Brain Reward Circuits Research Articles

Opioid-Induced Neuroplasticity: Insights from Animal Models

Synaptic plasticity is defined as the modification of the transmission of synapses. It has been proven to be strongly associated with learning. Thus, drug-evoked synaptic plasticity in brain reward circuits can establish persistent learning of addictive drugs, reflecting the neural basis underlying addiction. The mesolimbic dopamine pathway has been widely indicated to be strongly associated with opioid use disorder (OUD) and other drug addictions. The paper focuses on discussing the drug-evoked neural plasticity underlying two important stages called intoxication and withdrawal which are critical for addiction and reinstatement of drug use respectively. The paper first explores the neural basis of OUD, emphasizing drug-induced plasticity at glutamate and Gamma-aminobutyric acid (GABA) synapses on neurons of key substrates in the pathway and how they influence mesolimbic dopamine (DA) neuron transmission. Then, the review discussed withdrawal-induced neuroplasticity and reorganization of associated neuron circuits, which explain deficits led by withdrawal from opioid administration. An overall understanding of drug-evoked synaptic plasticity in key brain circuits in the development of addiction helps find possible therapeutic methods to prevent the initiation of OUD and reinstatement.

Rasd2 regulates depression-like behaviors via DRD2 neurons in the prelimbic cortex afferent to nucleus accumbens core circuit.

Depressive symptoms, such as anhedonia, decreased social interaction, and lack of motivation, implicate brain reward systems in the pathophysiology of depression. Exposure to chronic stress impairs the function of brain reward circuits and is well-known to be involved in the etiology of depression. A transcriptomic analysis found that stress alters the expression of Rasd2 in mice prefrontal cortex (PFC). Similarly, in our previous study, acute fasting decreased Rasd2 expression in mice PFC, and RASD2 modulated dopamine D2 receptor (DRD2)-mediated antidepressant-like effects in ovariectomized mice. This research suggests the role of RASD2 in stress-induced depression and its underlying neural mechanisms that require further investigation. Here, we show that 5-day unpredictable mild stress (5-d UMS) exposure reduces RASD2 expression in both the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) of mice, while overexpression (but not knock-down) of Rasd2 in the NAc core (NAcc) alleviates 5-d UMS-induced depression-like behaviors and activates the DRD2-cAMP-PKA-DARPP-32 signaling pathway. Further studies investigated neuronal projections between the mPFC (Cg1, PrL, and IL) and NAcc, labeled by the retrograde tracer Fluorogold. Depression-like behaviors induced by 5-d UMS were only related to inhibition of the PrL-NAcc circuit. DREADD (Designer receptors exclusively activated by designer drug) analysis found that the activation of PrL-NAcc glutaminergic projection alleviated depression-like behaviors and increased DRD2- and RASD2-positive neurons in the NAcc. Using Drd2-cre transgenic mice, we constructed mice with Rasd2 overexpression in DRD2PrL-NAcc neurons, finding that Rasd2 overexpression ameliorated 5-d UMS-induced depression-like behaviors. These findings demonstrate a critical role for RASD2 modulation of DRD2PrL-NAcc neurons in 5-d UMS-induced depression-like behaviors. In addition, the study identifies a new potential strategy for precision medical treatment of depression.

Clavulanic acid inhibits methamphetamine locomotor sensitization in mice and normalizes methamphetamine-induced changes in glutaminase mRNA levels in the nucleus accumbens

Clavulanic acid (CLAV) is a component of Augmentin® that preserves antibiotic efficacy by inhibiting β-lactamase activity. It also enhances cellular glutamate uptake and is a potential CNS therapeutic. Because increased glutamate transmission in brain reward circuits facilitates methamphetamine (METH) locomotor activation and sensitization, we tested the hypothesis that CLAV inhibits acute and sensitized locomotor responses to METH in mice and investigated effects of CLAV on METH-induced changes in glutaminase, the major glutamate-producing enzyme in the brain. Acute METH (3 mg/kg) produced hyperlocomotion that was reduced by CLAV (20 mg/kg but not 10 mg/kg). Mice injected with METH (3 mg/kg) every other day for 9 d and then challenged with METH 27 d later displayed locomotor sensitization. CLAV (10 mg/kg), when injected 15 min before each METH injection during the 9-d exposure interval, blocked locomotor sensitization induced by METH challenge. In METH-sensitized mice, mRNA levels of both isoforms of glutaminase (GLS and GLS2) were altered in the nucleus accumbens compared to mice exposed to a single injection of METH (i.e., GLS decreased and GLS2 increased). CLAV normalized the METH-induced GLS deficit but not the increase in GLS2. In summary, CLAV reduced acute and sensitized locomotor responses to METH and normalized the METH-induced reduction of GLS gene expression in the NAC. Given that glutaminases belong to the β-lactamase superfamily and CLAV is a β-lactamase inhibitor, our data point toward studying glutaminase as a therapeutic target of CLAV.

