New Drugs, Old Targets: Tweaking the Dopamine System to Treat Psychostimulant Use Disorders

2021 ◽  
Vol 61 (1) ◽  
pp. 609-628
Author(s):  
Amy Hauck Newman ◽  
Therese Ku ◽  
Chloe J. Jordan ◽  
Alessandro Bonifazi ◽  
Zheng-Xiong Xi
Keyword(s):  
Negative Reinforcement ◽  
Brain Regions ◽  
New Drugs ◽  
Dopamine System ◽  
Partial Agonists ◽  
Societal Challenges ◽  
Dopaminergic Tone ◽  
Future Drug ◽  
Reinforcing Effects ◽  
Significant Health

The abuse of illicit psychostimulants such as cocaine and methamphetamine continues to pose significant health and societal challenges. Despite considerable efforts to develop medications to treat psychostimulant use disorders, none have proven effective, leaving an underserved patient population and unanswered questions about what mechanism(s) of action should be targeted for developing pharmacotherapies. As both cocaine and methamphetamine rapidly increase dopamine (DA) levels in mesolimbic brain regions, leading to euphoria that in some can lead to addiction, targets in which this increased dopaminergic tone may be mitigated have been explored. Further, understanding and targeting mechanisms underlying relapse are fundamental to the success of discovering medications that reduce the reinforcing effects of the drug of abuse, decrease the negative reinforcement or withdrawal/negative affect that occurs during abstinence, or both. Atypical inhibitors of the DA transporter and partial agonists/antagonists at DA D3 receptors are described as two promising targets for future drug development.

scholarly journals The Chemistry and Pharmacology of Fungal Genus Periconia: A Review

2021 ◽  
Vol 89 (3) ◽  
pp. 34
Author(s):  
Azmi Azhari ◽  
Unang Supratman
Keyword(s):  
Aromatic Compounds ◽  
New Drugs ◽  
Cytotoxic Agents ◽  
Spectroscopic Methods ◽  
Pharmacological Agents ◽  
Inflammatory Agent ◽  
Immunodeficiency Virus ◽  
Future Drug ◽  
Endolichenic Fungi ◽  
Isolated Compound

Periconia is filamentous fungi belonging to the Periconiaceae family, and over the last 50 years, the genus has shown interest in natural product exploration for pharmacological purposes. Therefore, this study aims to analyze the different species of Periconia containing natural products such as terpenoids, polyketides, cytochalasan, macrosphelides, cyclopentenes, aromatic compounds, and carbohydrates carbasugar derivates. The isolated compound of this kind, which was reported in 1969, consisted of polyketide derivatives and their structures and was determined by chemical reaction and spectroscopic methods. After some years, 77 compounds isolated from endophytic fungus Periconia were associated with eight plant species, 28 compounds from sea hare Aplysia kurodai, and ten from endolichenic fungi Parmelia sp. The potent pharmacological agents from this genus are periconicin A, which acts as an antimicrobial, pericochlorosin B as an anti-human immunodeficiency virus (HIV), peribysin D, and pericosine A as cytotoxic agents, and periconianone A as an anti-inflammatory agent. Furthermore, information about taxol and piperine from Periconia producing species was also provided. Therefore, this study supports discovering new drugs produced by the Periconia species and compares them for future drug development.

scholarly journals Synaptic plasticity in the mesolimbic dopamine system

2003 ◽  
Vol 358 (1432) ◽  
pp. 815-819 ◽  
Author(s):  
Mark J. Thomas ◽  
Robert C. Malenka
Keyword(s):  
Synaptic Plasticity ◽  
Drugs Of Abuse ◽  
Neural Circuit ◽  
Long Term Potentiation ◽  
Brain Regions ◽  
Mesolimbic Dopamine ◽  
Dopamine System ◽  
Mesolimbic Dopamine System

Long-term potentiation (LTP) and long-term depression (LTD) are thought to be critical mechanisms that contribute to the neural circuit modifications that mediate all forms of experience-dependent plasticity. It has, however, been difficult to demonstrate directly that experience causes long-lasting changes in synaptic strength and that these mediate changes in behaviour. To address these potential functional roles of LTP and LTD, we have taken advantage of the powerful in vivo effects of drugs of abuse that exert their behavioural effects in large part by acting in the nucleus accumbens (NAc) and ventral tegmental area (VTA); the two major components of the mesolimbic dopamine system. Our studies suggest that in vivo drugs of abuse such as cocaine cause long-lasting changes at excitatory synapses in the NAc and VTA owing to activation of the mechanisms that underlie LTP and LTD in these structures. Thus, administration of drugs of abuse provides a distinctive model for further investigating the mechanisms and functions of synaptic plasticity in brain regions that play important roles in the control of motivated behaviour, and one with considerable practical implications.

