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Baik, Ja-Hyun. "Stress and the dopaminergic reward system." Experimental & Molecular Medicine 52, no. 12 (December 2020): 1879–90. http://dx.doi.org/10.1038/s12276-020-00532-4.
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AbstractDopamine regulates reward-related behavior through the mesolimbic dopaminergic pathway. Stress affects dopamine levels and dopaminergic neuronal activity in the mesolimbic dopamine system. Changes in mesolimbic dopaminergic neurotransmission are important for coping with stress, as they allow adaption to behavioral responses to various environmental stimuli. Upon stress exposure, modulation of the dopaminergic reward system is necessary for monitoring and selecting the optimal process for coping with stressful situations. Aversive stressful events may negatively regulate the dopaminergic reward system, perturbing reward sensitivity, which is closely associated with chronic stress-induced depression. The mesolimbic dopamine system is excited not only by reward but also by aversive stressful stimuli, which adds further intriguing complexity to the relationship between stress and the reward system. This review focuses on lines of evidence related to how stress, especially chronic stress, affects the mesolimbic dopamine system, and discusses the role of the dopaminergic reward system in chronic stress-induced depression.
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Huang, Minjie, Guoqing Wang, Yazhou Lin, Yanyan Guo, Xiuhua Ren, Jinping Shao, Jing Cao, Weidong Zang, and Zhihua Li. "Dopamine receptor D2, but not D1, mediates the reward circuit from the ventral tegmental area to the central amygdala, which is involved in pain relief." Molecular Pain 18 (April 2022): 174480692211450. http://dx.doi.org/10.1177/17448069221145096.
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Pain involves both sensory and affective dimensions. The amygdala is a key player in linking nociceptive stimuli to negative emotional behaviors or affective states. Relief of pain is rewarding and activates brain reward circuits. Whether the reward circuit from the ventral tegmental area (VTA) to the central amygdala (CeA) is involved in pain relief remains unexplored. Using a model of experimental postsurgical pain, we found that pain relief elicited conditioned place preference (CPP), activated CeA-projecting dopaminergic cells in the VTA, and decreased dopaminergic D2 receptor expression in the CeA. Activation of the VTA–CeA neural pathway using optogenetic approaches relieved incisional pain. Administration of a D2 receptor agonist reversed the pain relief elicited by light-induced activation of the VTA-CeA pathway. These findings indicate that the VTA-CeA circuit is involved in pain relief in mice via dopamine receptor D2 in the CeA.
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de Boer, Lieke, Benjamín Garzón, Jan Axelsson, Katrine Riklund, Lars Nyberg, Lars Bäckman, and Marc Guitart-Masip. "Corticostriatal White Matter Integrity and Dopamine D1 Receptor Availability Predict Age Differences in Prefrontal Value Signaling during Reward Learning." Cerebral Cortex 30, no. 10 (June 2, 2020): 5270–80. http://dx.doi.org/10.1093/cercor/bhaa104.
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Abstract Probabilistic reward learning reflects the ability to adapt choices based on probabilistic feedback. The dopaminergically innervated corticostriatal circuit in the brain plays an important role in supporting successful probabilistic reward learning. Several components of the corticostriatal circuit deteriorate with age, as it does probabilistic reward learning. We showed previously that D1 receptor availability in NAcc predicts the strength of anticipatory value signaling in vmPFC, a neural correlate of probabilistic learning that is attenuated in older participants and predicts probabilistic reward learning performance. We investigated how white matter integrity in the pathway between nucleus accumbens (NAcc) and ventromedial prefrontal cortex (vmPFC) relates to the strength of anticipatory value signaling in vmPFC in younger and older participants. We found that in a sample of 22 old and 23 young participants, fractional anisotropy in the pathway between NAcc and vmPFC predicted the strength of value signaling in vmPFC independently from D1 receptor availability in NAcc. These findings provide tentative evidence that integrity in the dopaminergic and white matter pathways of corticostriatal circuitry supports the expression of value signaling in vmPFC which supports reward learning, however, the limited sample size calls for independent replication. These and future findings could add to the improved understanding of how corticostriatal integrity contributes to reward learning ability.
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Kim, Jae-Ick, Subhashree Ganesan, Sarah X. Luo, Yu-Wei Wu, Esther Park, Eric J. Huang, Lu Chen, and Jun B. Ding. "Aldehyde dehydrogenase 1a1 mediates a GABA synthesis pathway in midbrain dopaminergic neurons." Science 350, no. 6256 (October 1, 2015): 102–6. http://dx.doi.org/10.1126/science.aac4690.
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Midbrain dopamine neurons are an essential component of the basal ganglia circuitry, playing key roles in the control of fine movement and reward. Recently, it has been demonstrated that γ-aminobutyric acid (GABA), the chief inhibitory neurotransmitter, is co-released by dopamine neurons. Here, we show that GABA co-release in dopamine neurons does not use the conventional GABA-synthesizing enzymes, glutamate decarboxylases GAD65 and GAD67. Our experiments reveal an evolutionarily conserved GABA synthesis pathway mediated by aldehyde dehydrogenase 1a1 (ALDH1a1). Moreover, GABA co-release is modulated by ethanol (EtOH) at concentrations seen in blood alcohol after binge drinking, and diminished ALDH1a1 leads to enhanced alcohol consumption and preference. These findings provide insights into the functional role of GABA co-release in midbrain dopamine neurons, which may be essential for reward-based behavior and addiction.
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Stanfill, Ansley Grimes, Yvette Conley, Ann Cashion, Carol Thompson, Ramin Homayouni, Patricia Cowan, and Donna Hathaway. "Neurogenetic and Neuroimaging Evidence for a Conceptual Model of Dopaminergic Contributions to Obesity." Biological Research For Nursing 17, no. 4 (January 9, 2015): 413–21. http://dx.doi.org/10.1177/1099800414565170.
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As the incidence of obesity continues to rise, clinicians and researchers alike are seeking explanations for why some people become obese while others do not. While caloric intake and physical activity most certainly play a role, some individuals continue to gain weight despite careful attention to these factors. Increasing evidence suggests that genetics may play a role, with one potential explanation being genetic variability in genes within the neurotransmitter dopamine pathway. This variability can lead to a disordered experience with the rewarding properties of food. This review of literature examines the extant knowledge about the relationship between obesity and the dopaminergic reward pathways in the brain, with particularly strong evidence provided from neuroimaging and neurogenetic data. Pubmed, Google Scholar, and Cumulative Index to Nursing and Allied Health Literature searches were conducted with the search terms dopamine, obesity, weight gain, food addiction, brain regions relevant to the mesocortical and mesolimbic (reward) pathways, and relevant dopaminergic genes and receptors. These terms returned over 200 articles. Other than a few sentinel articles, articles were published between 1993 and 2013. These data suggest a conceptual model for obesity that emphasizes dopaminergic genetic contributions as well as more traditional risk factors for obesity, such as demographics (age, race, and gender), physical activity, diet, and medications. A greater understanding of variables contributing to weight gain and obesity is imperative for effective clinical treatment.
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Chen, Xi, Xin Shu, Zhu-Kai Cong, Zheng-Yao Jiang, and Hong Jiang. "Nesfatin-1 acts on the dopaminergic reward pathway to inhibit food intake." Neuropeptides 53 (October 2015): 45–50. http://dx.doi.org/10.1016/j.npep.2015.07.004.
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Rhinehart, Erin, and Madison Waldron. "Gestational programming of ingestive behavior via effects on the mesolimbic dopaminergic reward pathway." FASEB Journal 34, S1 (April 2020): 1. http://dx.doi.org/10.1096/fasebj.2020.34.s1.07263.
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Proulx, Christophe D., Sage Aronson, Djordje Milivojevic, Cris Molina, Alan Loi, Bradley Monk, Steven J. Shabel, and Roberto Malinow. "A neural pathway controlling motivation to exert effort." Proceedings of the National Academy of Sciences 115, no. 22 (May 11, 2018): 5792–97. http://dx.doi.org/10.1073/pnas.1801837115.
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The neural mechanisms conferring reduced motivation, as observed in depressed individuals, is poorly understood. Here, we examine in rodents if reduced motivation to exert effort is controlled by transmission from the lateral habenula (LHb), a nucleus overactive in depressed-like states, to the rostromedial tegmental nucleus (RMTg), a nucleus that inhibits dopaminergic neurons. In an aversive test wherein immobility indicates loss of effort, LHb→RMTg transmission increased during transitions into immobility, driving LHb→RMTg increased immobility, and inhibiting LHb→RMTg produced the opposite effects. In an appetitive test, driving LHb→RMTg reduced the effort exerted to receive a reward, without affecting the reward’s hedonic property. Notably, LHb→RMTg stimulation only affected specific aspects of these motor tasks, did not affect all motor tasks, and promoted avoidance, indicating that LHb→RMTg activity does not generally reduce movement but appears to carry a negative valence that reduces effort. These results indicate that LHb→RMTg activity controls the motivation to exert effort and may contribute to the reduced motivation in depression.
