur NET (Dunlop and Nemeroff, 2007 (Talwar et al., 2002). (Tsai et al., 2009;Ilango et al., 2014). ...
Thesis
Le Binge Drinking (BD) est un mode de consommation d'alcool caractérisé par l'alternance récurrente entre des épisodes d'intoxication intense et d'abstinence, pouvant entraîner des conséquences cérébrales et cognitives. Il est nécessaire d'identifier les facteurs impliqués dans la vulnérabilité au développement de ce comportement, qui est un facteur de risque de l'addiction à l'alcool. La prise de décision (PdD), capacité d'adaptation fondamentale perturbée dans de nombreux troubles psychiatriques, et le sexe, jouent un rôle dans la vulnérabilité au BD. La transmission dopaminergique (DA) dans le noyau accumbens (Nacc) est impliquée à la fois dans le processus de PdD et dans les effets renforçants de l'alcool. Dans ce contexte, nos objectifs ont été de mieux comprendre les conséquences du BD sur la PdD, et les adaptations de la transmission DAergique dans le NAcc qui sont potentiellement impliquées. Nous avons évalué les capacités de PdD dans la Rat Gambling Task chez des rats mâles et femelles exposés à deux paradigmes mimant le binge : une procédure d'administration passive (injections intermittentes répétées) et une procédure d'administration volontaire (auto-administration opérante). Les modifications de la transmission DAergique dans le NAcc ont été étudiées avec la technique de voltamétrie cyclique rapide ex vivo, en condition de base et sous influence de l'alcool et/ou d'un agoniste sélectif des récepteurs D2/D3 (quinpirole). Nous montrons que le BD affecte à la fois le processus de PdD et la signalisation DAergique dans le NAcc. Ces effets pourraient jouer un rôle dans le cercle vicieux perpétuant la consommation nocive d'alcool et conduisant au développement précoce de l'addiction. Il sera maintenant intéressant de poursuivre ces études en analysant de manière plus approfondie les mécanismes impliqués dans les différences liées au sexe, ainsi que les effets sous influence de l'alcool
... Dopamine (DA) is the most abundant monoamine neurotransmitter in the CNS and regulates motivation, emotions, reward circuits, cognition, and reinforcement behaviors (5,6). It has been widely reported that dopaminergic neurotransmitter is deficient in depressive individuals (7,8). Mesocorticolimbic DA circuitry, originating from the ventral tegmental area (VTA) neurons, is a key part of the brain's reward circuitry and plays an important role in mediating stress response. ...
Article
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Objective: Early life adversity is a risk factor for depression in adulthood; however, the underlying mechanisms are not well understood. This study aims to investigate the effect of DNA methylation of DRD2 gene on early life stress-induced depression in adult rats. Methods: Newborn Sprague-Dawley rats were randomly assigned to four groups: maternal deprivation group (MD), chronic unpredictable stress (CUS) group, maternal deprivation plus chronic unpredictable stress (MD/CUS) group, and normal control group (NOR). Behaviors were measured by open field test (OFT), sucrose preference test (SPT), and Original Research Article forced swimming test (FST). Fecal CORT level was detected by ELISA. Bisulfite amplicon sequencing PCR was used to assess methylation levels of DRD2 promoter. Results: CUS and MD/CUS rats had a significantly shorter total distance, longer immobility time, and higher CORT level, while MD and MD/CUS rats had a significantly lower percentage of central distance, more feces, lower rate of sucrose preference, and lower levels of DRD2 protein and mRNA in the VTA than NOR rats. CUS rats showed a significantly higher DRD2 mRNA and protein levels in the VTA than NOR rats. CUS, MD, and MD/CUS rats showed a significantly higher level of DRD2 promoter methylation than NOR rats. CORT level was significantly correlated with the sucrose preference rate in SPT, the immobility time in FST, the total distance, and the number of fecal pellets in OFT. DRD2 protein level was significantly correlated with the sucrose preference rate and the number of fecal pellets. DRD2 mRNA level was significantly correlated with the percentage of central distance and the number of fecal pellets in OFT. The level of DRD2 promoter methylation was significantly correlated with the sucrose preference rate, immobility time, total distance, the percentage of central distance, and the number of fecal pellets. Conclusions: Early life MD increased vulnerability to stress-induced depressive-like behavior in adult rats. Enhanced DRD2 promoter methylation in the VTA may increase the susceptibility to depression.
... Moreover, in line with these results, it has been described that the stimulation of mPFC 5-HT 1A receptors increases phasic inputs onto dopaminergic neurons of the VTA [26] that project back to the mPFC [27]. Hence, increases in mPFC dopamine release may be involved in the improvement of mood, rewarding stimuli and cognitive dysfunction seen in depression [28][29][30][31]. As a matter of fact, optogenetic activation of VTA dopamine neurons reversed the anhedonic effects of a chronic stress model for depression [32]. ...
Article
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Depression is the most prevalent of the mental illnesses and serotonin (5-hydroxytryptamine, 5-HT) is considered to be the major neurotransmitter involved in its etiology and treatment. In this context, 5-HT1A receptors have attracted interest as targets for therapeutic intervention. Notably the activation of presynaptic 5-HT1A autoreceptors delays antidepressant effects whereas the stimulation of postsynaptic 5-HT1A heteroreceptors is needed for an antidepressant action. NLX-101 (also known as F15599) is a selective biased agonist which exhibits preferred activation of cortical over brain stem 5-HT1A receptors. Here, we used behavioral, neurochemical and molecular methods to examine the antidepressant-like effects in rats of a single dose of NLX-101 (0.16 mg/kg, i.p.). NLX-101 reduced immobility in the forced swim test when measured 30 min but not 24 h after drug administration. NLX-101 increased extracellular concentrations of glutamate and dopamine in the medial prefrontal cortex, but no changes were detected in the efflux of noradrenaline or 5-HT. NLX-101 also produced an increase in the activation of pmTOR, pERK1/2 and pAkt, and the expression of PSD95 and GluA1, which may contribute to its rapid antidepressant action.
... The DISC1 protein's role in neuronal development includes proliferation and migration of the neuronal progenitor cells and synapse formation and maintenance 18 , and it acts as a molecular hub that interacts with dopaminergic neurotransmission components OPEN such as Dopamine (DA) D2 receptors and transporter [19][20][21] . In this regard, the association between DISC1 and the function of DA, one of the leading candidate neurotransmitters in the pathology of different psychiatric disorders, has been profoundly investigated [22][23][24][25] . The findings suggest that DISC1 has a role in the dysregulation of DA functions, such as the increase in the proportion of striatal D 2 high receptors 26 , an increase of DAT levels in the striatum 27 , and a decrease of extracellular DA levels in the nucleus accumbens 28,29 . ...
