Receptor System Research Articles

Endogenous opioid receptor system mediates costly altruism in the human brain

Functional neuroimaging studies suggest that a large-scale brain network transforms others’ pain into its vicarious representation in the observer, potentially modulating helping behavior. However, the neuromolecular basis of individual differences in vicarious pain and helping is poorly understood. We investigated the role of the endogenous μ-opioid receptor (MOR) system in altruistic costly helping. MOR density was measured using [11C]carfentanil. In a separate fMRI experiment, participants could donate money to reduce a confederate’s pain from electric shocks. Participants were generally willing to help, and brain activity was observed in amygdala, anterior insula, anterior cingulate cortex (ACC), striatum, primary motor cortex, primary somatosensory cortex and thalamus when witnessing others’ pain. Haemodynamic responses were negatively associated with MOR availability in emotion circuits. However, MOR availability positively associated with the ACC and hippocampus during helping. These findings suggest that the endogenous MOR system modulates altruism in the human brain.

Differential temporal decline of cerebral oxytocin and μ-opioid receptor density during the aging process in mice.

Aging is often associated with changes in social, sexual, emotional and pain functioning, as well as with the increased prevalence of certain psychopathologies. However, the neurodevelopmental basis underpinning these age-related changes remains to be determined. Considering the key roles of oxytocin (OTR) and μ-opioid (MOPr) receptor systems in regulating social, sexual, pain, reward and emotional processing, it seems plausible that they are also implicated in age-related behavioural alterations. Although the ontogeny of both receptors has been well characterized in rodent brains from early development till adulthood, little is known concerning the neuroadaptations occurring from middle age to old age. Therefore, we mapped the neuroadaptations in OTR and MOPr in the brains of mice at those developmental endpoints. Quantitative OTR and MOPr autoradiographic binding was carried out in the brains of male mice at 2, 6, 9, 12 and 18 months of age. A significant whole brain decline in OTR density was detected between 2 and 6months of age, with no additional decline thereafter. Interestingly, for MOPrs, the decline in density was not detected until 9months of age. Region-specific age-related decline in OTR density was concentrated in the lateral anterior olfactory nuclei (AOL) and, for MOPr, in the AOL and the nucleus accumbens for MOPr. Identifying the tipping point of these age-related variations in both receptors may assist with our understanding of the neurobiology underlining age-related changes in social, pain and emotional functioning/processing. It may also help us target interventions to specific developmental windows to abrogate certain age-related psychopathologies.

Evolutionary Sequences and Structural Information-driven Reconstruction of New Insulin-like Growth Factor-I Peptide Variants.

Insulin-like growth factor-I (IGF-I) is crucial in controlling cell growth, proliferation, and apoptosis. Its strong link to the development of cancers such as breast, prostate, lung, thyroid, and colorectal has positioned the IGF-1 signalling pathway as a promising target for novel cancer therapies. When activated, the IGF-1 receptor (IGF-1R) binds to IGF-I, playing a central role in promoting tumour cell growth and survival. In this study, we combined evolutionary sequences with structural and functional data of IGF-1 to reconstruct ancestral sequences and design novel IGF-1 peptide variants. The insulin-like growth factor system exhibits a vast sequence diversity, yet it shares a similar structural topology with conserved three pairs of disulfide linkages. Our study reveals that IGF-1 is associated with the IGF system of cell surface receptors through protein-protein interactions. Reconstructed IGF-1 variants show similar structure fold to reported viral IGF-1 competitive antagonists. This new insight guides the design of novel natural IGF-1 mimic peptides. It enhances our understanding of IGF-1's functionality and opens new avenues for the development of therapeutic peptides and small molecules as anticancer agents.

Aβ-targeting synNotch Receptor for Alzheimer's Disease: Expanding Applications to Extracellular Protein Aggregates.

The synthetic Notch receptor (synNotch) system is a versatile platform that induces gene transcription in response to extracellular signals. However, its application has been largely confined to membrane-bound targets due to specific activation requirements. Whether synNotch can also target extracellular protein aggregates, such as amyloid beta (Aβ) in Alzheimer's disease (AD), is unclear. To address this, we engineered an Aβ-targeting synNotch receptor controlling the production of chimeric human-mouse versions of Lecanemab (Leqembi®) or Aducanumab (Aduhelm®), both FDA-approved antibodies for AD. We demonstrate that NIH 3T3 cells expressing this synNotch system detect and respond to extracellular Aβ aggregates by synthesizing and secreting Aducanumab or Lecanemab. These findings broaden the potential applications of synNotch, extending its targets beyond membrane-bound proteins to extracellular protein aggregates, providing obvious benefits to research in this scientific arena.