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Pallikaras, Vasilios, and Peter Shizgal. "Dopamine and Beyond: Implications of Psychophysical Studies of Intracranial Self-Stimulation for the Treatment of Depression." Brain Sciences 12, no. 8 (August 8, 2022): 1052. http://dx.doi.org/10.3390/brainsci12081052.
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Major depressive disorder is a leading cause of disability and suicide worldwide. Consecutive rounds of conventional interventions are ineffective in a significant sub-group of patients whose disorder is classified as treatment-resistant depression. Significant progress in managing this severe form of depression has been achieved through the use of deep brain stimulation of the medial forebrain bundle (MFB). The beneficial effect of such stimulation appears strong, safe, and enduring. The proposed neural substrate for this promising clinical finding includes midbrain dopamine neurons and a subset of their cortical afferents. Here, we aim to broaden the discussion of the candidate circuitry by exploring potential implications of a new “convergence” model of brain reward circuitry in rodents. We chart the evolution of the new model from its predecessors, which held that midbrain dopamine neurons constituted an obligatory stage of the final common path for reward seeking. In contrast, the new model includes a directly activated, non-dopaminergic pathway whose output ultimately converges with that of the dopaminergic neurons. On the basis of the new model and the relative ineffectiveness of dopamine agonists in the treatment of depression, we ask whether non-dopaminergic circuitry may contribute to the clinical efficacy of deep brain stimulation of the MFB.
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Appel, Sarah B., William J. McBride, Marco Diana, Ivan Diamond, Antonello Bonci, and Mark S. Brodie. "Ethanol Effects on Dopaminergic ???Reward??? Neurons in the Ventral Tegmental Area and the Mesolimbic Pathway." Alcoholism: Clinical & Experimental Research 28, no. 11 (November 2004): 1768–78. http://dx.doi.org/10.1097/01.alc.0000145976.64413.21.
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Bienvenu, Thierry, Nicolas Lebrun, Julia Clarke, Philibert Duriez, Philip Gorwood, and Nicolas Ramoz. "De novo deleterious variants that may alter the dopaminergic reward pathway are associated with anorexia nervosa." Eating and Weight Disorders - Studies on Anorexia, Bulimia and Obesity 25, no. 6 (October 29, 2019): 1643–50. http://dx.doi.org/10.1007/s40519-019-00802-9.
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Cléry-Melin, Marie-Laure, Fabrice Jollant, and Philip Gorwood. "Reward systems and cognitions in Major Depressive Disorder." CNS Spectrums 24, no. 1 (November 26, 2018): 64–77. http://dx.doi.org/10.1017/s1092852918001335.
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A lack of motivation and anhedonia represent frequent and pervasive symptoms in depression, although with poor specificity. Historically described as a response bias, reward-related impairments in depression may account for the important aspects of the cognitive impairments associated with diagnosis of major depressive disorder. Reward processing is a broad psychological construct that can be parsed into 3 distinct components known as “reinforcement learning” (learning), “reward responsiveness” (liking), and “motivation to obtain a reward” (wanting). Depressed patients respond hyposensitively to reward and maladaptively to punishment: this pattern is related to a dysfunction in the frontostriatal systems modulated by the monoamine systems; seems to be observed in medicated and unmedicated patients with depression and in healthy individuals with high levels of anhedonia; and could be observed in patients with a history of depression, even when in full remission. Considered to be cognitive impairments, reward-related-impairments may also constitute part of an underlying neurobiological vulnerability to major depressive disorder (MDD). For example, the reward-related impairment is state dependent and, more or less, correlated with symptom severity in some studies but has also been proposed as being trait like, with endophenotype characteristics, possibly contributing to the persistence of the disease or treatment resistance. The 3 core aspects of reward processing have specific neurobiological correlates that involve the ventral and dorsal striatum, lateral habenula, ventral tegmental area, orbitofrontal cortex, anterior cingulate cortex, and ventromedial and dorsolateral prefrontal cortex. These structures underline the important role of the dopaminergic mesolimbic pathway, but glutamate and serotonin could also have an important role, at least in some aspects of reward-related impairments.
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Yoo, S. B., V. Ryu, J. H. Lee, and J. W. Jahng. "Neonatal maternal separation may suppress dopaminergic activity in the reward pathway, affect palatable food intake in rats." Appetite 52, no. 3 (June 2009): 866. http://dx.doi.org/10.1016/j.appet.2009.04.213.
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Rice, Timothy R., and Leo Sher. "Low testosterone levels in aging men may mediate the observed increase in suicide in this age group." International Journal on Disability and Human Development 16, no. 1 (February 1, 2017): 123. http://dx.doi.org/10.1515/ijdhd-2016-0007.
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Abstract This short communication suggests that there may be biological in addition to psychosocial reasons underlying the rise in suicide among older men. Testosterone, the major male sex hormone, has attracted interest as a putative biological mediator of suicide risk, but observational data have been mixed. Age stratification may reveal that high levels of testosterone in adolescents and young adults but low levels in the elderly may mediate suicide risk. A putative age-testosterone-suicide differential may be mediated by divergent central nervous system architecture between adolescents and the elderly. Whereas the prefrontal and prefontal-limbic connectivity underdevelopment observed in adolescents may render vulnerability to testosterone-mediated increases in impulsivity as a risk factor for suicide, declining function of dopaminergic striato-thalamic reward pathways in the aging cohort may render older men vulnerable to the loss of testosterone’s protective effects against anhedonia, thereby increasing suicide risk through a different biological pathway. Further research is needed regarding the role of hypotestosteronemia in elderly suicide.
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Edwards, Sophie C., Zachary J. Hall, Eira Ihalainen, Valerie R. Bishop, Elisa T. Nicklas, Susan D. Healy, and Simone L. Meddle. "Neural Circuits Underlying Nest Building in Male Zebra Finches." Integrative and Comparative Biology 60, no. 4 (July 18, 2020): 943–54. http://dx.doi.org/10.1093/icb/icaa108.
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Abstract Nest building consists of a series of motor actions, which are concomitant with activity in regions of the anterior motor pathway, the social behavior network, and the reward circuity in nest building adult male zebra finches (Taeniopygia guttata). It is not clear, however, whether this activity is due to nest building, collection, and/or manipulation of nest material. To identify which areas of the brain are specifically involved, we used immunohistochemistry to quantify the immediate early gene c-Fos in male zebra finches that were nest building (Building), birds given a nest box but could interact only with tied down nest material (Fixed), and birds that were not given a nest box or nest material (Control). We investigated the following brain regions: the anterior motor pathway (anterior ventral mesopallium [AMV], AN, anterior striatum [ASt]), areas of the social behavior network (bed nucleus of the stria terminalis, dorsomedial subdivision [BSTmd], lateral septum [LS]), the dopaminergic reward circuitry (ventral tegmental area), and the cerebellum. We found that there was greater Fos immunoreactivity expression in the BSTmd, LS, and AMV with increased material deposition; in LS, AMV ASt, and Folium VI with increased material carrying; in LS, AMV, and ASt with increased nest material tucking; and in LS and all folia (except Folium VIII) with increased tugging at tied down material. These data confirm a functional role for areas of the anterior motor pathway, social behavior network, and the cerebellum in nest material collection and manipulation by birds.
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Ortega, Nancy Elizabeth, Bethany L. Stangl, Soundarya Soundararajan, Shaliciana Burrell, Hui Sun, Melanie L. Schwandt, and Vijay A. Ramchandani. "3255 Association between dopaminergic genetic variants, COMTrs4680 and DRD2rs1076560, and alcohol consumption and reward behaviors in non-dependent drinkers." Journal of Clinical and Translational Science 3, s1 (March 2019): 138–39. http://dx.doi.org/10.1017/cts.2019.313.
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OBJECTIVES/SPECIFIC AIMS: The objective of this exploratory study is to evaluate the relationship between the individual genetic variants in COMTrs4680 and DRDrs1076560 and relevant alcohol use behaviors (i.e. alcohol consumption and reward processing behaviors) in non-dependent drinkers within experimentally controlled IV-ASA CAIS sessions. The overall goal of this study is to begin gathering data on the influence of individual genetic variants on alcohol consumption and other drinking-related behaviors. This will aid in the creation of a polygenic model of risk for AUD which will provide more insight into how the mesolimbic pathway is affected by alcohol use. METHODS/STUDY POPULATION: Study population: The sample included male and female non-dependent drinkers (N=149). Genotypes for functional polymorphisms in COMT (rs4680) and DRD2 (rs1076560) genes were determined for all subjects from blood samples obtained during screening. Alcohol consumption was assessed using the 90-day Timeline Followback Interviews (TLFB). Study population demographics: Self-reported gender (53.5% identified as male); Self-reported race (61.2% identified as white); Age ranged from 21-46 years old, with 22 years being the mode. Experiment: Free access (open-bar) intravenous alcohol self-administration (IV-ASA) using the computer-assisted alcohol infusion system (CAIS) paradigm; Subjects had the choice of pressing a button ad libitum for IV alcohol infusions during the session, neurobehavioral questionnaires were collected throughout the 2.5-hr alcohol infusion session. Primary outcome measures included: Total Rewards, Peak breath alcohol concentration (BrAC) achieved, and Total Ethanol consumed. Statistical Analyses: Conducted using SPSS IBM Statistics Versions 1.0.0-2482; non-dependent drinkers were organized into two groups based on their genotypes, minor allele carriers and major allele homozygotes. Outcome measures were compared between genotype groups using analysis of variance or non-parametric Mann-Whitney U-test as appropriate. RESULTS/ANTICIPATED RESULTS: -We expect the genetic makeup of the sample to be reflective of larger genome samples that are publically available (e.g. e!Ensembl) - Initial analysis for COMTrs4680 did not reveal significant effects on IV-ASA measures. Specifically, the majo DISCUSSION/SIGNIFICANCE OF IMPACT: Alcohol Use Disorder (AUD) affects millions of men and women globally. The heterogeneity within AUD individuals has made it difficult to identify biological and/or psychological factors that could be targeted for the development of treatments. By using the human laboratory model of free access IV-ASA, this study evaluated the relationship between dopaminergic genetic variants, COMTrs4680 and DRDrs1076560, and alcohol consumption in non-dependent drinkers within a controlled experimental environment. This study will begin to evaluate genetic and behavioral data that can be used to create a polygenic model of risk for AUD, which will provide more insight as to how the mesolimbic reward pathway is affected by alcohol use and contributes to risk for AUD.