Article
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Deficits in social interaction or social cognition are key phenotypes in a variety of chronic mental diseases, yet, their modeling and molecular dissection are only in their infancy. The Disrupted-in-Schizophrenia 1 (DISC1) signaling pathway is considered to play a role in different psychiatric disorders such as schizophrenia, depression, and biopolar disorders. DISC1 is involved in regulating the dopaminergic neurotransmission in, among others, the mesolimbic reward system. A transgenic rat line tgDISC1 has been introduced as a model system to study behavioral phenotypes associated with abnormal DISC1 signaling pathways. Here, we evaluated the impact of impaired DISC1 signaling on social (social interaction) and non-social (sucrose) reward preferences in the tgDISC1 animal model. In a plus-maze setting, rats chose between the opportunity for social interaction with an unfamiliar juvenile conspecific (social reward) or drinking sweet solutions with variable sucrose concentrations (non-social reward). tgDISC1 rats differed from wild-type rats in their social, but not in their non-social reward preferences. Specifically, DISC1 rats showed a lower interest in interaction with the juvenile conspecific, but did not differ from wild-type rats in their preference for higher sucrose concentrations. These results suggest that disruptions of the DISC1 signaling pathway that is associated with altered dopamine transmission in the brain result in selective deficits in social motivation reminiscent of phenotypes seen in neuropsychiatric illness.
... Dopamine is a neurotransmitter and its high concentration in the CNS has been linked to love and decision making, attention, increased mental activity, motivation and goal-directed behaviour [69,70]. However, a low level of dopamine or impaired dopamine function has been associated with depression in individuals [71]. Although in this study, there was no significant difference in the reduction of brain dopamine level with an increase in the concentration of atrazine exposure, the observed reduction might still suggest the potential of atrazine to induce depression in the exposed animal. ...
Article
Introduction Diabetes is one of the main pandemics in recent years. Its association with depression increases the risk of mortality and morbidity. The coexistence of both diseases leads to poor management of diabetes, which leads to a worse quality of life. Objective To determine the frequency of depression in patients with diabetes mellitus and the effect of both pathologies on the quality of life in patients who attend outpatient appointments at public health facilities in Lima and Callao. Methodology Secondary analysis of the Epidemiological Study of Mental Health of depression in diabetic adults. The instrument used to determine the depressive episode was the MINI (Mini-International Neuropsychiatric Interview) while quality of life was measured using the Mezzich Quality of Life Index. Diagnosis information of type 1 or 2 diabetes was obtained from the daily medical record (HIS) of care. Results The frequency of depression in the 471 patients with diabetes was 5.8% in the last two weeks. While the annual frequency was 8.6% and 31.8% at some point in life. Being a woman was associated with a greater frequency of depression. Quality of life was lower in patients with diabetes and depression (p < 0.005). Conclusions The frequency of depression in patients with diabetes who are treated on an outpatient basis in public health centres is higher than the general population and their quality of life is significantly reduced, which raises the need for considering depression as an additional factor to the burden of morbidity of this condition.
Article
This randomized controlled trial examined the effects of mindfulness on anhedonic symptoms in a sample of adults reporting high levels of chronic stress. Meditation-naïve adults (N = 68, Mage = 32, 62% female) were randomized to either an 8-week group-based MBSR intervention (N = 35), or a waitlist control group (N = 33). We hypothesized that changes in mindfulness would mediate the relationship between condition and changes in anhedonic symptoms. Additionally, the present study aimed to determine if other theoretically linked mechanisms (i.e., stress, negative affect [NA], depression) were involved in producing changes in anhedonic symptoms. Results provided evidence for full mediation of the effect of MBSR on social anhedonia through its essential mechanism of ΔMindfulness. These results highlight specificity of anhedonic symptoms targeted by MBSR, with social anhedonia symptoms being modified by changes in mindfulness whereas other anhedonic domains were not. The specificity of effects to the social anhedonia domain may be in part due to the group-based nature of MBSR. Additionally, although associative relationships were present for stress, depression, NA, and anhedonic symptoms, no mediational relationships emerged. Results presented here should be evaluated in light of study limitations, such as the reliance on self-report measures as well as a lack of information regarding cultural or geographic diversity.
Article
Women are nearly twice as likely to develop mood disorders compared with men, and incidence is greatest during reproductive transitions, including pregnancy and postpartum. Because these periods are characterized by dramatic hormonal and physiologic changes, there is heightened susceptibility to external factors, such as exposure to environmental toxicants, which may play a role in maternal psychopathology. The purpose of this scoping review was to provide an overview of studies conducted in humans and animal models on the effects of nonoccupational exposure to environmental chemicals on maternal psychopathology during the perinatal period. The largest number of studies examined exposure to environmental tobacco smoke and antenatal depression and showed consistently positive findings, although more prospective studies using biomarkers for exposure assessment are needed. The few studies examining persistent organic pollutants such as polybrominated diphenyl ethers and perinatal depression were consistent in showing associations with increased depressive symptoms. Results were mixed for exposure to heavy metals and non-persistent chemicals, but a strong literature in animal models supported an association between bisphenols and phthalates and reduced maternal behavior and care of pups after parturition. Biological mechanisms may include endocrine disruption, neurotransmitter system impairment, alterations in gene expression, and immune activation and inflammation. Additional longitudinal studies that include biospecimen collection are essential to furthering the understanding of how environmental toxicants during pregnancy may affect perinatal psychopathology and the underlying mechanisms of action. Future work should also leverage the parallels between animal and human maternal behavior, thereby highlighting the opportunity for multidisciplinary work in this avenue.
Article
Background Depression is pleiotropic and influenced by diverse genetic, environmental, and pharmacological factors. Identifying patterns of circuit activity on which many of these factors converge would be important, because studying these patterns could reveal underlying pathophysiological processes and/or novel therapies. Depression is commonly assumed to involve changes within prefrontal circuits, and dopamine D2 receptor (D2R) agonists are increasingly used as adjunctive antidepressants. Nevertheless, how D2Rs influence disease-relevant patterns of prefrontal circuit activity remains unknown. Methods We used brain slice calcium imaging to measure how patterns of prefrontal activity are modulated by D2Rs, antidepressants, and manipulations that increase depression susceptibility. To validate the idea that prefrontal D2Rs might contribute to antidepressant responses, we used optogenetic and genetic manipulations to test how dopamine, D2Rs, and D2R+ neurons contribute to stress-coping behavior. Results Patterns of positively correlated activity in prefrontal microcircuits are specifically enhanced by D2R stimulation as well as by two mechanistically distinct antidepressants: ketamine and fluoxetine. Conversely, this D2R-driven effect was disrupted in two etiologically distinct depression models: a genetic susceptibility model and mice that are susceptible to chronic social defeat. Phasic stimulation of dopaminergic afferents to prefrontal cortex and closed-loop stimulation of D2R+ neurons both increased effortful responses to tail suspension stress, whereas prefrontal D2R deletion reduced the duration of individual struggling episodes. Conclusions Correlated prefrontal microcircuit activity represents a point of convergence for multiple depression-related manipulations. Prefrontal D2Rs enhance this activity. Through this mechanism, prefrontal D2Rs may promote network states associated with antidepressant actions and effortful responses to stress.