scholarly journals Plant-Derived Chemicals: A Source of Inspiration for New Drugs

Plants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1562
Author(s):  
Veronique Seidel
Keyword(s):  
Biologically Active ◽  
New Drugs ◽  
Plant Biodiversity ◽  
Ethnobotanical Knowledge ◽  
Special Issue ◽  
Traditional Remedies ◽  
Future Drug ◽  
History Of ◽  
History Of Use ◽  
Plant Sources

Plants have a long history of use as traditional remedies to treat a range of diseases and the diverse chemicals that they produce have provided great inspiration for the design of new drugs to date. Many plants have yet to be investigated for the presence of biologically-active products. This Special Issue presents a collection of scientific studies which report on the medicinal potential of plants. It also highlights the importance of preserving ethnobotanical knowledge and plant biodiversity worldwide to sustain future drug discovery from plant sources.

scholarly journals The Melanocortin System in Control of Inflammation

2010 ◽  
Vol 10 ◽  
pp. 1840-1853 ◽  
Author(s):  
Anna Catania ◽  
Caterina Lonati ◽  
Andrea Sordi ◽  
Andrea Carlin ◽  
Patrizia Leonardi ◽  
...  
Keyword(s):  
Receptor Activation ◽  
Brain Regions ◽  
New Drugs ◽  
Melanocortin Receptor ◽  
Receptor Subtypes ◽  
Melanocortin System ◽  
Inflammatory Disorders ◽  
Melanocyte Stimulating Hormone ◽  
Common Precursor ◽  
Anti Inflammatory

Melanocortin peptides, the collective term for α-, β-, and γ-melanocyte-stimulating hormone (α-, β-, γ-MSH) and adrenocorticotropic hormone (ACTH), are elements of an ancient modulatory system. Natural melanocortins derive from the common precursor pro-opiomelanocortin (POMC). Five receptor subtypes for melanocortins (MC1-MC5) are widely distributed in brain regions and in peripheral cells. Melanocortin receptor activation by natural or synthetic ligands exerts marked anti-inflammatory and immunomodulatory effects. The anticytokine action and the inhibitory influences on inflammatory cell migration make melanocortins potential new drugs for treatment of inflammatory disorders. Effectiveness in treatment of acute, chronic, and systemic inflammatory disorders is well documented in preclinical studies. Further, melanocortins are promising compounds in neuroprotection. This review examines the main signaling circuits in anti-inflammatory and immunomodulatory actions of melanocortins, and the potential therapeutic use of these molecules.

Impact of Pcbs On Thyroid Hormone Directed Brain Development

1998 ◽  
Vol 14 (1-2) ◽  
pp. 103-120 ◽  
Author(s):  
Susan P. Porterfield ◽  
Lawrence B. Hendry
Keyword(s):  
Thyroid Hormones ◽  
Brain Development ◽  
Brain Regions ◽  
Environmental Toxicants ◽  
Synaptic Development ◽  
Structural Resemblance ◽  
Partial Agonists ◽  
Process Outgrowth ◽  
Neuronal Proliferation ◽  
The Brain

Thyroid hormones regulate neuronal proliferation, migration, process outgrowth, synaptic development, and myelin formation in specific brain regions. Because brain development occurs during discrete windows of time, inappropriate levels of thyroid hormones in definitive periods can produce permanent damage, the nature of which depends upon the timing and magnitude of the insult. Thyroid hormones cross the placenta and enter the brain primarily as thyroxine (T4); therefore, conditions selectively lowering serum T4 levels alter brain hormone availability. Triiodothyronine (T3) is the predominant form of the hormone that binds to the receptor. T3 is produced from T4 in the brain by the enzyme type II, 5'-deiodinase. Polychlorinated biphenyls (PCBs) are synthetic environmental toxicants that bear a striking structural resemblance to the active thyroid hormones and can, depending upon the species, dosage, and congener used, act as agonists, antagonists, and partial agonists to thyroid hormones.

scholarly journals PROGNOSTIC BIOMARKERS IN TRIPLE NEGATIVE BREAST CANCER AS A POTENTIAL TARGET FOR FUTURE DRUG DISCOVERY