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Demery-Poulos, Catherine, and Joseph M. Chambers. "Genetic variation in alcoholism and opioid addiction susceptibility and treatment: a pharmacogenomic approach." AIMS Molecular Science 8, no. 4 (2021): 202–22. http://dx.doi.org/10.3934/molsci.2021016.
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<abstract> <p>Alcohol and opioid abuse have pervasive and detrimental consequences from the individual to societal level. The extent of genetic contribution to alcoholism has been studied for decades, yielding speculative and often inconsistent results since the previous discovery of two pharmacokinetic variants strongly protective against alcoholism. The neurobiology of addiction involves innumerate genes with combinatorial and epistatic interactions, creating a difficult landscape for concrete conclusions. In contrast, pharmacogenomic variation in the treatment of alcoholism yields more immediate clinical utility, while also emphasizing pathways crucial to the progression of addiction. An improved understanding of genetic predisposition to alcohol abuse has inherent significance for opioid addiction and treatment, as the two drugs induce the same reward pathway. This review outlines current knowledge, treatments, and research regarding genetic predisposition to alcoholism, focusing on pharmacodynamic variation within the dopaminergic system and shared implications for opioid abuse. Multifaceted and highly polygenic, the phenotype of addiction seems to grow more complex as new research extends the scope of its impact on the brain, body, and progeny.</p> </abstract>
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Brandão, Marcus L., and Norberto C. Coimbra. "Understanding the role of dopamine in conditioned and unconditioned fear." Reviews in the Neurosciences 30, no. 3 (April 24, 2019): 325–37. http://dx.doi.org/10.1515/revneuro-2018-0023.
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Abstract Pharmacological and molecular imaging studies in anxiety disorders have primarily focused on the serotonin system. In the meantime, dopamine has been known as the neurotransmitter of reward for 60 years, particularly for its action in the nervous terminals of the mesocorticolimbic system. Interest in the mediation by dopamine of the well-known brain aversion system has grown recently, particularly given recent evidence obtained on the role of D2 dopamine receptors in unconditioned fear. However, it has been established that excitation of the mesocorticolimbic pathway, originating from dopaminergic (DA) neurons from the ventral tegmental area (VTA), is relevant for the development of anxiety. Among the forebrain regions innervated by this pathway, the amygdala is an essential component of the neural circuitry of conditioned fear. Current findings indicate that the dopamine D2 receptor-signaling pathway connecting the VTA to the basolateral amygdala modulates fear and anxiety, whereas neural circuits in the midbrain tectum underlie the expression of innate fear. The A13 nucleus of the zona incerta is proposed as the origin of these DA neurons projecting to caudal structures of the brain aversion system. In this article we review data obtained in studies showing that DA receptor-mediated mechanisms on ascending or descending DA pathways play opposing roles in fear/anxiety processes. Dopamine appears to mediate conditioned fear by acting at rostral levels of the brain and regulate unconditioned fear at the midbrain level.
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Blum, Kenneth, Abdalla Bowirrat, Eric R. Braverman, David Baron, Jean Lud Cadet, Shan Kazmi, Igor Elman, et al. "Reward Deficiency Syndrome (RDS): A Cytoarchitectural Common Neurobiological Trait of All Addictions." International Journal of Environmental Research and Public Health 18, no. 21 (November 2, 2021): 11529. http://dx.doi.org/10.3390/ijerph182111529.
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Alcohol and other substance use disorders share comorbidity with other RDS disorders, i.e., a reduction in dopamine signaling within the reward pathway. RDS is a term that connects addictive, obsessive, compulsive, and impulsive behavioral disorders. An estimated 2 million individuals in the United States have opioid use disorder related to prescription opioids. It is estimated that the overall cost of the illegal and legally prescribed opioid crisis exceeds one trillion dollars. Opioid Replacement Therapy is the most common treatment for addictions and other RDS disorders. Even after repeated relapses, patients are repeatedly prescribed the same opioid replacement treatments. A recent JAMA report indicates that non-opioid treatments fare better than chronic opioid treatments. Research demonstrates that over 50 percent of all suicides are related to alcohol or other drug use. In addition to effective fellowship programs and spirituality acceptance, nutrigenomic therapies (e.g., KB220Z) optimize gene expression, rebalance neurotransmitters, and restore neurotransmitter functional connectivity. KB220Z was shown to increase functional connectivity across specific brain regions involved in dopaminergic function. KB220/Z significantly reduces RDS behavioral disorders and relapse in human DUI offenders. Taking a Genetic Addiction Risk Severity (GARS) test combined with a the KB220Z semi-customized nutrigenomic supplement effectively restores dopamine homeostasis (WC 199).
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Santana Hernández, Y., M. V. Redondo Vega, E. Zamora Gracia, A. L. Montejo Gonzalez, J. L. Blázquez Arroyo, and G. Llorca Ramón. "Study of the sexual dysfunction secondary to antidepressants in animal models." European Psychiatry 33, S1 (March 2016): s286. http://dx.doi.org/10.1016/j.eurpsy.2016.01.767.
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IntroductionSexual dysfunction is a very important problem in western countries. One of the causes is the treatment with antidepressants; most of the currently available produce sexual dysfunction in men and women (lower libido, anorgasmia, etc.).ObjectiveComparing the nervous system of the animals we expect to find differences to explain the biological substratum of the sexual dysfunction that produce the selective serotonin reuptake inhibitors.MethodTwenty Wistar rats; approximate weight 150 g. It is divided into 4 groups: 2 experimental (paroxetine and agomelatina mouth) and 2 controls. There is a daily conduct. Weighing at the beginning of the study, 14 and 28 days. Is performed sacrifice by decapitation, is extracted from the brain and after fixing paraffin cuts are carried out for their subsequent staining (immunohistochemistry) with their corresponding murine antibody and viewing through optical microscope.ResultsLower immunoreactivity with the antibody anti-TH in the animals treated with paroxetine, at all levels of the dopaminergic activity (tracks mesolimbica, cortical circuit, nigrostriatal pathway and tubero-infundibular). This decrease is reaffirmed after the statistical treatment of data.ConclusionsTreatment with paroxetine in animal models causes a depletion of the dopaminergic system that can be one of the biological bases of sexual dysfunction, altering the reward mechanisms as well as producing hyperprolactinemia.Disclosure of interestThe authors have not supplied their declaration of competing interest.
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de Oliveira, Antônio Carlos Pinheiro, Maria Carolina Machado da Silva, Lia Parada Iglesias, Eduardo Candelario-Jalil, Habibeh Khoshbouei, and Fabrício Araujo Moreira. "Role of Microglia in Psychostimulant Addiction." Current Neuropharmacology 21, no. 2 (February 2023): 235–59. http://dx.doi.org/10.2174/1570159x21666221208142151.
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Abstract: The use of psychostimulant drugs can modify brain function by inducing changes in the reward system, mainly due to alterations in dopaminergic and glutamatergic transmissions in the mesocorticolimbic pathway. However, the etiopathogenesis of addiction is a much more complex process. Previous data have suggested that microglia and other immune cells are involved in events associated with neuroplasticity and memory, which are phenomena that also occur in addiction. Nevertheless, how dependent is the development of addiction on the activity of these cells? Although the mechanisms are not known, some pathways may be involved. Recent data have shown psychoactive substances may act directly on immune cells, alter their functions and induce various inflammatory mediators that modulate synaptic activity. These could, in turn, be involved in the pathological alterations that occur in substance use disorder. Here, we extensively review the studies demonstrating how cocaine and amphetamines modulate microglial number, morphology, and function. We also describe the effect of these substances in the production of inflammatory mediators and a possible involvement of some molecular signaling pathways, such as the toll-like receptor 4. Although the literature in this field is scarce, this review compiles the knowledge on the neuroimmune axis that is involved in the pathogenesis of addiction, and suggests some pharmacological targets for the development of pharmacotherapy.