Advanced investigation of adsorption process of the five main responses of taste molecules onto the gerbil receptor sites (GCaMP3): Steric, molecular docking, and energy interpretations

In this research work, an adsorption phenomenon putatively in the process of taste at a molecular level for understanding the five principal tastes using experimental dose-gustatory responses on receptors sites of gerbil (GCaMP3). In order to perform theoretical interpretations of the experimental data of dose gustatory response curve were fitted with the single-layer physical model (PMM) for sucrose, cycloheximide, quinine and MSG. However, a two-layer with two-energies model for NaCl and citric acid. The modeling discussion indicated that all six molecules were linked with the gerbil receptor sites of tasting surface by a parallel and a no parallel orientations. In addition, the linking adsorption energies are ranged from 3.15 to 14.19 kJ/mol for all tasting molecules, which suggested that this process is performed by a reversible physical adsorption. These physico-chemical model parameters are utilized to determine the molar energy of adsorption for various taste-entities. By fitting the number of adsorbed molecules or molecular anchors per site, a stereographic and energetic characterization of interactions between six entities (sucrose, cycloheximide, MSG, citric acid, and NaCl) and the gerbil gustatory-receptor-sites is conducted. These distributions AED and PSD can be considered as a characterization of taste of not only not only not only of any gustatory entity but also a characterization of the gustatory receptor systems of the peripheric nerves. The docking computation between five gustatory molecules and the gerbil GCaMP3 cavity receptor sites is performed, showing a significant resemblance in the receptor-ligand detection process. Hence, the findings from docking confirm that the calculated binding affinities fell within the range of adsorption energies.

Gray matter volume differences based on sex in first-episode drug-naive patients with major depressive disorder and its molecular analysis.

This study analyzed whether gray matter volume (GMV) differences exist between the sexes in patients with major depressive disorder (MDD) and explored the relationships between these differences and neurotransmitter systems. This study enrolled 190 first-episode drug-naive patients with MDD and 293 healthy controls. All participants underwent T1-weighted high-resolution MRI. The interaction between the diagnosis (healthy controls vs. MDD) and sex (male vs. female) regarding GMV alterations was analyzed. The JuSpace toolbox, which covers a wide range of neurotransmitter systems, was used to identify the relationship between MDD-induced and sex-induced GMV alterations and specific receptor/transporter proteins in the brain. Sex-specific GMV differences were observed in the healthy controls but not in MDD patients. Male healthy controls had a larger GMV in the bilateral parahippocampal, lingual, inferior occipital, fusiform, cerebellar subregions, and left inferior temporal than female healthy controls, but several subregions of the thalamus had a larger GMV in female healthy controls than in male healthy controls. Sex-induced GMV alterations were associated with 5-hydroxytryptamine receptor subtype 1a, cannabinoid receptor, and dopamine receptor (P < 0.01, false discovery rate corrected). GMV differences were not detected in the main effect of diagnosis and the interaction of diagnosis and sex. Sex-specific GMV differences are associated with the spatial distribution of serotonin, dopamine, and cannabinoid neurotransmitter receptor systems. Sex-based physiological differences in the GMV may account for male and female susceptibility to and differences in the clinical symptoms of MDD.

Dinámica de los receptores de quimioquinas en la membrana celular

Chemokines are chemotactic cytokines that control the migratory patterns and positioning of many cells, including immune cells. Although chemokines were initially considered to be important mediators of acute inflammation, we now know that this complex system of ligands and receptors is essential for the generation of primary and secondary adaptive cellular and humoral immune responses. In addition, they also trigger other biological responses ranging from cell polarization or movement or the prevention of HIV-1 infection. Chemokine-mediated cell activation was believed to be due to the binding of a monomeric chemokine to its monomeric receptor. However, the biology of these mediators is more complex than initially anticipated, as several studies indicate that chemokines dimerize. In addition, the use of new advanced optical imaging techniques have made possible to determine that the receptors also form dimers, homo- and heterodimers, as well as higher order oligomers at the cell surface. These are very dynamic and plastic structures/conformations, influenced by the presence of ligands, the co-expression of other receptors and proteins, the lipid composition of the cell membrane or the environment where cells perform their function. Keywords: Chemokines; Chemokine receptors; Receptor conformation; Molecular dynamics; Signaling

Smoking-Related Increases in Alcohol Outcomes and Preliminary Evidence for the Protective Effect of a Functional Nicotine Receptor Gene (CHRNA5) Variant on Alcohol Consumption in Individuals Without Alcohol Use Disorder.