Brain gray matter volume of reward-related structures in Inuit adolescents pre- and postnatally exposed to lead, mercury and polychlorinated biphenyls

This study aimed to assess associations between prenatal and postnatal exposure to lead (Pb), mercury (Hg) and polychlorinated biphenyls (PCBs) and gray matter volume of key regions of the brain reward circuit, namely the caudate nucleus, putamen, nucleus accumbens (nAcc), the amygdala, the orbitofrontal cortex (OFC) and the anterior cingulate cortex (ACC). Structural magnetic resonance imaging (MRI) was conducted in 77 Inuit adolescents (mean age = 18.39) from Nunavik, Canada, who also completed the Brief Sensation Seeking Scale (BSSS-4) and Sensation Seeking – 2 (SS-2), two self-report questionnaires evaluating the tendency toward sensation seeking, which is a proxy of reward-related behaviors. Exposures to Pb, Hg and PCBs were measured in cord blood at birth, in blood samples at 11 years old and at time of testing (18 years old). Multivariate linear regressions were corrected for multiple comparisons and adjusted for potential confounders, such as participants’ sociodemographic characteristics and nutrient fish intake. Results showed that higher cord blood Pb levels predicted smaller gray matter volume in the bilateral nAcc, caudate nucleus, amygdala and OFC as well as in left ACC. A moderating effect of sex was identified, indicating that the Pb-related reduction in volume in the nAcc and caudate nucleus was more pronounced in female. Higher blood Hg levels at age 11 predicted smaller right amygdala independently of sex. No significant associations were found between blood PCBs levels at all three times of exposure. This study provides scientific support for the detrimental effects of prenatal Pb and childhood Hg blood concentrations on gray matter volume in key reward-related brain structures.

Transcriptional signatures of fentanyl use in the mouse ventral tegmental area.

Synthetic opioids such as fentanyl contribute to the vast majority of opioid-related overdose deaths, but fentanyl use remains broadly understudied. Like other substances with misuse potential, opioids cause lasting molecular adaptations to brain reward circuits, including neurons in the ventral tegmental area (VTA). The VTA contains numerous cell types that play diverse roles in opioid use and relapse; however, it is unknown how fentanyl experience alters the transcriptional landscape in specific subtypes. Here, we performed single nuclei RNA sequencing to study transcriptional programs in fentanyl-experienced mice. Male and female C57/BL6 mice self-administered intravenous fentanyl (1.5μg/kg/infusion) or saline for 10days. After 24 h abstinence, VTA nuclei were isolated and prepared for sequencing on the 10× platform. We identified different patterns of gene expression across cell types. In dopamine neurons, we found enrichment of genes involved in growth hormone signalling. In dopamine-glutamate-GABA combinatorial neurons, and some GABA neurons, we found enrichment of genes involved in Pi3k-Akt signalling. In glutamate neurons, we found enrichment of genes involved in cholinergic signalling. We identified transcriptional regulators for the differentially expressed genes in each neuron cluster, including downregulated transcriptional repressor Bcl6, and upregulated transcription factor Tcf4. We also compared the fentanyl-induced gene expression changes identified in mouse VTA with a published rat dataset in bulk VTA, and found overlap in genes related to GABAergic signalling and extracellular matrix interaction. Together, we provide a comprehensive picture of how fentanyl self-administration alters the transcriptional landscape of the mouse VTA that serves as the foundation for future mechanistic studies.

The rostromedial tegmental nucleus gates fat overconsumption through ventral tegmental area output in male rats.