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Wu, Min, Jean-Claude Walser, Lei Sun, and Mathias Kölliker. "The genetic mechanism of selfishness and altruism in parent-offspring coadaptation." Science Advances 6, no. 1 (January 2020): eaaw0070. http://dx.doi.org/10.1126/sciadv.aaw0070.
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The social bond between parents and offspring is characterized by coadaptation and balance between altruistic and selfish tendencies. However, its underlying genetic mechanism remains poorly understood. Using transcriptomic screens in the subsocial European earwig, Forficula auricularia, we found the expression of more than 1600 genes associated with experimentally manipulated parenting. We identified two genes, Th and PebIII, each showing evidence of differential coexpression between treatments in mothers and their offspring. In vivo RNAi experiments confirmed direct and indirect genetic effects of Th and PebIII on behavior and fitness, including maternal food provisioning and reproduction, and offspring development and survival. The direction of the effects consistently indicated a reciprocally altruistic function for Th and a reciprocally selfish function for PebIII. Further metabolic pathway analyses suggested roles for Th-restricted endogenous dopaminergic reward, PebIII-mediated chemical communication and a link to insulin signaling, juvenile hormone, and vitellogenin in parent-offspring coadaptation and social evolution.
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Heifets, Boris D., Juliana S. Salgado, Madison D. Taylor, Paul Hoerbelt, Daniel F. Cardozo Pinto, Elizabeth E. Steinberg, Jessica J. Walsh, Ji Y. Sze, and Robert C. Malenka. "Distinct neural mechanisms for the prosocial and rewarding properties of MDMA." Science Translational Medicine 11, no. 522 (December 11, 2019): eaaw6435. http://dx.doi.org/10.1126/scitranslmed.aaw6435.
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The extensively abused recreational drug (±)3,4-methylenedioxymethamphetamine (MDMA) has shown promise as an adjunct to psychotherapy for treatment-resistant psychiatric disease. It is unknown, however, whether the mechanisms underlying its prosocial therapeutic effects and abuse potential are distinct. We modeled both the prosocial and nonsocial drug reward of MDMA in mice and investigated the mechanism of these processes using brain region–specific pharmacology, transgenic manipulations, electrophysiology, and in vivo calcium imaging. We demonstrate in mice that MDMA acting at the serotonin transporter within the nucleus accumbens is necessary and sufficient for MDMA’s prosocial effect. MDMA’s acute rewarding properties, in contrast, require dopaminergic signaling. MDMA’s prosocial effect requires 5-HT1b receptor activation and is mimicked by d-fenfluramine, a selective serotonin-releasing compound. By dissociating the mechanisms of MDMA’s prosocial effects from its addictive properties, we provide evidence for a conserved neuronal pathway, which can be leveraged to develop novel therapeutics with limited abuse liability.
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Loiodice, Simon, Portia McGhan, Vitalina Gryshkova, Renaud Fleurance, David Dardou, Aziz Hafidi, Andre Nogueira da Costa, and Franck Durif. "Striatal changes underlie MPEP-mediated suppression of the acquisition and expression of pramipexole-induced place preference in an alpha-synuclein rat model of Parkinson’s disease." Journal of Psychopharmacology 31, no. 10 (June 20, 2017): 1323–33. http://dx.doi.org/10.1177/0269881117714051.
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Impulsive-compulsive disorders in Parkinson’s disease patients have been described as behavioural or substance addictions including pathological gambling or compulsive medication use of dopamine replacement therapy. A substantial gap remains in the understanding of these disorders. We previously demonstrated that the rewarding effect of the D2/D3 agonist pramipexole was enhanced after repeated exposure to L-dopa and alpha-synuclein mediated dopaminergic nigral loss with specific transcriptional signatures suggesting a key involvement of the glutamatergic pathway. Here, we further investigate the therapeutic potential of metabotropic glutamate receptor 5 antagonism in Parkinson’s disease/dopamine replacement therapy related bias of reward-mediated associative learning. We identified protein changes underlying the striatal remodelling associated with the pramipexole-induced conditioned place preference. Acquisition and expression of the pramipexole-induced conditioned place preference were abolished by the metabotropic glutamate receptor 5 antagonist 2-methyl-6-phenylethynyl (pyridine) (conditioned place preference scores obtained with pramipexole conditioning were reduced by 12.5% and 125.8% when 2-methyl-6-phenylethynyl (pyridine) was co-administrated with pramipexole or after the pramipexole conditioning, respectively). Up-regulation of the metabotropic glutamate receptor 5 was found in the dorsomedial-striatum and nucleus accumbens core. Activation of these two brain sub-regions was also highlighted through FosB immunohistochemistry. Convergent molecular and pharmacological data further suggests metabotropic glutamate receptor 5 as a promising therapeutic target for the management of Parkinson’s disease/dopamine replacement therapy related reward bias.
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Colón-Semenza, Cristina, Daniel Fulford, and Terry Ellis. "Effort-Based Decision-Making for Exercise in People with Parkinson’s Disease." Journal of Parkinson's Disease 11, no. 2 (April 13, 2021): 725–35. http://dx.doi.org/10.3233/jpd-202353.
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Background: People with Parkinson’s disease (PwPD) are less active than their age-matched peers. Non-motor symptoms, specifically, deficient motivation, may influence decision-making for exercise due to the impaired mesolimbic dopaminergic pathway. Objective: The purpose of this study was to determine if effort-based decision-making for physical effort was different in PwPD compared to healthy controls. We sought to determine the relationship between effort-based decision making for exercise and a discrete motor task as well as the impact of components of motivation on decision-making for physical effort in PwPD. Methods: An effort-based decision-making paradigm using a discrete motor task (button pressing) and a continuous exercise task (cycling) was implemented in 32 PwPD and 23 healthy controls. Components of motivation were measured using the Apathy Scale and the Temporal Experience of Pleasure Scale- Anticipatory Pleasure scale. Results: The presence of Parkinson’s disease (PD) did not moderate decisions for either physical effort task. There was a moderate correlation between decisions for both tasks, within each group. The anticipation of pleasure and apathy were predictors of decisions for both physical effort tasks in PwPD, but not in healthy controls. Conclusion: PwPD responded similarly to effort and reward valuations compared to those without PD. Individuals were consistent in their decisions, regardless of the physical effort task. The anticipation of pleasure and apathy were significant predictors of decisions for exercise in PwPD only. Increased anticipation of pleasure, reduction of apathy, and the use of rewards may enhance engagement in high effort exercise among PwPD.
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Kupnicka, Patrycja, Joanna Listos, Maciej Tarnowski, Agnieszka Kolasa-Wołosiuk, Agnieszka Wąsik, Agnieszka Łukomska, Katarzyna Barczak, Izabela Gutowska, Dariusz Chlubek, and Irena Baranowska-Bosiacka. "Fluoride Affects Dopamine Metabolism and Causes Changes in the Expression of Dopamine Receptors (D1R and D2R) in Chosen Brain Structures of Morphine-Dependent Rats." International Journal of Molecular Sciences 21, no. 7 (March 29, 2020): 2361. http://dx.doi.org/10.3390/ijms21072361.
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Disturbances caused by excess or shortages of certain elements can affect the cerebral reward system and may therefore modulate the processes associated with the development of dependence as was confirmed by behavioural studies on animals addicted to morphine. Earlier publications demonstrated and proved the neurodegenerative properties of both low and high doses of fluoride ions in animal experiments and in epidemiological and clinical studies. The aim of the experiments conducted in the course of the present study was to analyse the effect of pre- and postnatal exposure to 50 ppm F− on the initiation/development of morphine dependence. For this purpose, the following were conducted: behavioural studies, the analysis of concentrations of dopamine and its metabolites, and the analyses of mRNA expression and dopamine receptor proteins D1 and D2 in the prefrontal cortex, striatum, hippocampus, and cerebellum of rats. In this study, it was observed for the first time that pre- and postnatal exposure to fluoride ions influenced the phenomenon of morphine dependence in a model expressing withdrawal symptoms. Behavioural, molecular, and neurochemical studies demonstrated that the degenerative changes caused by toxic activity of fluoride ions during the developmental period of the nervous system may impair the functioning of the dopaminergic pathway due to changes in dopamine concentration and in dopamine receptors. Moreover, the dopaminergic disturbances within the striatum and the cerebellum played a predominant role as both alterations of dopamine metabolism and profound alterations in striatal D1 and D2 receptors were discovered in these structures. The present study provides a new insight into a global problem showing direct associations between environmental factors and addictive disorders.
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Anwar, Haroon, Simon Caby, Salvador Dura-Bernal, David D’Onofrio, Daniel Hasegan, Matt Deible, Sara Grunblatt, et al. "Training a spiking neuronal network model of visual-motor cortex to play a virtual racket-ball game using reinforcement learning." PLOS ONE 17, no. 5 (May 11, 2022): e0265808. http://dx.doi.org/10.1371/journal.pone.0265808.