Alcohol and nicotine interact with the nicotinic acetylcholine receptor system to alter reward-related responses, thereby contributing to the co-use and misuse of these drugs. A missense polymorphism rs16969968 (G>A) in the CHRNA5 gene has shown a strong association with nicotine-related phenotypes. However, less is known about the impact of this variant on alcohol-related phenotypes. We assessed the main and interactive effect of smoking and rs16969968 polymorphism on alcohol consumption using the Alcohol Use Disorders Identification Test (AUDIT), Timeline Follow Back (TLFB), and Lifetime Drinking History (LDH) in 980 healthy adults without alcohol use disorder. We further examined the effect of the rs16969968 polymorphism on acute alcohol consumption using a free-access i.v. alcohol self-administration (IV-ASA) human laboratory paradigm in a subset of 153 nonsmoking participants. Subjective alcohol responses, alcohol sensitivity, and expectancy measures were compared between genotype groups (GG; AA/AG). We observed a significant association of smoking with AUDIT, TLFB, and LDH measures across genotype groups, with smokers showing higher scores compared with nonsmokers. Additionally, we found an association between genotype and TLFB-total drinks in the IV-ASA subset, with the GG group showing higher scores than AA/AG group. Relatedly, the alcohol negative expectancy score was significantly lower in the GG group than the AA/AG group. Our findings underscore the association of smoking with alcohol measures. We found preliminary evidence for the protective effect of the functional CHRNA5 polymorphism on alcohol consumption and its association with increased negative alcohol expectancies, which highlights the substantial heterogeneity in alcohol responses.

Calcitriol/vitamin D receptor system alleviates PM2.5-induced human bronchial epithelial damage through upregulating mitochondrial bioenergetics in association with regulation of HIF-1α/PGC-1α signaling

PM2.5 exposure causes lung injury by triggering oxidative stress, mitochondrial dysfunction, and modulating HIF-1α signaling. Calcitriol activates VDR, which regulates cellular homeostasis. This study evaluated the protective role of the calcitriol/VDR system in PM2.5-induced damage to BEAS-2B bronchial epithelial cells by reducing oxidative stress, upregulating mitochondrial bioenergetics, and downregulating HIF-1α. We found that the calcitriol/VDR system decreased ROS formation and restored mitochondrial bioenergetics in PM2.5-treated cells. This improvement correlated with reduced HIF-1α nuclear translocation and increased PGC-1α protein and mitochondrial gene expressions. This study is the first to suggest that targeting the calcitriol/VDR system could be a promising pharmacological strategy for mitigating PM2.5-induced lung epithelial damage by promoting mitochondrial bioenergetics and regulating PGC-1α and HIF-1α signaling.

Effects of Stress Exposure to Pain Perception in Pre-Clinical Studies: Focus on the Nociceptin/Orphanin FQ-NOP Receptor System.

Exposure to physical and psychological stress modulates pain transmission in a dual manner. Stress-induced analgesia (SIA) refers to the reduction in pain sensitivity that can occur in response to acute stress. On the contrary, chronic stress exposure may lead to a phenomenon named stress-induced hyperalgesia (SIH). SIH is a clinically relevant phenomenon since it has been well documented that physical and psychological stress exacerbates pain in patients with several chronic pain syndromes, including migraine. The availability of animal models of SIA and SIH is of high importance for understanding the biological mechanisms leading to these phenomena and for the identification of pharmacological targets useful to alleviate the burden of stress-exacerbated chronic pain. Among these targets, the nociceptin/orphanin FQ (N/OFQ)-N/OFQ peptide (NOP) receptor system has been identified as a key modulator of both pain transmission and stress susceptibility. This review describes first the experimental approaches to induce SIA and SIH in rodents. The second part of the manuscript summarizes the scientific evidence that suggests the N/OFQ-NOP receptor system as a player in the stress-pain interaction and candidates NOP antagonists as useful drugs to mitigate the detrimental effects of stress exposure on pain perception.

Spatial and signaling overlap of growth factor receptor systems at clathrin-coated sites.