Excessive consumption of palatable foods that are rich in fats and sugars has contributed to the increasing prevalence of obesity worldwide. Similar to addictive drugs, such foods activate the brain's reward circuit, involving mesolimbic dopaminergic projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) and the prefrontal cortex. Neuroadaptations occurring in this circuitare hypothesized to contribute to uncontrolled consumption of such foods, a common feature of most of eating disorders and obesity. The rostromedial tegmental nucleus (RMTg), also named tail of the VTA (tVTA), is an inhibitory structure projecting to the VTA and the lateral hypothalamus (LH), two key brain regions in food intake regulation. Prior research has demonstrated that the RMTg responds to addictive drugs and influences their impact on mesolimbic activity and reward-related behaviors. However, the role of the RMTg in food intake regulation remains largely unexplored. The present study aimed to investigate the role of the RMTg and its projections to the VTA and the LH in regulating food intake in rats. To do so, we examined eating patterns of rats with either bilateral excitotoxic lesions of the RMTg or specific lesions of RMTg-VTA and RMTg-LH pathways. Rats were exposed to a 6-week 'free choice high-fat and high-sugar' diet, followed by a 4-week palatable food forced abstinence and a 24 h re-access period. Our results indicate that an RMTg-VTA pathway lesion increases fat consumption following 6 weeks of diet and at time of re-access. The RMTg-LH pathway lesion produces a milder effect with a decrease in global calorie intake. These findings suggest that the RMTg influences palatable food consumption and relapse through its projections to the VTA.

Non-invasive suppression of the human nucleus accumbens (NAc) with transcranial focused ultrasound (tFUS) modulates the reward network: a pilot study.

The nucleus accumbens (NAc) is a key node of the brain reward circuit driving reward-related behavior. Dysregulation of NAc has been demonstrated to contribute to pathological markers of addiction in substance use disorder (SUD) making it a potential therapeutic target for brain stimulation. Transcranial focused ultrasound (tFUS) is an emerging non-invasive brain stimulation approach that can modulate deep brain regions with a high spatial resolution. However, there is currently no evidence showing how the brain activity of NAc and brain functional connectivity within the reward network neuromodulated by tFUS on the NAc. In this pilot study, we carried out a single-blind, sham-controlled clinical trial using functional magnetic resonance imaging (fMRI) to investigate the underlying mechanism of tFUS neuromodulating the reward network through NAc in ten healthy adults. Specifically, the experiment consists of a 20-min concurrent tFUS/fMRI scan and two 24-min resting-state fMRI before and after the tFUS session. Firstly, our results demonstrated the feasibility and safety of 20-min tFUS on NAc. Additionally, our findings demonstrated that bilateral NAc was inhibited during tFUS on the left NAc compared to sham. Lastly, increased functional connectivity between the NAc and medial prefrontal cortex (mPFC) was observed after tFUS on the left NAc, but no changes for the sham group. Delivering tFUS to the NAc can modulate brain activations and functional connectivity within the reward network. These preliminary findings suggest that tFUS could be potentially a promising neuromodulation tool for the direct and non-invasive management of the NAc and shed new light on the treatment for SUD and other brain diseases that involve reward processing.

Morphological study of neuropeptide Y expression in human and mouse anterior insular cortex: Overexpression in the insular cortex and nucleus accumbens in obese mice on a long-term obesogenic diet

BackgroundThe anterior lobe of the insular cortex (aINS) is a cortical region that has reciprocal connections with limbic centers such as the anterior cingulate cortex, prefrontal cortex, amygdala and nucleus accumbens (NAc). In fact, the aINS has been involved in the integration of autonomic information for emotional and motivational functions. The compulsive consumption of drugs or high-fat foods induces alterations at both behavioural and brain levels. Brain reward circuits are altered in response to continued intake, in particular the dopaminergic projections from the ventral tegmental area (VTA) to the NAc. The aINS has multiple connections with the components of this system. In recent years, efforts have been made to better understand the fundamental role of the aINS in addiction, making it one of the key centres of interest for research into new treatments for addiction. ObjectivesThe present work focuses on studying 1.- whether the human aINS expresses orexigenic peptides such as neuropeptide Y (NPY), a peptide known to induce hyperphagia, and which has been implicated in the onset and development of obesity, 2.- the long-term effect of an obesogenic diet on NPY expression in the aINS and NAc of C57BL/6 mice. MethodsA total of 17 female C57BL/6 J mice were used in this study. Female mice were fed ad libitum with water and, either a standard diet (SD) or a high-fat diet (HFD) to induce obesity. There were seven female mice on the SD and ten on the HFD. The duration of the experiment was 180 days. We also studied 3 human adult brains (1 male and 2 females, mean age 55.7 ± 5.2 years). The morphological study was performed using immunohistochemistry and double immunofluorescence techniques to study the neurochemical profile of NPY neurons of the aINS and NAc of humans and mice. ResultsOur morphological analysis demonstrates for the first time the basal expression of NPY in different layers of the human cortex (II, III, IV, V/VI), in a pattern similar to previous studies in other species. Furthermore, we observed an increase in the number of NPY-positive cells and their intracytoplasmic signal in the aINS and NAc of the obese mice subjected to a long-term obesogenic diet. ConclusionsTo our knowledge, this is the first study to show the distribution and expression of NPY in the human INS and how its expression is altered after prolonged treatment with an obesogenic diet in obese mice. Our findings may contribute to the understanding of the pathophysiological mechanisms underlying obesity in regions related to the reward system and associated with uncontrolled intake of high-fat foods, thus facilitating the identification of novel therapeutic targets.