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Recent models of spiking neuronal networks have been trained to perform behaviors in static environments using a variety of learning rules, with varying degrees of biological realism. Most of these models have not been tested in dynamic visual environments where models must make predictions on future states and adjust their behavior accordingly. The models using these learning rules are often treated as black boxes, with little analysis on circuit architectures and learning mechanisms supporting optimal performance. Here we developed visual/motor spiking neuronal network models and trained them to play a virtual racket-ball game using several reinforcement learning algorithms inspired by the dopaminergic reward system. We systematically investigated how different architectures and circuit-motifs (feed-forward, recurrent, feedback) contributed to learning and performance. We also developed a new biologically-inspired learning rule that significantly enhanced performance, while reducing training time. Our models included visual areas encoding game inputs and relaying the information to motor areas, which used this information to learn to move the racket to hit the ball. Neurons in the early visual area relayed information encoding object location and motion direction across the network. Neuronal association areas encoded spatial relationships between objects in the visual scene. Motor populations received inputs from visual and association areas representing the dorsal pathway. Two populations of motor neurons generated commands to move the racket up or down. Model-generated actions updated the environment and triggered reward or punishment signals that adjusted synaptic weights so that the models could learn which actions led to reward. Here we demonstrate that our biologically-plausible learning rules were effective in training spiking neuronal network models to solve problems in dynamic environments. We used our models to dissect the circuit architectures and learning rules most effective for learning. Our model shows that learning mechanisms involving different neural circuits produce similar performance in sensory-motor tasks. In biological networks, all learning mechanisms may complement one another, accelerating the learning capabilities of animals. Furthermore, this also highlights the resilience and redundancy in biological systems.
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Dalle Molle, R., A. R. Bischoff, A. K. Portella, and P. P. Silveira. "The fetal programming of food preferences: current clinical and experimental evidence." Journal of Developmental Origins of Health and Disease 7, no. 3 (September 28, 2015): 222–30. http://dx.doi.org/10.1017/s2040174415007187.
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Increased energy consumption is one of the major factors implicated in the epidemic of obesity. There is compelling evidence, both clinical and experimental, that fetal paucity of nutrients may have programming effects on feeding preferences and behaviors that can contribute to the development of diseases. Clinical studies in different age groups show that individuals born small for their gestational age (SGA) have preferences towards highly caloric foods such as carbohydrates and fats. Some studies have also shown altered eating behaviors in SGA children. Despite an apparent discrepancy in different age groups, all studies seem to converge to an increased intake of palatable foods in SGA individuals. Small nutrient imbalances across lifespan increase the risk of noncommunicable diseases in adult life. Homeostatic factors such as altered responses to leptin and insulin and alterations in neuropeptides associated with appetite and satiety are likely involved. Imbalances between homeostatic and hedonic signaling are another proposed mechanism, with the mesocorticolimbic dopaminergic pathway having differential reward and pleasure responses when facing palatable foods. Early exposure to undernutrition also programs hypothalamic–pituitary–adrenal axis, with SGA having higher levels of cortisol in different ages, leading to chronic hyperactivity of this neuroendocrine axis. This review summarizes the clinical and experimental evidence related to fetal programming of feeding preferences by SGA.
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Wahl, Hans-Werner, Becca Levy, Brad Meisner, Andrea Gröppel-Klein, Deidre Robertson, Serena Sabatini, and Anna Lücke. "Impact of Age Views on Cognition: Experimental, Longitudinal, and Ecological Momentary Findings." Innovation in Aging 4, Supplement_1 (December 1, 2020): 596–97. http://dx.doi.org/10.1093/geroni/igaa057.2006.
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Abstract Research on the impact of age views on cognition has seen a strong momentum in recent years, fitting the stereotype embodiment theory prediction that the stereotypes taken in from a culture can impact older persons‘ cognition. These studies utilize experimental, longitudinal, and ecological momentary assessments (EMA), as well as a wide reach of cognitive outcomes. This symposium starts with two experimental studies. One demonstrates that negative age stereotypes reduce cognitive processing in older consumers (Gröppel-Klein et al.). A second study strives to better understand the pathway by which age stereotypes influence cognitive outcomes by focusing on dysregulation of reward-seeking behaviors and the downregulation of the dopaminergic system (Robertson et al.). We next explore two longitudinal studies that reveal differential relations among views of aging and various cognitive indicators. The first study found that older persons with more positive age beliefs are less likely to develop dementia even in a high-risk gene subpopulation of older adults (Levy et al.). The second study examined the association between awareness of age-related changes and cognitive scores (Sabatini et al.) Finally, Lücke et al. examine in their EMA study with 6 measurement occasions per day across 7 days that such a fine-tuned seems not to clearly support a linkage among subjective age and working memory for which beginning but not consistent evidence has been reported previously. Brad Meisner will discuss contributions in the light of meta-analytic finding revealing that older persons‘ negative age stereotypes can impair whereas their positive age stereotypes can improve cognitive performance.
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Luo, Sarah X., and Eric J. Huang. "Dopaminergic Neurons and Brain Reward Pathways." American Journal of Pathology 186, no. 3 (March 2016): 478–88. http://dx.doi.org/10.1016/j.ajpath.2015.09.023.
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Singh, Aatma, Kiran Bains, and Harpreet Kaur. "Progression of anorexia nervosa: An insight into neurological and biological mechanisms influencing the personality patterns of anorexics." Journal of Applied and Natural Science 13, no. 2 (June 5, 2021): 571–84. http://dx.doi.org/10.31018/jans.v13i2.2495.
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Anorexia nervosa has emerged as a prominent eating disorder affecting young women. This disorder's fundamental characteristic is an abnormally low weight achieved by severe calorie restriction and refusal to maintain body weight at or above the minimally normal weight for age and height. It is a complex disorder with its origins still not explicitly defined. In anorexic individuals, an imbalance in the molecular signalling and hypothalamic neuropeptides is believed to be significantly responsible for alterations in the biological mechanisms associated with body weight, appetite and energy homeostasis. The imbalance between the genetic systems such as serotonin, dopamine, brain-derived neurotrophic factor, estrogen and their interactions are significantly observed in anorexic as well as recovered anorexic individuals. The dopaminergic pathway is involved in reward mechanisms but its dysfunction might cause weight loss, food aversion, hyperactivity, obsessive compulsive behaviours, distorted body image. An abnormal serotonin function reveals personality traits such as rigidity, inhibition, anxiety, inflexibility, perfectionism and harm avoidance. The Met66 variant of brain derived neurotrophic factor is strongly associated with the development of restricting-type anorexia nervosa. The development of anorexia has been linked to estrogen receptor beta gene variants, which also regulate food intake and states of anxiety and depression.This review discusses the neurobiological dysregulations because of which anorexics tend to have a distinct personality profile characterized by behaviour patterns comprising perfectionism, obsessive-compulsive disorder, harm avoidance, alexithymia, anger suppression, anxiety, rigidity, novelty seeking, anhedonia, depression, impulsivity, substance abuse, self harm etc. Heterogeneities in the characteristic profile are observed based on the subdivisions of anorexia nervosa. The impact of malnutrition has also been scrutinized.
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Khemiri, Lotfi, Pia Steensland, Joar Guterstam, Örjan de Manzano, Johan Franck, and Nitya Jayaram-Lindström. "Effects of the monoamine stabilizer (-)OSU6162 on cognitive function in alcohol dependence." Psychopharmacology 237, no. 1 (October 18, 2019): 69–82. http://dx.doi.org/10.1007/s00213-019-05345-6.
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Abstract Introduction Alcohol dependence (AD) is associated with a dysregulated mesolimbocortical dopamine system—a pathway which is also implicated in both reward and cognition. The monoamine stabilizer (-)-OSU6162 (OSU) is a novel pharmacological compound with the ability to reduce ethanol intake and ethanol seeking in long-term drinking rats as well as reducing alcohol craving in AD patients. Dopaminergic drugs can both impair and improve cognitive functions, and the aim of the current study was to investigate the effect of OSU treatment on cognitive functioning in AD patients. Method In a randomized double-blind placebo-controlled study, 56 individuals with AD received 14 days of OSU or placebo treatment. Neuropsychological tasks from the Cambridge Automated Neuropsychological Test Battery (CANTAB®) and other tasks were used to evaluate treatment effect on executive function/impulsivity, working memory, attention, emotional recognition, and divergent thinking. Results Treatment with OSU did not impair neuropsychological function in any of the cognitive domains investigated (all p > 0.1). In fact, OSU treatment did, compared to placebo, improve future planning ability (F(1,46) = 6.9; p = 0.012; Cohen’s d = 0.54), verbal divergent thinking (F(1,44) = 10.1; p = 0.003; d = 0.96), and response time for emotional recognition (F(1,47) = 6.7; p = 0.013; d = 0.44). Conclusion OSU treatment did not cause short-term cognitive side effects, further supporting the potential of OSU as a clinically feasible pharmacological treatment in AD patients. OSU treatment might improve future planning, verbal divergent thinking, and emotional recognition latency, which in turn may have a beneficial impact on alcohol use outcomes. Future studies are needed to confirm these preliminary findings.
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Saji, Kanako, Yumiko Ikeda, Woochan Kim, Yoshitoshi Shingai, Amane Tateno, Hidehiko Takahashi, Yoshiro Okubo, Haruhisa Fukayama, and Hidenori Suzuki. "Acute NK1 receptor antagonist administration affects reward incentive anticipation processing in healthy volunteers." International Journal of Neuropsychopharmacology 16, no. 7 (August 1, 2013): 1461–71. http://dx.doi.org/10.1017/s1461145712001678.