Cellular communication is regulated at the plasma membrane by the interactions of receptor, adhesion, signaling, exocytic,and endocytic proteins. Yet, the composition and control of these complexes in response to external cues remain unclear. We use high-resolution and high-throughput fluorescence imaging to map the localization of growth factor receptors and related proteins at single clathrin-coated structures in human squamous HSC3 cells. We find distinct protein signatures between control cells and cells stimulated with growth factors. Clathrin sites at the plasma membrane are preloaded with some receptors but not others. Stimulation with epidermal growth factor induces capture and concentration of epidermal growth factor, fibroblast growth factor1, and low-density lipoprotein receptor (EGFR, FGFR1, and LDLR). Regulatory proteins including ubiquitin ligase Cbl, the scaffold Grb2, and the mechanoenzyme dynamin2 are also recruited. Disrupting FGFR1 or EGFR activity with drugs prevents the recruitment of both EGFR and FGFR1. EGF was able to activate FGFR1 phosphorylation. Our data reveal novel coclustering and activation of receptors and regulatory factors at clathrin-coated sites in response to stimulation by a single growth factor, EGF or FGF. This behavior integrates growth factor signaling and allows for complex responses to extracellular cues and drugs at the plasma membrane of human cells.

Fractal-fractional model for the receptor in a 3D printing system

A critical hurdle in three-dimensional printing is the low printing accuracy. In particular, the deformation of the printed object on the receptor makes accurate printing impossible due to insufficient solvent evaporation. We address this challenge by establishing a Murray-like receptor to control the morphology of the printed object, which can be used for accurate printing through efficient residual energy absorption and active vibration attenuation. A fractal oscillator is established and He’s frequency formulation is used to reveal the fractal response of the Murray-like receptor, and an experiment was carried out to show that the receptor system can keep the printed object in good shape without any deformation.

Asuhan Keperawatan pada Keluarga Tn.K dengan Gangguan Sistem Endokrin : Diabetes Melitus di Desa Kalibuntu Rt 04 Rw 02 Kecamatan Losari Kabupaten Brebes

Diabetes Mellitus (DM) is a long-term metabolic disorder caused by the body's insulin hormone which cannot be used properly to regulate blood sugar balance, resulting in hyperglycemia (Zakiudin et al., 2023). There are two factors that can affect a person's glucose levels, the first is endogenous factors such as insulin, glucagon, and cortisol which act as receptor systems in liver and muscle cells. The second factor is the amount and type of food consumed, which is an exogenous factor. Blood glucose levels are also influenced by a person's character (gender, family history of diabetes, and age), dietary factors (high energy, high carbohydrates, high fat, high protein, and low fiber), lack of physical activity, nutritional status, hypertension and knowledge about nutrition (Viera Valencia &amp; Garcia Giraldo, 2019).

Molecular mechanism of prolactin-releasing peptide recognition and signaling via its G protein-coupled receptor

Prolactin-releasing peptide (PrRP) is an RF-amide neuropeptide that binds and activates its cognate G protein-coupled receptor, prolactin-releasing peptide receptor (PrRPR), also known as GPR10. PrRP and PrRPR are highly conserved across mammals and involved in regulating a range of physiological processes, including stress response, appetite regulation, pain modulation, cardiovascular function, and potentially reproductive functions. Here we present cryo-electron microscopy structures of PrRP-bound PrRPR coupled to Gq or Gi heterotrimer, unveiling distinct molecular determinants underlying the specific recognition of the ligand’s C-terminal RF-amide motif. We identify a conserved polar pocket that accommodates the C-terminal amide shared by RF-amide peptides. Structural comparison with neuropeptide Y receptors reveals both similarities and differences in engaging the essential RF/RY-amide motifs. Our findings demonstrate the general mechanism governing RF-amide motif recognition by PrRPR and RF-amide peptide receptors, and provide a foundation for elucidating activation mechanisms and developing selective drugs targeting this important peptide–receptor system.

The oxytocin-oxytocin receptors system — a new pathogenetic mechanism in the development of diabetic phenotype of heart failure with preserved ejection fraction in women