Article
Objective Most men suffering from depression have different degrees of erectile dysfunction (ED), but the relationship between depression and ED is not clear. This study explored the effect of depression on erectile function in rats and the underlying mechanism. Methods The potential targets and key signaling pathways of depression and ED were predicted through bioinformatics analysis, and a depression rat model was established by inducing chronic restraint stress. Pathological changes in rat penis tissue were studied by hematoxylin and eosin staining. The serum dopamine level was quantified by an enzyme-linked immunosorbent assay. The expression of related proteins and mRNA was detected by western blotting and real-time quantitative reverse transcription-polymerase chain reaction. Results Hematoxylin and eosin staining showed pathological damage in the penile tissue of the model group rats. The serum dopamine level, dopamine receptor D2 (DRD2) and solute carrier family 6 member 3 (SLC6A3) protein levels in penile tissue, and DRD2 and SLC6A3 mRNA levels were lower in the model group than in the control group. Conclusion The decrease in erectile function in the depression rat model was related to dysfunction of the dopamine system and dopaminergic synapse signaling pathway.
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Anhedonia – the reduced ability to experience or respond to pleasure – is an important symptom domain for many psychiatric disorders. It is particularly relevant to depression and other mood disorders and it is a diagnostic criterion of a major depressive episode. Developing safe and effective pharmacological interventions for anhedonia is a critical public health need. The current chapter will review the state of the field with respect to both the efficacy of currently available pharmacotherapies for anhedonia and the recent clinical research focusing on new brain targets, including the kappa-opioid receptor and the KCNQ2/3 receptors. The evidence for anti-anhedonic effects of ketamine and psychedelic agents will be reviewed, as well.
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RESUMEN Antecedentes: La salud mental puede deteriorarse en varias situaciones y ser la consecuencia de eventos que marcaron a la persona a lo largo de su vida o simplemente la vivencia de situaciones específicas lo cual conlleva a un desequilibrio en la homeostasis del ser humano; haciendo referencia al tema de este estudio, un conflicto armado es una situación que se lleva a cabo debido a causas territoriales, políticas, administra-tivas, religiosas, ideológicas o de narcotráfico, que puede ser entre un mismo pueblo o diferentes pueblos y que abarca un problema externo o interno (Bembire,2013). A lo largo de la historia se han documentado innumerables conflictos en la población mundial teniendo como denominador común consecuencias y secuelas tanto políticas, económicas, ideológicas sociales y biológicas como psíquicas en las personas que han vivido estas situaciones directa o indirectamente. Objetivo: Identificar y analizar cuáles son las prácticas, conocimientos y actitudes con relación a la salud-enfermedad en las personas que vivieron y fueron víctimas de un conflicto armado y así mismo clarificar las consecuencias y percepciones de lo experimentado. Materiales y métodos: Se llevó a cabo una investigación cualitativa-descriptiva analítica en la cual se seleccionó a 15 informantes civiles adultos, de ambos sexos respetando criterios de diversidad y pluralidad que viven en los cantones afectados por el conflicto armado suscitado en el año 2018 en la frontera con Colombia de la provincia de Esmeraldas en el primer trimestre del año 2019, y con diagnóstico de patolo-gía psiquiátrica o en tratamiento de los diferentes servicios del Hospital General Esmeraldas Sur "Delfina Torres de Concha" de la provincia de Esmeraldas y a través de la aplicación del test de Hamilton y poste-riormente la aplicación de una entrevista abierta semi estructurada, así también se realizó una ficha para bosquejar el perfil sociodemográfico de los individuos. Esta investigación tuvo la aprobación del Comité de Bioética de la PUCE y con el consentimiento informado de los participantes. Resultados: Se encontró que el 87% (n: 13) de los sujetos estudiados fueron ecuatorianos mientras que Recibido el 25 de junio de 2021. Aceptado el 20 de septiembre de 2021.
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Electroconvulsive therapy (ECT) is a treatment modality for patients with treatment resistant depression (TRD), defined as failure of two adequate antidepressant medication trials. We provide a qualitative review of ECT's effectiveness for TRD, methods to optimize ECT parameters to improve remission rates and side effect profiles, and ECT's proposed neurobiological mechanisms. Right unilateral (RUL) electrode placement has been shown to be as effective for major depression as bilateral ECT, and RUL is associated with fewer cognitive side effects. There is mixed evidence on how to utilize ECT to sustain remission (i.e., continuation ECT, psychotropic medications alone, or a combination of ECT and psychotropic medications). Related to neurobiological mechanisms, an increase in gray matter volume in the hippocampus-amygdala complex is reported post-ECT. High connectivity between the subgenual anterior cingulate and the middle temporal gyrus before ECT is associated with better treatment response. Rodent models have implicated changes in neurotransmitters including glutamate, GABA, serotonin, and dopamine in ECT's efficacy; however, findings in humans are limited. Altogether, while ECT remains a highly effective therapy, the neurobiological underpinnings associated with improvement of depression remain uncertain.
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Recent research has provided novel insights into the major depressive disorder (MDD) and identified certain biomarkers of this disease. There are four main mechanisms playing a key role in the related pathophysiology, namely (1) monoamine systems dysfunction, (2) stress response, (3) neuroinflammation, and (4) neurotrophic factors alteration. Robust evidence on the decreased homovanillic acid in the cerebrospinal fluid (CSF) of patients with MDD supports a rationale for therapeutic stimulation of the medial forebrain bundle activating the dopamine reward system. Both activation and suppression of the hypothalamic-pituitary-adrenal (HPA) axis in MDD and related conditions indicate usefulness of its evaluation for the disease subtyping. Elevated proinflammatory cytokines (specifically, interleukin-6) in CSF imply the role of neuroinflammation resulting in activation of the tryptophan-kynurenine pathway. Finally, neuroplasticity and trophic effects of the brain-derived neurotrophic factor (BDNF) may be related to both structural abnormalities of the brain in MDD and the underlying mechanisms of various therapies. In addition, the gut-brain interaction is pivotal, since lack of beneficial microbes confer the risk of MDD through negative effects on the dopamine system, HPA axis, and vagal nerve. All these factors may be highly relevant to treatment of MDD with contemporary brain stimulation therapies.