The Role of the Endocannabinoid System in Binge Eating Disorder.

Eating disorders are multifactorial disorders that involve maladaptive feeding behaviors. Binge eating disorder (BED), the most prevalent of these in both men and women, is characterized by recurrent episodes of eating large amounts of food in a short period of time, with a subjective loss of control over eating behavior. BED modulates the brain reward circuit in humans and animal models, which involves the dynamic regulation of the dopamine circuitry. The endocannabinoid system plays a major role in the regulation of food intake, both centrally and in the periphery. Pharmacological approaches together with research using genetically modified animals have strongly highlighted a predominant role of the endocannabinoid system in feeding behaviors, with the specific modulation of addictive-like eating behaviors. The purpose of the present review is to summarize our current knowledge on the neurobiology of BED in humans and animal models and to highlight the specific role of the endocannabinoid system in the development and maintenance of BED. A proposed model for a better understanding of the underlying mechanisms involving the endocannabinoid system is discussed. Future research will be necessary to develop more specific treatment strategies to reduce BED symptoms.

Brain Reward Circuits Promote Stress Resilience and Health: Implications for Reward-Based Interventions

From the COVID-19 global pandemic to racial injustice and the continued impact of climate change on communities across the globe, the past couple of years have demonstrated the need for a greater understanding of how to protect people from the negative consequences of stress. Here, I outline a perspective on how the brain’s reward system might be an important, but often understudied, protective mechanism for stress resilience and stress-related health outcomes. I describe work suggesting that engagement of the reward system inhibits the stress response and is associated with improved health outcomes, including reduced depressive symptomatology and slowed cancer progression. I then highlight important future directions for translational research and illustrate the value of this perspective for improving behavioral interventions in clinical psychology and beyond.

Multidimensional Pain Modulation by Acupuncture Analgesia: The Reward Effect of Acupuncture on Pain Relief.

Pain is an intrinsically unpleasant experience with features that protect an organism by promoting motivation and learning. Pain relief, a negative reinforcement of pain, is considered a reward and activates the brain's reward system. The reward circuit in the brain involves reward and pain. Acupuncture has a multidimensional and comprehensive regulating effect on chronic pain. However, the reward effect of acupuncture in relieving chronic pain and the mechanism of the brain reward circuit involved in acupuncture analgesia are not thoroughly studied. In this article, we have reviewed the definition of pain abnormalities and negative emotions in patients with chronic pain, the conceptual characteristics of analgesic reward, and the new progress in studying brain reward circuits and functions. Moreover, we have expounded on the critical clinical and scientific significance of studying the reward effect of acupuncture analgesia and related brain reward circuits, the pain mechanism obtained from human neuroimaging studies, and the survey results on the effects of acupuncture on reward/motivation circuits. Some viewpoints and suggestions on the reward effect of acupuncture analgesia and related reward circuits have been put forward to clarify the multidimensional characteristics and benign regulation of acupuncture analgesia. Studies on the reward effect of acupuncture in relieving chronic pain and the regulating effect of the brain reward loop on acupuncture analgesia help to deepen the clinical understanding of acupuncture analgesia, innovate the research concept of acupuncture analgesia, and provide help for further studies on the central mechanism of acupuncture in improving chronic pain in the future.