2017 ◽  
Vol 10 (6) ◽  
pp. 24
Author(s):  
Mekhla Gupta ◽  
Sanjeev Kumar Gupta ◽  
Rajesh Kumar Singh ◽  
Seema Khanna
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Poor Prognosis ◽  
Triple Negative ◽  
Treatment Options ◽  
New Drugs ◽  
Cancerous Cell ◽  
Cause Of Deaths ◽  
Future Drug ◽  
Common Malignancy

Breast cancer is the most common malignancy in women globally, in which triple-negative breast cancer (TNBC) is more aggressive with poor prognosis and very less response to targeted hormone based treatment. It is a major cause of deaths among the women with breast cancer because of very few treatment options. The biomarkers could be a product of cancerous cell or molecule generated in response to cancer. It is used to understand the mechanism, prognosis, diagnosis as well as target for design and discovery of new drugs. The purpose of the study is to give a brief review onmarkers of TNBC.

scholarly journals Modulation of the Serotonergic Receptosome in the Treatment of Anxiety and Depression: A Narrative Review of the Experimental Evidence

2021 ◽  
Vol 14 (2) ◽  
pp. 148
Author(s):  
Gustavo R. Villas-Boas ◽  
Stefânia N. Lavorato ◽  
Marina M. Paes ◽  
Pablinny M. G. de Carvalho ◽  
Vanessa C. Rescia ◽  
...  
Keyword(s):  
Experimental Evidence ◽  
Rational Design ◽  
Brain Regions ◽  
G Protein Coupled Receptors ◽  
New Drugs ◽  
Anxiety And Depression ◽  
Pharmacological Mechanism ◽  
Art Research ◽  
G Protein Coupled ◽  
The Brain

Serotonin (5-HT) receptors are found throughout central and peripheral nervous systems, mainly in brain regions involved in the neurobiology of anxiety and depression. 5-HT receptors are currently promising targets for discovering new drugs for treating disorders ranging from migraine to neuropsychiatric upsets, such as anxiety and depression. It is well described in the current literature that the brain expresses seven types of 5-HT receptors comprising eighteen distinct subtypes. In this article, we comprehensively reviewed 5-HT1-7 receptors. Of the eighteen 5-HT receptors known today, thirteen are G protein-coupled receptors (GPCRs) and represent targets for approximately 40% of drugs used in humans. Signaling pathways related to these receptors play a crucial role in neurodevelopment and can be modulated to develop effective therapies to treat anxiety and depression. This review presents the experimental evidence of the modulation of the “serotonergic receptosome” in the treatment of anxiety and depression, as well as demonstrating state-of-the-art research related to phytochemicals and these disorders. In addition, detailed aspects of the pharmacological mechanism of action of all currently known 5-HT receptor families were reviewed. From this review, it will be possible to direct the rational design of drugs towards new therapies that involve signaling via 5-HT receptors.

scholarly journals Central amygdala circuits modulate food consumption through a positive valence mechanism

2017 ◽  
Author(s):  
Amelia M. Douglass ◽  
Hakan Kucukdereli ◽  
Marion Ponserre ◽  
Milica Markovic ◽  
Jan Gründemann ◽  
...  
Keyword(s):  
Food Consumption ◽  
Positive Reinforcement ◽  
Serotonin Receptor ◽  
Brain Regions ◽  
Central Nucleus ◽  
Dopamine System ◽  
Mesolimbic Dopamine System ◽  
Neuronal Mechanisms ◽  
Positive Valence

SummaryThe complex behaviors underlying the pursuit and consumption of rewards are integral to an organism’s survival. The hypothalamus and mesolimbic dopamine system are key mediators of these behaviors, yet regulation of appetitive and consummatory behaviors outside of these regions is not well understood. The central nucleus of the amygdala (CeA) is implicated in feeding and reward behavior, but the specific neural players and circuit mechanisms that positively regulate these behaviors remain unclear. Here, we define the neuronal mechanisms by which the CeA promotes consumption of food. We show, using in vivo activity manipulations and Ca2+ imaging, that CeA GABAergic neurons expressing the serotonin receptor 2a (Htr2a) modulate food consumption in multiple contexts, promote positive reinforcement and are active in vivo during eating. We demonstrate using electrophysiology, anatomical tracing methods and in vivo optogenetics that both intra-CeA and long-range circuit mechanisms underlie these functional effects. Finally, we show that CeAHtr2a neurons are poised to regulate food consumption through inputs from feeding-relevant brain regions. Our study highlights a mechanism by which defined CeA neural circuits positively regulate food consumption.