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Abstract The primary brain structures of reward processing are mainly situated in the mid-brain dopamine system. The nucleus accumbens (NAc) receives dopaminergic projections from the ventral tegmental area and works as a key brain region for the positive incentive value of rewards. Because neurokinin-1 (NK1) receptor, the cognate receptor for substance P (SP), is highly expressed in the NAc, we hypothesized that the SP/NK1 receptor system might play a role in positive reward processing in the NAc in humans. Therefore, we conducted a functional MRI (fMRI) study to assess the effects of an NK1 receptor antagonist on human reward processing through a monetary incentive delay task that is known to elicit robust activation in the NAc especially during gain anticipation. Eighteen healthy adults participated in two series of an fMRI study, taking either a placebo or the NK1 receptor antagonist aprepitant. Behavioural measurements revealed that there was no significant difference in reaction time, hit rate, or self-reported effort for incentive cues between the placebo and aprepitant treatments. fMRI showed significant decrease in blood oxygenation-level-dependent signals in the NAc during gain anticipation with the aprepitant treatment compared to the placebo treatment. These results suggest that SP/NK1 receptor system is involved in processing of positive incentive anticipation and plays a role in accentuating positive valence in association with the primary dopaminergic pathways in the reward circuit.
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Hauser, Tobias U., Eran Eldar, and Raymond J. Dolan. "Separate mesocortical and mesolimbic pathways encode effort and reward learning signals." Proceedings of the National Academy of Sciences 114, no. 35 (August 14, 2017): E7395—E7404. http://dx.doi.org/10.1073/pnas.1705643114.
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Optimal decision making mandates organisms learn the relevant features of choice options. Likewise, knowing how much effort we should expend can assume paramount importance. A mesolimbic network supports reward learning, but it is unclear whether other choice features, such as effort learning, rely on this same network. Using computational fMRI, we show parallel encoding of effort and reward prediction errors (PEs) within distinct brain regions, with effort PEs expressed in dorsomedial prefrontal cortex and reward PEs in ventral striatum. We show a common mesencephalic origin for these signals evident in overlapping, but spatially dissociable, dopaminergic midbrain regions expressing both types of PE. During action anticipation, reward and effort expectations were integrated in ventral striatum, consistent with a computation of an overall net benefit of a stimulus. Thus, we show that motivationally relevant stimulus features are learned in parallel dopaminergic pathways, with formation of an integrated utility signal at choice.
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Zhou, Huanyuan, KongFatt Wong-Lin, and Da-Hui Wang. "Parallel Excitatory and Inhibitory Neural Circuit Pathways Underlie Reward-Based Phasic Neural Responses." Complexity 2018 (2018): 1–20. http://dx.doi.org/10.1155/2018/4356767.
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Phasic activity of dopaminergic (DA) neurons in the ventral tegmental area or substantia nigra compacta (VTA/SNc) has been suggested to encode reward-prediction error signal for reinforcement learning. Recent studies have shown that the lateral habenula (LHb) neurons exhibit a similar response, but for nonrewarding or punishment signals. Hence, the transient signaling role of LHb neurons is opposite that of DA neurons and also that of several other brain nuclei such as the border region of the globus pallidus internal segment (GPb) and the rostral medial tegmentum (RMTg). Previous theoretical models have investigated the neural circuit mechanism underlying reward-based phasic activity of DA neurons, but the feasibility of a larger neural circuit model to account for the observed reward-based phasic activity in other brain nuclei such as the LHb has yet to be shown. Here, we propose a large-scale neural circuit model and show that parallel excitatory and inhibitory pathways underlie the learned neural responses across multiple brain regions. Specifically, the model can account for the phasic neural activity observed in the GPb, LHb, RMTg, and VTA/SNc. Based on sensitivity analysis, the model is found to be robust against changes in the overall neural connectivity strength. The model also predicts that striosomes play a key role in the phasic activity of VTA/SNc and LHb neurons by encoding previous and expected rewards. Taken together, our model identifies the important role of parallel neural circuit pathways in accounting for phasic activity across multiple brain areas during reward and punishment processing.
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Li, Changsheng, Sufang Liu, Xihua Lu, and Feng Tao. "Role of Descending Dopaminergic Pathways in Pain Modulation." Current Neuropharmacology 17, no. 12 (November 12, 2019): 1176–82. http://dx.doi.org/10.2174/1570159x17666190430102531.
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Pain, especially when chronic, is a common reason patients seek medical care and it affects the quality of life and well-being of the patients. Unfortunately, currently available therapies for chronic pain are often inadequate because the neurobiological basis of such pain is still not fully understood. Although dopamine has been known as a neurotransmitter to mediate reward and motivation, accumulating evidence has shown that dopamine systems in the brain are also involved in the central regulation of chronic pain. Most importantly, descending dopaminergic pathways play an important role in pain modulation. In this review, we discuss dopamine receptors, dopaminergic systems in the brain, and the role of descending dopaminergic pathways in the modulation of different types of pain.
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Goldstein Ferber, Sari, Aron Weller, Gal Yadid, and Alexander Friedman. "Discovering the Lost Reward: Critical Locations for Endocannabinoid Modulation of the Cortico–Striatal Loop That Are Implicated in Major Depression." International Journal of Molecular Sciences 22, no. 4 (February 13, 2021): 1867. http://dx.doi.org/10.3390/ijms22041867.
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Depression, the most prevalent psychiatric disorder in the Western world, is characterized by increased negative affect (i.e., depressed mood, cost value increase) and reduced positive affect (i.e., anhedonia, reward value decrease), fatigue, loss of appetite, and reduced psychomotor activity except for cases of agitative depression. Some forms, such as post-partum depression, have a high risk for suicidal attempts. Recent studies in humans and in animal models relate major depression occurrence and reoccurrence to alterations in dopaminergic activity, in addition to other neurotransmitter systems. Imaging studies detected decreased activity in the brain reward circuits in major depression. Therefore, the location of dopamine receptors in these circuits is relevant for understanding major depression. Interestingly, in cortico–striatal–dopaminergic pathways within the reward and cost circuits, the expression of dopamine and its contribution to reward are modulated by endocannabinoid receptors. These receptors are enriched in the striosomal compartment of striatum that selectively projects to dopaminergic neurons of substantia nigra compacta and is vulnerable to stress. This review aims to show the crosstalk between endocannabinoid and dopamine receptors and their vulnerability to stress in the reward circuits, especially in corticostriatal regions. The implications for novel treatments of major depression are discussed.
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Geniole, Shawn N., Tanya L. Procyshyn, Nicole Marley, Triana L. Ortiz, Brian M. Bird, Ashley L. Marcellus, Keith M. Welker, et al. "Using a Psychopharmacogenetic Approach To Identify the Pathways Through Which—and the People for Whom—Testosterone Promotes Aggression." Psychological Science 30, no. 4 (February 21, 2019): 481–94. http://dx.doi.org/10.1177/0956797619826970.
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Little is known about the neurobiological pathways through which testosterone promotes aggression or about the people in whom this effect is observed. Using a psychopharmacogenetic approach, we found that testosterone increases aggression in men ( N = 308) with select personality profiles and that these effects are further enhanced among those with fewer cytosine-adenine-guanine (CAG) repeats in exon 1 of the androgen receptor (AR) gene, a polymorphism associated with increased AR efficiency. Testosterone’s effects were rapid (~30 min after administration) and mediated, in part, by subjective reward associated with aggression. Testosterone thus appears to promote human aggression through an AR-related mechanism and to have stronger effects in men with the select personality profiles because it more strongly upregulates the subjective pleasure they derive from aggression. Given other evidence that testosterone regulates reward through dopaminergic pathways, and that the sensitivity of such pathways is enhanced among individuals with the personality profiles we identified, our findings may also implicate dopaminergic processes in testosterone’s heterogeneous effects on aggression.
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Meng, Ying, Susan W. Groth, Joyce A. Smith, and Harriet Kitzman. "2125 What genes are involved in the brain food reward circuitry: Findings from a large candidate gene analysis." Journal of Clinical and Translational Science 2, S1 (June 2018): 36. http://dx.doi.org/10.1017/cts.2018.149.
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OBJECTIVES/SPECIFIC AIMS: The food reward circuitry regulates hedonic eating especially in relation to palatable hypercaloric foods, which can lead to chronic overeating and consequent overweight and obesity. Evidence supports that there is considerable overlap within the brain reward circuitry between palatable hypercaloric food intake and substance addiction. The goal of this study was to identify associations between addiction-related genes and body mass index. We hypothesized that addiction-related genes potentially participate in the food reward circuitry if they are associated with obesity traits. METHODS/STUDY POPULATION: A secondary analysis was conducted with 1093 African American adolescents and young adults from the New Mother’s Study. Anthropometric, genetic, demographic and lifestyle measurements were available at the 18-year follow-up assessments. A total of 1350 single nucleotide polymorphisms mapped to 127 addiction-related genes were assessed. A total of 186 ancestry informative markers were used to adjust for population stratification. Generalized estimating equation models were used to identify genetic associations, including additive, dominant, and recessive models, and control for correlations within families. RESULTS/ANTICIPATED RESULTS: The participants ranged from 15 to 23 years of age. Of them, 42.7% were overweight or obese. Significant associations with body mass index were identified for 13 single nucleotide polymorphisms mapped to 11 addiction-related genes, including LEP (p 0.027–<0.001). Most of these genes are involved in dopaminergic, opioidergic, serotonergic pathways, and stress. DISCUSSION/SIGNIFICANCE OF IMPACT: Our results support the role of dopaminergic and opioidergic pathways in the food reward circuitry, and suggest a potential involvement of serotonergic pathways and genes related to stress in the food reward circuitry. Further investigation of the identified genes will facilitate delineation and understanding of the brain food reward system and its relationship with obesity.