Acupuncture attenuates comorbid anxiety- and depressive-like behaviors of atopic dermatitis through modulating neuroadaptation in the brain reward circuit in mice

Atopic dermatitis (AD) is highly comorbid with negative emotions such as anxiety and depression. Although acupuncture has demonstrated efficacy in AD, its influence on comorbid anxiety and depression remains unclear. We sought to explore the impact and mechanisms of action of acupuncture on comorbid anxiety and depression of AD. AD-like skin lesions were induced by the topical application of MC903 to the mouse cheek. Acupuncture was performed at Gok-Ji (LI11) acupoints. AD-like phenotypes were quantified by lesion scores, scratching behavior, and histopathological changes. The effects of acupuncture on comorbid anxiety and depression-like behaviors were assessed using the elevated plus-maze (EPM), open-field tests (OFT), and tail-suspension test (TST). In addition, biochemical changes in the brain reward regions were investigated by immunoblotting for the expression of tyrosine hydroxylase (TH), dopamine D1 receptor (D1R), phospho-dopamine and cAMP-regulated phosphoprotein-32 kDa (pDARPP-32), phospho-cAMP response element binding protein (pCREB), ΔFosB, and brain-derived neurotrophic factor (BDNF) in the nucleus accumbens, dorsolateral striatum, and ventral tegmental area. Acupuncture effectively improved the chronic itching and robust AD-like skin lesions with epidermal thickening. Additionally, it considerably reduced comorbid anxiety- and depression-like symptoms, as indicated by more time spent in the open arms of the EPM and in the center of the open field and less time spent immobile in the TST. Higher pCREB, ΔFosB, BDNF, and pDARPP-32 levels, and reduced TH and D1R protein expression in the brain reward regions of AD mice were reversed by acupuncture treatment. The beneficial effects of acupuncture on clinical symptoms (scratching behavior) and comorbid psychological distress in AD strongly correlated with dorsal striatal ΔFosB levels. Collectively, these data indicate that acupuncture had a significant, positive impact on comorbid anxiety- and depression-like behaviors by modulating neuroadaptation in the brain reward circuit in mice with AD, providing a novel perspective for the non-pharmacological management of psychiatric comorbidities of AD.

A Novel CaMKII Inhibitory Peptide Blocks Relapse to Morphine Seeking by Influencing Synaptic Plasticity in the Nucleus Accumbens Shell.

Drugs of abuse cause enduring functional disorders in the brain reward circuits, leading to cravings and compulsive behavior. Although people may rehabilitate by detoxification, there is a high risk of relapse. Therefore, it is crucial to illuminate the mechanisms of relapse and explore the therapeutic strategies for prevention. In this research, by using an animal model of morphine self-administration in rats and a whole-cell patch–clamp in brain slices, we found changes in synaptic plasticity in the nucleus accumbens (NAc) shell were involved in the relapse to morphine-seeking behavior. Compared to the controls, the amplitude of long-term depression (LTD) induced in the medium spiny neurons increased after morphine self-administration was established, recovered after the behavior was extinguished, and increased again during the relapse induced by morphine priming. Intravenous injection of MA, a new peptide obtained by modifying Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor “myr-AIP”, decreased CaMKII activity in the NAc shell and blocked the reinstatement of morphine-seeking behavior without influence on the locomotor activity. Moreover, LTD was absent in the NAc shell of the MA-pretreated rats, whereas it was robust in the saline controls in which morphine-seeking behavior was reinstated. These results indicate that CaMKII regulates morphine-seeking behavior through its involvement in the change of synaptic plasticity in the NAc shell during the relapse, and MA may be of great value in the clinical treatment of relapse to opioid seeking.

Mepirapim, a Novel Synthetic Cannabinoid, Induces Addiction-Related Behaviors through Neurochemical Maladaptation in the Brain of Rodents.

Mepirapim is a synthetic cannabinoid that has recently been abused for recreational purposes. Although serious side effects have been reported from users, the dangerous pharmacological effects of Mepirapim have not been scientifically demonstrated. In this study, we investigated the addictive potential of Mepirapim through an intravenous self-administration test and a conditioned place preference test in rodents. Moreover, to determine whether the pharmacological effects of Mepirapim are mediated by cannabinoid receptors, we investigated whether Mepirapim treatment induces cannabinoid tetrad symptoms in mice. Lastly, to identify Mepirapim induced neurochemical maladaptation in the brains of mice, we performed microdialysis, western blots and neurotransmitter enzyme-linked immunosorbent assays. In the results, Mepirapim supported the maintenance of intravenous self-administration and the development of conditioned place preference. As a molecular mechanism of Mepirapim addiction, we identified a decrease in GABAeric signalling and an increase in dopaminergic signalling in the brain reward circuit. Finally, by confirming the Mepirapim-induced expression of cannabinoid tetrad symptoms, we confirmed that Mepirapim acts pharmacologically through cannabinoid receptor one. Taken together, we found that Mepirapim induces addiction-related behaviours through neurochemical maladaptation in the brain. On the basis of these findings, we propose the strict regulation of recreational abuse of Mepirapim.