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Background: Catechol-O-methyltransferase (COMT) regulates cortical dopaminergic transmission and prefrontal-dependent cognitive function. However, its role in other cognitive processes, including emotional processing, is relatively unexplored. We therefore investigated the separate and interactive influences of COMT inhibition and Val158Met (rs4680) genotype on performance on an emotional test battery. Methods: We recruited 74 healthy men homozygous for the functional COMT Val158Met polymorphism. Volunteers were administered either a single 200 mg dose of the brain-penetrant COMT inhibitor tolcapone or placebo in a double-blind, randomised manner. Emotional processing was assessed using the emotional test battery, and mood was rated using visual analogue scales and the Profile of Mood States (POMS) questionnaire across the test day. Results: There were no main or interactive effects of Val158Met genotype or tolcapone on any of the emotional processing measures or mood ratings. Conclusions: Our findings suggest that, at least in healthy adult men, COMT has little or no effect on emotional processing or mood. These findings contrast with several neuroimaging studies that suggest that COMT modulates neural activity during emotional processing. Thus, further studies are required to understand how COMT impacts on the relationship between behavioural output and neural activity during emotional processing. Nevertheless, our data suggest that novel COMT inhibitors under development for treating cognitive dysfunction are unlikely to have acute off target effects on emotional behaviours.
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Central post-stroke pain (CPSP) and associated depression remain poorly understood and pharmacological treatments are unsatisfactory. Recently, microglia activation was suggested to be involved in CPSP pathophysiology. The goal of this study was to investigate the effectiveness of a co-ultramicronized combination of N-palmitoylethanolamide and luteolin (PEALut) in a mouse model of thalamic hemorrhage (TH)-induced CPSP. TH was established through the collagenase-IV injection in thalamic ventral-posterolateral-nucleus. PEALut effects in CPSP-associated behaviors were evaluated during a 28-days observation period. We found that repeated administrations of co-ultra PEALut significantly reduced mechanical hypersensitivity after TH, as compared to vehicle, by reducing the early microglial activation in the perilesional site. Moreover, PEALut prevented the development of depressive-like behavior (21 days post-TH). These effects were associated with the restoration of synaptic plasticity in LEC-DG pathway and monoamines levels found impaired in TH mice. Hippocampal MED1 and TrkB expressions were significantly increased in TH compared to sham mice 21 days post-TH, whereas BDNF levels were decreased. PEALut restored MED1/TrkB/BDNF expression in mice. Remarkably, we found significant overexpression of MED1 in the human autoptic brain specimens after stroke, indicating a translational potential of our findings. These results pave the way for better-investigating depression in TH- induced CPSP, together with the involvement of MED1/TrkB/BDNF pathway, proposing PEALut as an adjuvant treatment.
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In the era of antiretroviral therapy, inflammation is a central factor in a numerous HIV-associated comorbidities, such as cardiovascular disease, cognitive impairment, and neuropsychiatric disorders. This highlights the value of developing therapeutics that both reduce HIV-associated inflammation and treat associated co-morbidities. Previous research on monoamine oxidase inhibitors (MAOIs) suggests this class of drugs has anti-inflammatory properties in addition to neuropsychiatric effects. Therefore, we examined the impact of deprenyl, an MAOI, on SIV-associated inflammation during acute SIV infection using the rhesus macaque model of HIV infection. Our results show deprenyl decreased both peripheral and CNS inflammation but had no effect on viral load in either the periphery or CNS. These data show that the MAOI deprenyl may have broad anti-inflammatory effects when given during the acute stage of SIV infection, suggesting more research into the anti-inflammatory effects of this drug could result in a beneficial adjuvant for antiretroviral therapy.
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Suplemento especial de Cuadernos Médico Sociales, dedicado a Antropología de la Salud
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Patients with Parkinson's Disease (PD) often present symptoms of anxiety, depression and apathy. These negative affect manifestations have been recently associated with the presence of Impulsive Compulsive Behaviours (ICBs). However, their relation with the use of dopamine replacement therapy (DRT), a renewed risk factor for ICBs, is still not fully understood. Elucidating the role of these different ICBs predictors in PD could inform both prevention/intervention recommendations as well as theoretical models. In the present study, we have analyzed data collected in 417 PD patients: 50 patients with Parkinsonian symptoms but with scan without evidence of dopaminergic deficit (SWEDD), and 185 healthy controls (HC). We examined each patient's clinical profile over a two-year time window, investigating the role of the negative affect on both DRT on ICBs. Results confirmed the presence of higher levels of anxiety in both the clinical groups, and of higher level of ICBs in SWEDD patients, respect to both PD and HC. Mixed model analyses revealed results supporting a statistically significant association between anxiety and ICBs in the SWEDD patients, who did not take any DRT. Findings suggest the independence between the role of anxiety and DRT in ICBs development and provide new evidence for the motivational opponency theoretical framework.
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NPRL2 is a requisite subunit of the epilepsy-linked GATOR1 complex that functions as a negative regulator of mTORC1 kinase when intracellular amino acids are limited. Here we report the generation and characterization of a new neurological model of GATOR1-dependent mTORopathy, caused by the loss of NPRL2 function in glutamatergic neurons. Loss of NPRL2 increases mTORC1 signal transduction, significantly alters amino acid homeostasis in the brain, and causes SUDEP. In addition, loss of NPRL2 increases the strength of electrically stimulated action potentials and the expression of epilepsy-linked sodium channels. These data reveal an unanticipated link between intracellular amino acid signaling by NPRL2 and a novel mTORC1-dependent regulation of sodium-channel expression in epilepsy
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Background The reward system regulates motivated behavior, and repeated practice of specific motivated behavior might conversely modify the reward system. However, the detailed mechanisms by which they reciprocally regulate each other are not clearly understood. Methods Mice subjected to chronic restraint stress show long-lasting depressive behavior, which is rescued by continual engagement with playable objects. A series of molecular, pharmacological, genetic, and behavioral analyses, combined with microarray, liquid chromatography, and chemogenetic tools are used to investigate the neural mechanisms of anti-depressive effects of playable objects. Results Here we show that repeated restraint induces dopamine surges into the nucleus accumbens-lateral shell (NAc-lSh), which cause upregulation of the neuropeptide PACAP in the NAc-lSh. As repeated stress is continued, the dopamine surge by stressors is adaptively suppressed without restoring the PACAP upregulation, and the resulting enhanced PACAP inputs from NAc-lSh neurons to the ventral pallidum (VP) facilitate depressive-like behaviors. Continual engagement with playable objects in mice subjected to chronic stress remediates the reduced dopamine response to new stressors, enhanced PACAP upregulation, and depressive-like behaviors. Overactivation of D1 dopamine receptors over the action of D2 receptors in the NAc-lSh promotes depressive-like behaviors. Conversely, inhibition of D1 receptors or PACAP upregulation in the NAc-lSh confers resilience to chronic stress-induced depressive-like behaviors. Histochemical and chemogenetic analyses reveal that engagement with playable objects produces anti-depressive effects by reshaping the ventral tegmental area-to-NAc-lSh and NAc-lSh-to-VP circuits. Conclusions These results suggest that behavioral engagement with playable objects remediates depressive-like behaviors by resolving stress-induced maladaptive changes in the reward system.