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Shih, Hsuan-Chu, Mu-En Kuo, Changwei W. Wu, Yi-Ping Chao, Hsu-Wen Huang, and Chih-Mao Huang. "The Neurobiological Basis of Love: A Meta-Analysis of Human Functional Neuroimaging Studies of Maternal and Passionate Love." Brain Sciences 12, no. 7 (June 26, 2022): 830. http://dx.doi.org/10.3390/brainsci12070830.
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Maternal and passionate love are both crucial for reproduction and involve attachment behaviors with high rewards. Neurobiological studies of attachment in animal and human neuroimaging studies have suggested that the coordination of oxytocinergic and vasopressinergic pathways, coupled with the dopaminergic reward system, contribute to the formation and maintenance of maternal and passionate love. In the present study, we carried out a quantitative meta-analysis of human neuroimaging to identify common and dissociable neural substrates associated with maternal and passionate love, using the activation likelihood estimation (ALE) approach. The ALE results showed significant activation of the brain regions in the left ventral tegmental area (VTA), right thalamus, left substantia nigra, and the left putamen for maternal love, but in the bilateral VTA for passionate love. The meta-analytic neuroimaging evidence suggests the greater involvement of cognitive–affective regulation in maternal attachment and the greater desire to combine liking and wanting in romantic love behaviors. The conjunction analysis highlights the functional convergence of the VTA across the two types of human love, indicating a shared neurobiological mechanism of maternal and passionate love with evolutionary roots. Our findings suggest that the processing of both maternal and passionate love involve the affective and motivational regulation associated with dopaminergic systems; our neuroimaging evidence supports the notion that maternal and passionate love share a common evolutionary origin and neurobiological basis in the human brain.
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Miyazaki, Masayuki, Yukihiro Noda, Akihiro Mouri, Kazuto Kobayashi, Masayoshi Mishina, Toshitaka Nabeshima, and Kiyofumi Yamada. "Role of convergent activation of glutamatergic and dopaminergic systems in the nucleus accumbens in the development of methamphetamine psychosis and dependence." International Journal of Neuropsychopharmacology 16, no. 6 (July 1, 2013): 1341–50. http://dx.doi.org/10.1017/s1461145712001356.
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Abstract Methamphetamine (Meth) abuse can result in long-lasting psychosis and dependence. The nucleus accumbens (NAc), which controls psychomotor and reward behaviours, is an important interface between the limbic system and receives convergent projections from dopaminergic and glutamatergic terminals. This study investigated the involvements of dopaminergic and glutamatergic transmission in the development of Meth psychosis and dependence by using tyrosine hydroxylase heterozygous mutant (TH+/−) mice and N-methyl-d-aspartate receptor knockout (NR2A−/−) mice. Repeated treatment with Meth (1 mg/kg s.c.) for 7 d in wild-type mice led to the development of behavioural abnormalities such as hyperactivity, sensory motor gating deficits and place preference. Associated with the behavioural changes, repeated treatment with Meth led to protein kinase A activation and phosphorylation of Ca2+/calmodulin kinase II and cyclic AMP response element binding protein in the NAc. In contrast, TH+/− and NR2A−/− mice displayed neither behavioural abnormalities nor activation of intracellular signalling pathways in the NAc. These results suggest that both dopaminergic and glutamatergic transmission play a crucial role in the development of Meth psychosis and dependence, which are associated with convergent activation of intracellular signalling pathways in the NAc.
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Huppertz, Charlotte, Meike Bartels, Maria M. Groen-Blokhuis, Conor V. Dolan, Marleen H. M. de Moor, Abdel Abdellaoui, Catharina E. M. van Beijsterveldt, et al. "The Dopaminergic Reward System and Leisure Time Exercise Behavior: A Candidate Allele Study." BioMed Research International 2014 (2014): 1–9. http://dx.doi.org/10.1155/2014/591717.
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Purpose. Twin studies provide evidence that genetic influences contribute strongly to individual differences in exercise behavior. We hypothesize that part of this heritability is explained by genetic variation in the dopaminergic reward system. Eight single nucleotide polymorphisms (SNPs in DRD1: rs265981, DRD2: rs6275, rs1800497, DRD3: rs6280, DRD4: rs1800955, DBH: rs1611115, rs2519152, and in COMT: rs4680) and three variable number of tandem repeats (VNTRs inDRD4, upstream ofDRD5, and inDAT1) were investigated for an association with regular leisure time exercise behavior.Materials and Methods. Data on exercise activities and at least one SNP/VNTR were available for 8,768 individuals aged 7 to 50 years old that were part of the Netherlands Twin Register. Exercise behavior was quantified as weekly metabolic equivalents of task (MET) spent on exercise activities. Mixed models were fitted in SPSS with genetic relatedness as a random effect.Results. None of the genetic variants were associated with exercise behavior (P>.02), despite sufficient power to detect small effects.Discussion and Conclusions. We did not confirm that allelic variants involved in dopaminergic function play a role in creating individual differences in exercise behavior. A plea is made for large genome-wide association studies to unravel the genetic pathways that affect this health-enhancing behavior.
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Chmielowiec, Krzysztof, Monika Michałowska-Sawczyn, Jolanta Masiak, Jolanta Chmielowiec, Grzegorz Trybek, Marta Niewczas, Wojciech Czarny, et al. "Analysis of DRD2 Gene Polymorphism in the Context of Personality Traits in a Group of Athletes." Genes 12, no. 8 (August 6, 2021): 1219. http://dx.doi.org/10.3390/genes12081219.
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The presented study showed the relationship between dopamine receptor gene polymorphism and personality traits in athletes training in martial arts. Behavioral modulation resulting from a balance of the neurotransmitters dopamine and norepinephrine to inactivation of the dorsolateral prefrontal cortex and dysregulation of various pathways involved in attention and impulse control processes; Methods: The study was conducted among martial arts athletes. The study group included 258 volunteers and 284 controls. The genetic test was performed using the real-time PCR method; psychological tests were performed using standardized TCI questionnaires. All analyses were performed using STATISTICA 13. Results: Interaction between martial arts and DRD2 rs1799732 (manual) G/-(VIC/FAM)-ins/del and RD- Harm avoidance and Reward Dependence scale were demonstrated. In athletes, a lower Reward Dependence scale score was associated with the DRD2 rs1799732 (manual)-/-polymorphism compared to the control group. Conclusions: It seems justified to study not only genetic aspects related to brain transmission dopamine in martial arts athletes. In the studied athletes, the features related to reward addiction and harm avoidance are particularly important in connection with the dopaminergic reward system in the brain.
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Comings, David E. "The Molecular Genetics of Pathological Gambling." CNS Spectrums 3, no. 6 (June 1998): 20–37. http://dx.doi.org/10.1017/s109285290000599x.
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AbstractAs gambling becomes available to more and more individuals in this country, the problem of compulsive or pathological gambling (PG) will also increase. As with other forms of addiction, both environmental and genetic factors are involved in PG. Identification of the genes that play a role in increasing a person's risk for PG will lead to a better understanding of the disorder and to more rational and effective treatment. Although studies of the molecular genetics of PG are just beginning, a number of interesting observations have been made and are reviewed in this article. As with other addictive behaviors, abnormalities in dopaminergic reward pathways a likely to be involved. Consistent with this, we have observed a significant association between PG and the D1, D2, D3, and D4 dopamine receptor genes. The fact that each these genes has an effect is consistent with a polygenic inheritance of a susceptibility to PG The involvement of multiple dopamine genes consistent with the “reward deficiency syndrome,” which suggests that addictive impulsive disorders are due, at least in part, to genetic abnormalities of the dopamine reward pathways. On the basis of this hypothesis, we describe other genes also likely to play a role in a person's susceptibility to PG.
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Huang, Chieh-Liang, Ping-Ho Chen, Hsien-Yuan Lane, Ing-Kang Ho, and Chia-Min Chung. "Risk Assessment for Heroin Use and Craving Score Using Polygenic Risk Score." Journal of Personalized Medicine 11, no. 4 (April 1, 2021): 259. http://dx.doi.org/10.3390/jpm11040259.