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.

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.

Evidence of Intact Corticostriatal and Altered Subcortical-striatal Resting-state Functional Connectivity in Chronic Pain

Highly relevant to both pain and reward, corticostriatal circuits are important for understanding chronic pain. Previous research has demonstrated importance of the nucleus accumbens (NAcc) - medial prefrontal cortex (MPFC) circuit in predicting localized pain chronification in chronic back pain (CBP). The aims of our study were to extend prior evidence of brain reward/value circuit alterations to new cohorts of chronic pain patients and further evaluate activity within reward/value networks in chronic pain. As outlined in our pre-registered plan on the Open Science Framework (OSF, https://osf.io/cj9u8), we hypothesized that resting-state brain reward circuits (i.e., fMRI-indicated NAcc-MPFC resting-state functional connectivity [rsFC] measurements) are altered in patients with fibromyalgia (FM). In a first study, we examined corticostriatal rsFC strength of the NAcc-MPFC circuit in patients with FM (N=17) compared to healthy controls (HC, N=17). Robust NAcc-MPFC functional connectivity was found among patients with FM and HCs, but no significant group differences were observed, indicating intact NAcc-MPFC rsFC in FM. Because previous resting-state studies in patients with CBP involved a pain-monitoring/rating task, in a second study, we compared our results from FM and HC cohorts to a separate cohort of patients with CBP (publicly available dataset, N=31) during resting-state fMRI with no rating task. We again found no significant group differences in NAcc-MPFC rsFC. In a third study, we conducted an expanded analysis of NAcc rsFC to mesolimbic (i.e., subcortical) circuit regions in chronic pain. We found reduced rsFC of the right NAcc with mesolimbic circuit regions (putamen, thalamus, and ventral pallidum) in FM vs. HC, and additional NAcc-mesolimbic alterations across FM and CBP vs. HC groups. Together, our results expand upon prior observed alterations in brain reward circuits, providing novel evidence of intact corticostriatal but altered subcortical-striatal circuits in chronic pain. This project was funded by the National Institutes of Health, National Institute of Drug Abuse (NIDA), K99/R00 DA040154 (awarded to K.T.M.), K24 NS126781 (awarded to S.C.M.), and the Redlich Pain Research Endowment (S.C.M.). Data used in this project from the Open Pain Project (OPP; Principal Investigator: A. Vania Apkarian, PhD, Northwestern University) was funded by the National Institute of Neurological Disorders and Stroke (NINDS) and National Institute of Drug Abuse (NIDA).

Frequency of the Dopamine Receptor D3 (rs6280) vs. Opioid Receptor µ1 (rs1799971) Polymorphic Risk Alleles in Patients with Opioid Use Disorder: A Preponderance of Dopaminergic Mechanisms?

While opioids are a powerful class of drugs that inhibit transmission of pain signals, their use is tarnished by the current epidemic of opioid use disorder (OUD) and overdose deaths. Notwithstanding published reports, there remain gaps in our knowledge of opioid receptor mechanisms and their role in opioid seeking behavior. Thus, novel insights into molecular, neurogenetic and neuropharmacological bases of OUD are needed. We propose that an addictive endophenotype may not be entirely specific to the drug of choice but rather may be generalizable to altered brain reward circuits impacting net mesocorticolimbic dopamine release. We suggest that genetic or epigenetic alterations across dopaminergic reward systems lead to uncontrollable self-administration of opioids and other drugs. For instance, diminished availability via knockout of dopamine D3 receptor (DRD3) increases vulnerability to opioids. Building upon this concept via the use of a sophisticated polymorphic risk analysis in a human cohort of chronic opioid users, we found evidence for a higher frequency of polymorphic DRD3 risk allele (rs6280) than opioid receptor µ1 (rs1799971). In conclusion, while opioidergic mechanisms are involved in OUD, dopamine-related receptors may have primary influence on opioid-seeking behavior in African Americans. These findings suggest OUD-targeted novel and improved neuropharmacological therapies may require focus on DRD3-mediated regulation of dopaminergic homeostasis.