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The main features of MBE are reviewed and special emphasis is placed on the role of MBE growth mechanisms of both lattice-matched and lattice-mismatched epitaxial structures. It will be shown that the different mechanisms allow the growth either of two-dimensional advanced structures with interfaces smooth on an atomic scale and of zero-dimensional systems with carriers confined on a nanometric scale. A few examples of such structures will be given, and their physical properties will be briefly discussed
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Despite the well-documented loss of brain dopamine activity with age, little is known about its functional consequences in healthy individuals. This study investigates the relationship between measures of brain dopamine D(2) receptors (molecules that transmit dopamine signals) and regional brain glucose metabolism (a marker of brain function) in healthy individuals. Thirty-seven healthy volunteers aged 24-86 years underwent positron emission tomography scans after injection of [(11)C]raclopride to assess dopamine D(2) receptors and [(18)]fluorodeoxyglucose to assess regional brain glucose metabolism. Two methods used to assess the correlations between metabolism and dopamine D(2) receptors-pixel-by-pixel correlations and correlations in preselected regions of interest-were then compared. D(2) receptors as well as frontal and cingulate metabolism declined with age. Regardless of the method used, significant correlations between metabolism and D(2) receptors were found in the frontal cortex (Brodmann's areas 6, 7, 8, 9, 10, 11, 44, 45, 47), anterior cingulate gyrus (areas 24, 32), temporal cortex (area 21), and caudate. These correlations remained significant after removing age effects (partial correlation). These results provide the first link between age-related declines in brain dopamine activity and frontal and cingulate metabolism, which supports the need to investigate the therapeutic utility of interventions that enhance dopamine function in the elderly. The fact that correlations remained significant after removing age effects suggests that dopamine may influence frontal, cingulate, and temporal metabolism regardless of age.
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The dopamine transporter (DAT) critically regulates the duration of the cellular actions of dopamine and the extent to which dopamine diffuses in the extracellular space. We sought to determine whether the reportedly greater diffusion of dopamine in the rat prefrontal cortex (PFC) as compared with the striatum is associated with a more restricted axonal distribution of the cortical DAT protein. By light microscopy, avidin-biotin-peroxidase immunostaining for DAT was visualized in fibers that were densely distributed within the dorsolateral striatum and the superficial layers of the dorsal anterior cingulate cortex. In contrast, DAT-labeled axons were distributed only sparsely to the deep layers of the prelimbic cortex. By electron microscopy, DAT-immunoreactive profiles in the striatum and cingulate cortex included both varicose and intervaricose segments of axons. However, DAT-labeled processes in the prelimbic cortex were almost exclusively intervaricose axon segments. Immunolabeling for tyrosine hydroxylase in adjacent sections of the prelimbic cortex was localized to both varicosities and intervaricose segments of axons. These qualitative observations were supported by a quantitative assessment in which the diameter of immunoreactive profiles was used as a relative measure of whether varicose or intervaricose axon segments were labeled. These results suggest that considerable extracellular diffusion of dopamine in the prelimbic PFC may result, at least in part, from a paucity of DAT content in mesocortical dopamine axons, as well as a distribution of the DAT protein at a distance from synaptic release sites. The results further suggest that different populations of dopamine neurons selectively target the DAT to different subcellular locations.
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We measured the growth hormone (GH) response to clonidine (an alpha-2-adrenergic agonist) and to apomorphine (a dopaminergic agonist) in 15 major endogenous and 15 minor depressive in-patients matched for gender and age. Results showed a significantly smaller GH response in the major depressives to both clonidine (P less than 0.01) and apomorphine (P less than 0.001). No significant difference existed between the two groups with regard to changes in blood pressure and pulse rate during either test. While major depressives showed a trend toward smaller sedative side-effects than minor depressives after clonidine, they showed significantly smaller sedative and gastro-intestinal side-effects after apomorphine. No significant correlation was present either in the major depressive or in the minor depressive group between the GH responses following clonidine and apomorphine challenges. These results support the hypothesis of both noradrenergic and dopaminergic neurotransmitter disturbances in major depression, with individual variability with regard to those biochemical anomalies.
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The title of this review would be regarded by some psychiatrists as provocative; they would relegate the biochemical concomitants of depression and mania to a secondary position and deny that biochemical changes have any place in the aetiology of these conditions. However, in my view, the weight of evidence, although it is by no means conclusive, suggests that biochemical changes are most important in the aetiology of affective disorders. A biochemical aetiology implies that there are certain biochemical changes in the brain which need to be restored to normal before the patient's clinical condition will improve. This does not deny that psychological and environmental events may precipitate and maintain the biochemical events which in turn lead to the affective disorder. The study of these biochemical events is clearly at too early a stage for speculations about the interrelationship between environmental and endogenous elements to be fruitful; this study must wait until the biochemical aetiology is clearer than at present.
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Unexpected stimuli that are behaviourally significant have the capacity to elicit a short-latency, short-duration burst of firing in mesencephalic dopaminergic neurones. An influential interpretation of the experimental data that characterize this response proposes that dopaminergic neurones have a crucial role in reinforcement learning because they signal error in the prediction of future reward. In this article we propose a different functional role for this ‘short-latency dopamine response’ in the mechanisms that underlie associative learning. We suggest that the initial burst of dopaminergic-neurone firing could represent an essential component in the process of switching attentional and behavioural selections to unexpected, behaviourally important stimuli. This switching response could be a crucial prerequisite for associative learning and might be part of a general short-latency response that is mediated by catecholamines and prepares the organism for an appropriate reaction to biologically significant events. Any act which in a given situation produces satisfaction becomes associated with that situation so that when the situation recurs the act is more likely than before to recur also. E.L. Thorndike (1911) .
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It has been suggested that accumbens dopamine (DA) is involved in the process of enabling organisms to expend energy in various situations, including foraging, maze running, and leverpressing. Although accumbens DA depletions impair stimulant self-administration, the effects of these depletions on various food-reinforced operant schedules are highly variable. Accumbens DA depletions have little or no effect on total response output in rats responding on the simplest schedule of food reinforcement (i.e., the fixed ratio 1). In addition, it has been shown clearly that the effects of accumbens DA depletions do not resemble the effects of extinction or prefeeding to reduce food motivation. Over the last several years, our laboratory has investigated the effects of accumbens DA depletions on several schedules, including fixed ratio 1, variable interval 30 sec, fixed interval 30 sec, progressive ratio, and fixed ratio 4, 5, 16, and 64. These schedules generate very different rates of responding, ranging from 300 to 3,000 responses per 30 min. Regression analyses of all these studies indicates a significant linear relation between control rates of responding and the degree of suppression of responding produced by accumbens DA depletions. Schedules that generate relatively low response rates, such as fixed ratio 1 or variable interval 30 sec, are little affected by accumbens DA depletions, yet schedules that generate high response rates (e.g., fixed ratio 64) are severely disrupted. Prefeeding shows different patterns of suppression as a function of response rate. Microanalysis of the temporal characteristics of leverpressing has shown that accumbens DA depletions produce a response slowing, as measured by the interresponse time; extinction and prefeeding produce a different pattern of effects. These results indicate that accumbens DA depletions do not blunt the reinforcing effects of food, but do suppress responding in a rate-dependent manner. In addition, microdialysis studies have shown that accumbens DA release is positively correlated with leverpressing response rate. Accumbens DA appears to be involved in energy expenditure, behavioral activation, or maintenance of high local rates of responding, which are functions that represent an area of overlap between motor and motivational processes.