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Addiction is characterized by drug-craving, compulsive drug-taking, and relapse, and results from the interaction between multiple genetic and environmental factors. Reward pathways play an important role in mediating drug-seeking and drug-taking behaviors, and relapse. The objective of this study was to identify heroin addicts who carry specific genetic variants in their dopaminergic reward systems. A total of 326 heroin-dependent patients undergoing methadone maintenance therapy (MMT) were recruited from the Addiction Center of the China Medical University Hospital. A heroin-use and craving questionnaire was used to evaluate the urge for heroin, the daily or weekly frequency of heroin usage, daily life disturbance, anxiety, and the ability to overcome heroin use. A general linear regression model was used to assess the associations of genetic polymorphisms in one’s dopaminergic reward system with heroin-use and craving scores. Results: The most significant results were obtained for rs2240158 in GRIN3B (p = 0.021), rs3983721 in GRIN3A (p = 0.00326), rs2129575 in TPH2 (p = 0.033), rs6583954 in CYP2C19 (p = 0.033), and rs174699 in COMT (p = 0.036). These were all associated with heroin-using and craving scores with and without adjustments for age, sex, and body mass index. We combined five variants, and the ensuing dose-response effect indicated that heroin-craving scores increased with the numbers of risk alleles (p for trend = 0.0008). These findings will likely help us to understand the genetic mechanism of craving, which will help in predicting the risk of relapse in clinical practice and the potential for therapies to target craving in heroin addiction.
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Klaus, Andreas, Joaquim Alves da Silva, and Rui M. Costa. "What, If, and When to Move: Basal Ganglia Circuits and Self-Paced Action Initiation." Annual Review of Neuroscience 42, no. 1 (July 8, 2019): 459–83. http://dx.doi.org/10.1146/annurev-neuro-072116-031033.
Full textAbstract:
Deciding what to do and when to move is vital to our survival. Clinical and fundamental studies have identified basal ganglia circuits as critical for this process. The main input nucleus of the basal ganglia, the striatum, receives inputs from frontal, sensory, and motor cortices and interconnected thalamic areas that provide information about potential goals, context, and actions and directly or indirectly modulates basal ganglia outputs. The striatum also receives dopaminergic inputs that can signal reward prediction errors and also behavioral transitions and movement initiation. Here we review studies and models of how direct and indirect pathways can modulate basal ganglia outputs to facilitate movement initiation, and we discuss the role of cortical and dopaminergic inputs to the striatum in determining what to do and if and when to do it. Complex but exciting scenarios emerge that shed new light on how basal ganglia circuits modulate self-paced movement initiation.
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Fisher, Helen E., Arthur Aron, and Lucy L. Brown. "Romantic love: a mammalian brain system for mate choice." Philosophical Transactions of the Royal Society B: Biological Sciences 361, no. 1476 (November 13, 2006): 2173–86. http://dx.doi.org/10.1098/rstb.2006.1938.
Full textAbstract:
Mammals and birds regularly express mate preferences and make mate choices. Data on mate choice among mammals suggest that this behavioural ‘attraction system’ is associated with dopaminergic reward pathways in the brain. It has been proposed that intense romantic love, a human cross-cultural universal, is a developed form of this attraction system. To begin to determine the neural mechanisms associated with romantic attraction in humans, we used functional magnetic resonance imaging (fMRI) to study 17 people who were intensely ‘in love’. Activation specific to the beloved occurred in the brainstem right ventral tegmental area and right postero-dorsal body of the caudate nucleus. These and other results suggest that dopaminergic reward and motivation pathways contribute to aspects of romantic love. We also used fMRI to study 15 men and women who had just been rejected in love. Preliminary analysis showed activity specific to the beloved in related regions of the reward system associated with monetary gambling for uncertain large gains and losses, and in regions of the lateral orbitofrontal cortex associated with theory of mind, obsessive/compulsive behaviours and controlling anger. These data contribute to our view that romantic love is one of the three primary brain systems that evolved in avian and mammalian species to direct reproduction. The sex drive evolved to motivate individuals to seek a range of mating partners; attraction evolved to motivate individuals to prefer and pursue specific partners; and attachment evolved to motivate individuals to remain together long enough to complete species-specific parenting duties. These three behavioural repertoires appear to be based on brain systems that are largely distinct yet interrelated, and they interact in specific ways to orchestrate reproduction, using both hormones and monoamines. Romantic attraction in humans and its antecedent in other mammalian species play a primary role: this neural mechanism motivates individuals to focus their courtship energy on specific others, thereby conserving valuable time and metabolic energy, and facilitating mate choice.
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Speranza, Luisa, Umberto di Porzio, Davide Viggiano, Antonio de Donato, and Floriana Volpicelli. "Dopamine: The Neuromodulator of Long-Term Synaptic Plasticity, Reward and Movement Control." Cells 10, no. 4 (March 26, 2021): 735. http://dx.doi.org/10.3390/cells10040735.
Full textAbstract:
Dopamine (DA) is a key neurotransmitter involved in multiple physiological functions including motor control, modulation of affective and emotional states, reward mechanisms, reinforcement of behavior, and selected higher cognitive functions. Dysfunction in dopaminergic transmission is recognized as a core alteration in several devastating neurological and psychiatric disorders, including Parkinson’s disease (PD), schizophrenia, bipolar disorder, attention deficit hyperactivity disorder (ADHD) and addiction. Here we will discuss the current insights on the role of DA in motor control and reward learning mechanisms and its involvement in the modulation of synaptic dynamics through different pathways. In particular, we will consider the role of DA as neuromodulator of two forms of synaptic plasticity, known as long-term potentiation (LTP) and long-term depression (LTD) in several cortical and subcortical areas. Finally, we will delineate how the effect of DA on dendritic spines places this molecule at the interface between the motor and the cognitive systems. Specifically, we will be focusing on PD, vascular dementia, and schizophrenia.
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Nakanishi, S., T. Hikida, and S. Yawata. "Distinct dopaminergic control of the direct and indirect pathways in reward-based and avoidance learning behaviors." Neuroscience 282 (December 2014): 49–59. http://dx.doi.org/10.1016/j.neuroscience.2014.04.026.
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Christodoulou, Christiana C., Margarita Zachariou, Marios Tomazou, Evangelos Karatzas, Christiana A. Demetriou, Eleni Zamba-Papanicolaou, and George M. Spyrou. "Investigating the Transition of Pre-Symptomatic to Symptomatic Huntington’s Disease Status Based on Omics Data." International Journal of Molecular Sciences 21, no. 19 (October 8, 2020): 7414. http://dx.doi.org/10.3390/ijms21197414.
Full textAbstract:
Huntington’s disease is a rare neurodegenerative disease caused by a cytosine–adenine–guanine (CAG) trinucleotide expansion in the Huntingtin (HTT) gene. Although Huntington’s disease (HD) is well studied, the pathophysiological mechanisms, genes and metabolites involved in HD remain poorly understood. Systems bioinformatics can reveal synergistic relationships among different omics levels and enables the integration of biological data. It allows for the overall understanding of biological mechanisms, pathways, genes and metabolites involved in HD. The purpose of this study was to identify the differentially expressed genes (DEGs), pathways and metabolites as well as observe how these biological terms differ between the pre-symptomatic and symptomatic HD stages. A publicly available dataset from the Gene Expression Omnibus (GEO) was analyzed to obtain the DEGs for each HD stage, and gene co-expression networks were obtained for each HD stage. Network rewiring, highlights the nodes that change most their connectivity with their neighbors and infers their possible implication in the transition between different states. The CACNA1I gene was the mostly highly rewired node among pre-symptomatic and symptomatic HD network. Furthermore, we identified AF198444 to be common between the rewired genes and DEGs of symptomatic HD. CNTN6, DEK, LTN1, MST4, ZFYVE16, CEP135, DCAKD, MAP4K3, NUPL1 and RBM15 between the DEGs of pre-symptomatic and DEGs of symptomatic HD and CACNA1I, DNAJB14, EPS8L3, HSDL2, SNRPD3, SOX12, ACLY, ATF2, BAG5, ERBB4, FOCAD, GRAMD1C, LIN7C, MIR22, MTHFR, NABP1, NRG2, OTC, PRAMEF12, SLC30A10, STAG2 and Y16709 between the rewired genes and DEGs of pre-symptomatic HD. The proteins encoded by these genes are involved in various biological pathways such as phosphatidylinositol-4,5-bisphosphate 3-kinase activity, cAMP response element-binding protein binding, protein tyrosine kinase activity, voltage-gated calcium channel activity, ubiquitin protein ligase activity, adenosine triphosphate (ATP) binding, and protein serine/threonine kinase. Additionally, prominent molecular pathways for each HD stage were then obtained, and metabolites related to each pathway for both disease stages were identified. The transforming growth factor beta (TGF-β) signaling (pre-symptomatic and symptomatic stages of the disease), calcium (Ca2+) signaling (pre-symptomatic), dopaminergic synapse pathway (symptomatic HD patients) and Hippo signaling (pre-symptomatic) pathways were identified. The in silico metabolites we identified include Ca2+, inositol 1,4,5-trisphosphate, sphingosine 1-phosphate, dopamine, homovanillate and L-tyrosine. The genes, pathways and metabolites identified for each HD stage can provide a better understanding of the mechanisms that become altered in each disease stage. Our results can guide the development of therapies that may target the altered genes and metabolites of the perturbed pathways, leading to an improvement in clinical symptoms and hopefully a delay in the age of onset.