Sensing metabolomics landscape unfold molecular connectivity between mental illness and drug abuse

Environmental threats to mental equity have recently gained much attention in the sphere of public and curative health due to their toll on the individual, families, the public, and their economic sphere. Mental health or soundness of mind is important at every stage of life from childhood and adolescence through adulthood to protect the brain from environmental stress. What makes mental health unlike genetic rare disorders is that there is no known single cause for this rising public health issue because it arises from multiple factors. These factors include early adverse life experiences, such as trauma or a history of abuse either because of child abuse, sexual assault or seeing any form of violence, experiences related to other ongoing (chronic) medical conditions, such as cancer or diabetes, biological factors or chemical exposure resulting in hormonal imbalances in the brain, and to a large extent having feelings of loneliness or isolation leading to suicidal action. Furthermore, the increase in mental health and its accompanying conditions depend on environmental with or without behavioral changes due to genetic stability may be associated with drug, alcohol, or substance abuse which is associated with the brain reward circuit which may need to compromise the neural circuit over a wide range of stressors on the human body interacting with the sequential neuronal cell cascade. Although humoral networking is associated with socio-behavioral change, work through family, religious, organizational engagement, and community support play major roles in its solution and management, it is consensually accepted that defining key determinants underlying molecular network altering by epigenetic and genetic factors have promise in empowering future systematic health and personal care including surveillance, prevention, treatment, and monitoring process. In the modern global and urbanization era, emerging new biomedical technological advances such as epigenetic tools, genomics editing, human genomics study utilizing sequencing technology, and reverse genetic resources from worm to animal models have enabled us to take a closer look at mechanisms that could be involved in mental illness and drug abuse or addiction using a pattern of metabolomics and its connectivity reflecting the interplay between mental illness and drug abuse and/or addiction. This paper describes a molecular-driven surveillance platform as a part of the power of prevention to care of populational health which could be beneficial by predicting risk and unfolding the impact of daily lifestyle on human behavior such as food intake, alcohol intoxication, and its outcome likely the effect of metabolism on mental illness and drug abuse. Interaction between environmental cues to neural circuits which may interplay with metabolic networks as well as potential risk resulting in various forms of phenotypic complications and behavioral alteration might be detectable using multi-omics platforms.

New perspective of acupuncture analgesia: reward of chronic pain relief and related brain reward circuits

Relief of the chronic pain, as the negative reinforcement of pain, is recognized as a reward and it activates related brain's reward circultries. Brian's reward circuits not only relate to rewards, but also participate in pain process. Currently, the reward effect of acupuncture on chronic pain relief and the mechanism of brain's reward circuits involved in acupuncture analgeisa have not been revealed adequately yet. This paper reviewed the conceptual features of analgesia reward and the new progression of brain's reward circuits and function, expounded the valuable clinical and scientific significance of the researches for the reward effect of acupuncture analgesia and related brain's reward circuits, proposed the ideas and suggestions on many questions in the study of reward effect of acupuncture analgesia and related brain's reward circuits, and then, determined the multi-dimensional characteristis and positive regulation of acupuncture analgesia. Focusing on the reward effect of acupuncture and related brain's reward circuits for chronic pain relief, the research on the regulatory effect of acupuncture analgesia will be conductive to deepen the understanding of acupuncture analgies in clinical practice and innovate a research concept of acupuncture analgeis. Eventually, a new approach can be provided to further elaborate neurobiolgical mechanism of acupuncture analgesia.

Oxytocin and the social facilitation of placebo effects.

Significant clinical improvement is often observed in patients who receive placebo treatment in randomized double-blind placebo-controlled trials. While a proportion of this “improvement” reflects experimental design limitations (e.g., reliance on subjective outcomes, unbalanced groups, reporting biases), some of it reflects genuine improvement corroborated by physiological change. Converging evidence across diverse medical conditions suggests that clinically-relevant benefits from placebo treatment are associated with the activation of brain reward circuits. In parallel, evidence has accumulated showing that such benefits are facilitated by clinicians that demonstrate warmth and proficiency during interactions with patients. Here, we integrate research on these neural and social aspects of placebo effects with evidence linking oxytocin and social reward to advance a neurobiological account for the social facilitation of placebo effects. This account frames oxytocin as a key mediator of treatment success across a wide-spectrum of interventions that increase social connectedness, thereby providing a biological basis for assessing this fundamental non-specific element of medical care.