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• Piribedil, a compound that stimulates dopamine receptors in a relatively specific fashion, was administered to 11 hospitalized depressed patients. The dopamine agonist significantly decreased rapid eye movement (REM) sleep and percent REM sleep and increased REM latency. Piribedil decreased the probenecid-induced accumulation of the dopamine metabolite homovanillic acid (HVA) in CSF. A range of mild to moderate antidepressant effects was noted; one patient worsened and one developed recurrent manic episodes. The degree of improvement in depression was negatively correlated with pretreatment values of HVA in CSF (r = —.66, p <.05). These data suggest that the heterogeneity of clinical response may be related to biological differences in depressed patients and that those with low initial dopaminergic function respond best to increased dopamine receptor stimulation.
Article
Concentrations of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured in lumbar CSF from 33 patients with affective illnes and from 23 neurological controls. The group of patients with affective illness comprised 29 depressed and four manic patients. During illness, the concentration of HVA was higher in the depressed patients (P >0.001) than in the controls. Both unipolar and bipolar depressed patients had increased HVA levels (P >0.001 and P >0.05, respectively). The concentration of MHPG was greater than control values in the unipolar (P < 0.001) and bipolar (P < 0.002) subgroups but did not differ from control values in the depressed group as a whole. The concentration of 5-HIAA in the depressed patients as a whole and in the unipolar and bipolar subgroups did not differ from control concentrations. During illness the manic patients had increased levels of HVA (P >0.01) and normal levels of 5-HIAA and MHPG. Sixteen of the 29 depressed patients had a second lumbar puncture after they had recovered. Compared with the pre-recovery values, the concentration of HVA was reduced in the unipolar depressives (P < 0.01) and the concentration of 5-HIAA lowered in the depressed group as a whole (P >0.02). The present findings suggest involvement of catecholamines in affective disorders.
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In patients with Alzheimer-type dementia, in addition to the well-known losses of cholinergic neurones, there is evidence of degeneration of the noradrenergic and serotonergic innervation of the cerebral cortex. While noradrenergic and cholinergic receptors are preserved there is a loss of serotonin S1 and S2 receptors, particularly in the temporal lobe. The loss of serotonin S2 receptors may occur at an early stage of the disease and, in temporal and frontal cortex, is correlated with the loss of somatostatin immunoreactivity. In patients dying in hospital with depression, and in individuals committing suicide, there are no consistent changes in monoamine metabolites. Noradrenergic, serotonergic, and other neurotransmitter receptors were found to be unchanged, although there was a moderate decrease in imipramine binding in a small group (n = 6) of subjects with a history of depression, who had committed suicide.
Article
Objective: This study compared dopamine D(2) receptor binding potential in patients with social phobia and healthy comparison subjects. Method: Dopamine D(2) receptor binding potential was assessed in 10 unmedicated subjects with generalized social phobia and no significant lifetime psychiatric comorbidity and 10 healthy comparison subjects matched for age and sex. Binding potential was measured in the striatum by using single photon emission computerized tomography and constant infusion of the D(2) receptor radiotracer [(123)I]iodobenzamide ([(123)I]IBZM). Results: Mean D(2) receptor binding potential was significantly lower in the subjects with social phobia than in the comparison subjects. Within the social phobia group, there was a nonsignificant correlation of binding potential with the Liebowitz Social Anxiety Scale score. Conclusions: Generalized social phobia may be associated with low binding of [(123)I]IBZM to D(2) receptors in the striatum.
Article
Indirect observations suggest that dopamine function may be altered in depressed patients, notably in bipolar patients. The purpose of this study was to assess the dopamine receptor sensitivity at the hypothalamic-pituitary level in 19 drug-free DSM-IV major depressed patients: 10 bipolar depression (BP), 9 unipolar depression (UP), compared with 15 sex and age matched hospitalized controls (HC). We evaluated the multihormonal responses to the dopamine agonist apomorphine (APO, 0,75 mg SC) in order to obtain an indirect index of dopaminergic neurotransmission at the post synaptic level. We also examined, in the same subjects, prolactin (PRL) response to 8AM and 11PM protirelin challenges (TRH, 200μg IV) and cortisol response to dexamethasone suppression test (DST, 1 mg orally). No significant difference in cortisol, ACTH and GH values was found between controls, UP and BP patients (i.e. at baseline and in response to apomorphine test). However, BP had lower APO-induced PRL suppression than HC (P=0.0003) and UP (P=0.04). Taken together these results suggest that decreased APO-induced PRL suppression in bipolar depressed patients is not due to deficiency of pituitary lactrophs and/or increased HPA axis activity, but may reflect altered post synaptic receptor sensitivity D2 in the tuberoinfundibular dopamine system.
Article
Background: Prior research has suggested reductions in the density of serotonin transporter (SERT) binding sites in blood platelets and post-mortem brain tissue of depressed patients. We sought to determine whether patients with unipolar major depression have diminished SERT availability as assessed by both brainstem [123I] beta-CIT SPECT and platelet [3H]paroxetine binding. Methods: Drug-free depressed and healthy subjects were injected with 211 +/- 22 MBq [123I] beta-CIT and imaged 24 +/- 2 h later under equilibrium conditions. A ratio of specific to nonspecific brain uptake (V3" = (brainstem-occipital)/occipital), a measure proportional to the binding potential (Bmax/Kd), was used for all comparisons. Results: Results showed a statistically significant reduction in brainstem V3" values in depressed as compared to healthy subjects (3.1 +/- .9 vs. 3.8 +/- .8, p = .02). Platelet [3H]paroxetine binding was not altered (Bmax = 2389 +/- 484 vs. 2415 +/- 538 fmol/mg protein, p = .91) and was not significantly correlated with brainstem [123I] beta-CIT binding (r = -0.14, p = .48). Conclusions: These data are the first to suggest reductions in the density of brain SERT binding sites in living depressed patients. These findings provide further support for a preeminent role for alterations in serotonergic neurons in the pathophysiology of depression.