scholarly journals Control of non-homeostatic feeding in sated mice using associative learning of contextual food cues

2018 ◽  
Author(s):  
Sarah A. Stern ◽  
Katherine R. Doerig ◽  
Estefania P. Azevedo ◽  
Elina Stoffel ◽  
Jeffrey M. Friedman
Keyword(s):  
Food Consumption ◽  
Food Availability ◽  
Molecular Mechanisms ◽  
Negative Reinforcement ◽  
Sensory Information ◽  
Insular Cortex ◽  
Brain Regions ◽  
Appetitive Conditioning ◽  
Functional Neuroanatomy ◽  
Intensive Training

ABSTRACTFeeding is a complex motivated behavior controlled by a distributed neural network that processes sensory information to generate adaptive behavioral responses. Accordingly, studies using appetitive Pavlovian conditioning confirm that environmental cues that are associated with food availability can induce feeding even in satiated subjects. However, in mice, appetitive conditioning generally requires intensive training and thus can impede molecular studies that often require large numbers of animals. To address this, we developed and validated a simple and rapid context-induced feeding (ctx-IF) task in which cues associated with food availability can later lead to increased food consumption in sated mice. We show that the associated increase in food consumption is driven by both positive and negative reinforcement and that spaced training is more effective than massed training. Ctx-IF can be completed in ∼1 week and provides an opportunity to study the molecular mechanisms and circuitry underlying non-homeostatic eating. We have used this paradigm to map brain regions that are activated during Ctx-IF with cFos immunohistochemistry and found that the insular cortex, and other regions, are activated following exposure to cues denoting the availability of food. Finally, we show that inhibition of the insular cortex using GABA agonists impairs performance of the task. Our findings provide a novel assay in mice for defining the functional neuroanatomy of appetitive conditioning and identify specific brain regions that are activated during the development of learned behaviors that impact food consumption.

scholarly journals Medication overuse headache associated with decreased dopamine transporter availability in the left orbitofrontal cortex: A 11CFT PET/MR study

2021 ◽  
Author(s):  
Huanxian Liu ◽  
Jiajin Liu ◽  
Shuping Sun ◽  
Wei Dai ◽  
Binbin Nie ◽  
...  
Keyword(s):  
Dopamine Transporter ◽  
Orbitofrontal Cortex ◽  
Medication Overuse ◽  
Medication Overuse Headache ◽  
Standardized Uptake Value ◽  
Brain Regions ◽  
Seed Region ◽  
Dopamine System ◽  
Mesocorticolimbic Dopamine System ◽  
Clinical Measures

Abstract BackgroundsThe dysfunction of dopamine in the mesocorticolimbic dopamine system in MOH is unknown. Dopamine transporter (DAT) regulates dopamine clearance and neurotransmission and is sensitive to dopamine levels. A decrease in DAT availability can reflect a decrease in dopamine. To determine DAT availability abnormalities in the mesocorticolimbic dopamine system and explore functional network changes in medication overuse headache (MOH) patients.MethodsWe examined 17 MOH patients and 16 healthy controls (HCs) using integrated positron emission tomography (PET)/magnetic resonance (MR) brain scans with 11CFT, a radioligand that binds to DAT. Standardized uptake value ratio (SUVr) images were compared voxelwise between MOH patients and HCs. Then, the significantly changed cluster (p < 0.01, GRF correction) with abnormal DAT availability was selected as a specific seed region to further evaluate altered functional connectivity (FC) in MOH. SUVr and mean FC values from significantly changed regions were extracted, and partial correlation analyses with clinical measures were conducted.ResultsMOH patients had lower SUVr levels in the left rather than right orbitofrontal cortex (OFC) than HCs. There was altered FC between the left OFC and the left superior temporal pole and bilateral calcarine gyri. SUVr levels in the left OFC and the connectivity strength linking the positive brain regions with the left OFC were not correlated with clinical measures in the MOH patients.ConclusionsMOH is characterized by decreased DAT availability in the left OFC, which might reflect compensatory downregulation due to low dopamine signalling within the mesocorticolimbic dopamine system. In addition, the OFC on both sides may have different functions in the pathogenesis of MOH. Altered intrinsic FC in the left OFC was identified in MOH patients, which may provide a new perspective to understand the pathogenesis of MOH.

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