Article
Objectives: The evaluation of the possible role of dopamine in psychiatric disorders has been limited by the relative inadequacy of tools. A tempting approach to examine alterations of dopaminergic system in major depression is to examine the expression of dopamine receptors in peripheral blood mononuclear cells (PBMC). Methods: D4 dopamine receptor (D4DR) messenger RNA (mRNA) expression in PBMC from 12 patients with major depressive disorder was examined before and after an 8-week treatment with paroxetine at 20-50 mg/day. Ten healthy subjects were analyzed in parallel. The relative content of D4DR mRNA was determined by reverse transcriptase-polymerase chain reaction (RT-PCR). using beta-actin as internal standard. Results: D4DR mRNA levels were significantly decreased in untreated depressed patients as compared to controls. D4DR mRNA expression returned to control levels after paroxetine treatment, when patients achieved a significant improvement of depressive symptoms. Conclusions: Results of our study suggest the role of PBMC D4DR mRNA expression as a peripheral marker of the central dopaminergic function in major depression.
Article
Pramipexole, a dopamine D2 receptor agonist, was tested in 174 patients with major depression, with or without melancholia and without psychotic features. Three daily dose levels (0.375 mg, 1.0 mg, and 5.0 mg) were compared to fluoxetine (Prozac) at 20 mg and placebo in a randomized, double-blind, parallel-group study. After a 1 week placebo run-in period, patients were treated for 8 weeks, had a post-study follow-up (week 9), and were evaluated primarily with the Hamilton Psychiatric Rating Scale for Depression (HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Clinician's Global Impressions-Severity of Illness scale (CGI-SI). All patients who received one dose of study medication were included in the observed-case analysis (no missing data were replaced). Results indicated that by endpoint (week 8), patients receiving pramipexole at the 1.0 mg per day dose had significant improvement over baseline compared to the placebo group by measure of the HAM-D, MADRS, and CGI-SI. Significant improvement in this dose group was seen at other timepoints as well. The most obvious improvement was seen in the pramipexole 5.0 mg group, although a substantial dropout rate for this group precluded statistical tests vs. placebo late in the study. Patients taking fluoxetine also showed significant improvements at endpoint on the MADRS and earlier in the study on the HAM-D. No new or unusual safety concerns were generated during this study. Pramipexole helped safely alleviate the symptoms of depression at 1.0 mg per day and especially in those patients who could tolerate the escalation to 5 mg per day. Depression and Anxiety 11:58–65, 2000. © 2000 Wiley-Liss, Inc
Article
The present review focuses on the hypothesized D1/D2 dopamine (DA) receptor classification, originally based on the form of receptor coupling to adenylate cyclase activity. The pharmacological effects of compounds exhibiting putative selective agonist or antagonist profiles at those DA receptors positively coupled to adenylate cyclase activity (D1 DA receptors) are extensively reviewed. Comparisons are made with the effects of putative selective D2 DA receptor agonists and antagonists, and on the basis of this work, the DA receptor classification is critically evaluated. A variety of biochemical, behavioral, and electrophysiological evidence is presented which supports the view that D1 and D2 DA receptors can interact in both an opposing and synergistic fashion. Particular attention is focused on the possibility that D1 receptor stimulation is required to enable the expression of certain D2 receptor-mediated effects, and the functional consequences of this form of interaction are considered. A hypothetical model is presented which considers how both the opposing and enabling forms of interaction between D1 and D2 DA receptos can control behavioral expression. Finally, the clinical relevance of this work is discussed and the potential use of selective D1 receptor agonists and antagonists in the treatment of psychotic states and Parkinson's disease is considered.
Article
Objective: To assess the effectiveness and safety of pramipexole as an adjunctive medication in refractory bipolar and unipolar depression in a naturalistic setting. Methods: Retrospective chart review by psychiatrists on staff at a university hospital identified all patients who had received pramipexole. Response was based on moderate to marked improvement in the Clinical Global Impression-Improvement (CGI-I) scale. Results: Pramipexole (mean dose 0.70 mg/d, mean duration 24.4 weeks) was effective in 6/12 (50.0%) of patients with bipolar depression, and 8/20 (40%) of patients with unipolar depression, mean duration of follow-up of 24.4 weeks. One case of transient hypomania was noted. Eight patients discontinued pramipexole due to lack of response and four due to side effects. Conclusions: Pramipexole, used as an adjunct to antidepressants or mood stabilizers, appeared to be effective and safe in the treatment of unipolar and bipolar depression. These uncontrolled, retrospective, naturalistic pilot data require confirmation by controlled research before conclusions can be made.
Article
Chronic sequential exposure to a variety of mild unpredictable stressors has previously been found to depress the consumption of a dilute (1%) sucrose solution and to inhibit food-induced place preference conditioning. In the present study, using a simplified version of the mild stress procedure, the decreased sucrose intake was reversed by chronic (4 weeks) treatment with the atypical antidepressant mianserin. The racemic compound ()-mianserin (5 mg/kg per day) and one of its enantiomers, (+)-mianserin (2.5 mg/kg) were effective in this model; a lower dose of ()-mianserin (2.5 mg/kg), and the other enantiomer, (–)-mianserin (2.5 mg/kg), were ineffective. Vehicle-treated stressed animals were also subsensitive to food reward in the place conditioning procedure: normal place preference conditioning was reinstated by chronic treatment with ()-mianserin (5 mg/kg) or (+)-mianserin, but not by the lower dose of ()-mianserin (2.5 mg/kg) or by (–)-mianserin. Raclopride (100 g/kg) reinstated the decrease in sucrose intake in stressed animals successfully treated with ()- or (+)-mianserin. The results suggest that (+)-mianserin is the active enantiomer in reversing chronic mild stress-induced anhedonia, and further support the hypothesis of a dopaminergic mechanism of antidepressant action in this paradigm.
Article
The effect of the selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor, fluoxetine (10 mg/kg s.c.), two tricyclic antidepressants, clomipramine (10 mg/kg s.c.) and imipramine (10 mg/kg s.c.), and vehicle on extracellular dopamine levels was studied in rat nucleus accumbens and striatum by in vivo microdialysis. Fluoxetine produced significant decreases in extracellular dopamine levels in both the nucleus accumbens and striatum (mean maximum percentage decrease: 58% and 57% of pre-drug baseline, respectively). In contrast, imipramine and clomipramine significantly increased extracellular dopamine in the striatum (148% and 150%, respectively) compared to the effect of vehicle alone (118%). These results suggest that the selective serotonin reuptake inhibitor, fluoxetine, and the tricyclic antidepressants, clomipramine and imipramine, affect dopaminergic activity in diverse ways and in a region-specific manner. Thus, the antidepressant effect of these drugs is unlikely to be related to their acute effects on dopaminergic neurotransmission. The differential effects of the selective serotonin reuptake inhibitor and tricyclic antidepressants on extracellular dopamine could account for other differences in their clinical and side effect profiles. Further studies of the chronic effects of the selective serotonin reuptake inhibitor and the tricyclic antidepressants on dopaminergic activity are required to elucidate the role of dopamine in the antidepressant effect.
Article
We have investigated the effects of agents active in the presynaptic dopaminergic system on the characterization of the rat striatal dopamine transporter. The dopamine transporter was characterized by high-affinity [3H]GBR 12935 (1-[2-diphenylmethoxy)-ethyl]-4-(3-phenylpropyl)-piperazine) binding to a membrane preparation and by [3H]dopamine uptake into striatal synaptosomes. Subchronic treatment with reserpine (2.5 mg/kg, 4 days), a monoamine depletor, caused a significant decrease in both [3H]GBR 12935 binding (20%) and [3H]dopamine uptake (51%). In contrast, amantadine (a dopamine releaser) treatment (20 mg/kg, 21 days) induced an increase (28%) in the maximal number of [3H]GBR 12935 sites. Chronic levo-dopa (dopamine precursor) treatment combined with carbidopa (50 mg/kg and 5 mg/kg respectively, 21 days) as well as benztropine (dopamine uptake inhibitor) treatment (10 mg/kg, 21 days) did not affect the striatal dopamine transporter characteristics. The present results showed that the striatal dopamine transporter is sensitive to changes in dopaminergic neurotransmission caused by agents that do not interact directly with the dopamine carrier.
Article
We review the literature on the effectiveness of the monoamine oxidase inhibitors (MAOIs) and present metaanalyses of controlled trials comparing the FDA-approved MAOIs with both placebo and comparator tricyclic antidepressants. For outpatients, metaanalyses with intent-to-treat samples revealed generally comparable overall efficacy for phenelzine, isocarboxazid, and tranylcypromine. Drug—placebo differences were 29.5% (± 11.1%) (phenelzine; nine studies), 41.3% (± 18.0%) (isocarboxazid; three studies), and 22.1% (± 25.4%) (tranylcypromine; three studies). For inpatients, phenelzine was 22.3% (± 30.7%) (five studies) more effective than placebo, whereas the isocarboxazid—placebo difference was lower (15.3%) (± 12.6%). Both phenelzine and isocarboxazid were significantly less effective than comparator tricyclics for inpatients, whereas tranylcypromine has not been adequately studied. Both phenelzine and tranylcypromine appear to be more effective than tricyclics in depressed outpatients with atypical features. Monoamine oxidase inhibitors are also effective treatments for outpatients who have failed to respond to tricyclic antidepressants. Our review also suggests (1) the FDA-approved MAOIs treat a somewhat different group of patients than tricyclics; (2) more severely depressed inpatients may not respond as well to MAOIs as to tricyclics; and (3) because of preferential MAOI responsivity, atypical or anergic depressions may be biologically different than classical depressions.
Article
Chronic sequential administration of a variety of mild stressors causes a decrease in responsiveness to rewards in rats, which is reversed by chronic administration of antidepressant drugs. This paper reviews the validity of chronic mild stress-induced anhedonia as an animal model of depression, and the evidence that changes in hedonic responsiveness in this model are mediated by changes in the sensitivity of dopamine D2 receptors in the nucleus accumbens. The review opens with an analysis of the design features of animal models of depression, and ends with a brief account of other animal models of anhedonia.
Article
Fifteen depressed patients were treated with increasing doses of bromocriptine in an open study. Twelve were treated for 5 weeks (final dose 20-60 mg daily) and nine of these recovered almost completely. As expected from a dopamine agonist, bromocriptine decreased the level of homovanillic acid (HVA) in cerebrospinal fluid (CSF) by 15% (P less than 0.05) and 23% (P less than 0.01) after 2 and 5 weeks of treatment, respectively. After 2 but not after 5 weeks of treatment there was also a small but significant decrease (13%; P less than 0.001) of the noradrenaline metabolite HMPG in CSF. Although there was no mean effect on 5-HIAA in CSF, there was a significant relationship between the HVA and 5-HIAA levels (as % of pretreatment level) both after 2 and 5 weeks of treatment (r = 0.96 and r = 0.62, respectively). This may indicate that the drug has an effect on the serotonin system secondary to the dopamine receptor stimulation. The amelioration of depression was not related to HVA, but did correlate to HMPG in CSF (r = 0.65; P less than 0.05) both metabolites measured before treatment. These results indicate that bromocriptine may have antidepressant effects possibly mediated through the noradrenergic system rather than the dopaminergic system.
Article
Following exposure to inescapable shock, subsequent escape performance is disrupted if the task is one in which animals receive forced exposure to shock for several seconds before escape is possible. The extent of the deficit is directly related to the severity of the initial stress and the duration of escape delay used during test. Treatment with a tyrosine hydroxylase inhibitor, -methyl-p-tyrosine (-MpT), a dopamine--hydroxylase inhibitor, FLA-63, or dopamine antagonists, haloperidol, and pimozide, mimicked the effects of inescapable shock in the different escape paradigms. The effects of haloperidol were antagonized by treatment with scopolamine. As observed in the case of inescapable shock, prior escape training abated the disruptive effects of the drug treatments. Finally, decreasing or blocking catecholamine activity or increasing cholinergic activity exacerbated the effect of a moderate amount of inescapable shock on subsequent escape performance. These treatments also induced reductions in shock-elicited activity. Conversely, treatment with a catecholamine stimulant, l-dopa, or a cholinergic blocker, scopolamine, anatagonized the reduction in shock-elicited activity and the escape deficits engendered by prior inescapable shock. It was hypothesized that both DA and NE, as well as ACh, are involved in the escape deficit observed after inescapable shock, and that these transmitters mediate the interference by their influence on response initiation and maintenance, rather than on associative or cognitive processes.
Article
Following exposure to inescapable shock, mice exhibit deficits of escape performance, which are progressively more pronounced as training continues. Comparable effects were produced by DA and NE depletion by alpha-MpT and reserpine, NE depletion by FLA-63, and DA receptor blockade through haloperidol. Treatment with PCPA or 5-HTP did not influence performance. The disruptive effects of reserpine and alpha-MpT, as well as haloperidol and FLA-63, were additive. Unexpectedly, mice that received both reserpine and FLA-63 exhibited escape latencies that were significantly lower than those of mice that received either treatment alone. Consistent with the view that increased DA synthesis in the reserpine plus FLA-63 condition prevented the escape interference, L-DOPA antagonized the effects of both alpha-MpT and FLA-63. The results suggest that DA and NE act in a serial fashion to produce the escape deficits. Moreover, although both newly synthesized and previously stored amines contribute to the interference, the short latency responses seen during initial test trials could not be ascribed to previously stored amines.