Aim. To determine the pathogenetic role of the oxytocinergic system in the development of myocardium structural and functional changes in women with heart failure with preserved ejection fraction (HFpEF) associated with type 2 diabetes mellitus (DM2T) (diabetic phenotype of HFpEF).Material and methods. The study included 60 women aged 67.0±4.9 years with HFpEF stage I-IIA, FC I-III, 30 of them had DM2T who were admitted for elective coronary artery bypass grafting. The development of HFpEF is caused by coronary artery disease (CAD) and arterial hypertension (AH). Prior to surgery, all patients underwent a standard examination, blood levels of NT-proBNP, oxytocin (Ox), echocardiography were determined to find the types of left ventricular (LV) myocardial remodeling and diastolic dysfunction (DD). Myocardium biopsies of the right atrium auricle obtained during coronary bypass surgery were studied by microscopy, morphometry and immunohistochemistry (the expression of oxytocin receptors (OxR), a marker of proliferation ki-67).Results. According to echocardiography, eccentric LV hypertrophy (46.7/36.7%) and DD type 2 (47/17%, p=0.003) prevailed in the group of women with the diabetic phenotype of HFpEF. A higher content of NT-proBNP (480.72±241.87/434.46±282.78 ng/ml, p=0.06) and a lower concentration of Ox (102.11±35.89/320.37±294.71 pg/ml, p=0.0016) in blood serum were established, as well as an increase in the number of cardiomyocytes (CMC) with a high expression level OxR (63.69±19.47/12.16±23.09%, p=0.000) in patients with the diabetic phenotype of HFpEF. Negative associations were determined between the blood level of Ox and the CMC diameter (r=-0.10, p=0.020), the area of their cytoplasm (r=-0.16, p=0.000) and the area of the nuclei (r=-0.11, p=0.015) in patients of both groups. A decrease in Ox concentration in the blood of patients with diabetic phenotype of HFpEF was accompanied by an increase in the number of CMCs with a high level of OxR expression (r=-0.63, p=0.000).Conclusion. The study has shown the important involvement of oxytocinergic signaling pathways in the HFpEF pathogenesis. HFpEF associated with DM2T in women was characterized by more unfavorable structural and functional changes in the myocardium, a significant increase in the number of hypertrophied CMCs with a high level of OxR expression and Ox decrease in blood serum. The mechanisms of the first-established significant increase in the content of Ox in the blood of patients with HFpEF without diabetes and its significant decrease in patients with diabetic phenotype of HFpEF leading to more pronounced structural and functional changes in the myocardium, require further study.

Abstract P431: Crosstalk Between Dopamine Receptors and AT1R in Hypertension Induced Cardiac Remodeling

Dopamine receptors are implicated in the regulation of cardiovascular function, yet their specific roles in the modulation of hypertension and cardiac remodeling are not fully understood. The angiotensin II type 1 receptor (AT1R) plays a critical role in the pathophysiology of hypertension by mediating vasoconstriction, sodium retention, and sympathetic nervous system activation. Previous studies from our lab have demonstrated that in Ang II-induced hypertension, there are alterations in D1R and D3R expression in the left ventricle (LV) compared to wild-type (WT) mice. Evidence indicates that AT1R and D1R form heterodimers and inhibition of AT1R has been shown to enhance D1R signaling in proximal tubules, suggesting a significant interaction between these receptor systems. However, the role of intracardiac dopamine receptors on AT1R expression during hypertension remains understudied. Therefore, this study aims to elucidate the crosstalk between intracardiac dopamine receptors and AT1R in the context of hypertension and cardiac remodeling by using in vitro and in vivo pharmacological and molecular methods combined with novel genetic models. Using global D3R deficient (D3KO) and WT mice, we observed that D3KO leads to alterations in AT1R gene expression in LV compared to WT hearts (p&lt;0.001) and in isolated LV cardiac fibroblasts (p&lt;0.0001). D3KO and WT mouse cardiac fibroblasts (mCFb) and human cardiac fibroblasts (hCFb) were stimulated with Ang II (300nM) ± D1R antagonist (SCH, 10µM) or D3R antagonist (SB, 10µM). D1R antagonism significantly increased AT1R (Agtr1 gene) levels in both WT and D3KO mCFb (p&lt;0.01), whereas D3R antagonism reduced AT1R gene expression following Ang II stimulation (p&lt;0.01). Furthermore, these data were confirmed in hCFb. To determine crosstalk between dopamine receptors and AT1R, we used proximity ligation assay (PLA) to examine the close proximity (&lt;40nm) of receptor-receptor expression and interaction. Our results indicate that in mCFb and hCFb, there is an increase in D1R-AT1R interactions following Ang II both with and without D1R antagonism (p&lt;0.05), however, AT1R-D3R interactions were reduced (p&lt;0.05). These data suggest that dopamine receptor activity significantly influences AT1R gene expression, highlighting a potential modulatory role for dopamine receptors in the regulation of AT1R during hypertension.

Salvinorin A ameliorates pilocarpine-induced seizures by regulating hippocampal microglia polarization

Ethnopharmacological relevanceSalvia divinorum (Epling and Játiva) is a psychoactive plant traditionally used by the Latinos for various medicinal purposes. Salvinorin A (Sal A), the main bioactive constituent of S. divinorum, is a natural highly selective kappa opioid receptor (KOR) agonist. Considering the anti-inflammatory effect of S. divinorum and endogenous hippocampal dynorphin/kappa opioid receptor (KOR) system playing an anticonvulsant function, we hypothesis that Sal A can be a potential candidate to treat epilepsy. Here, we identified whether Sal A ameliorated epileptic seizures and neuronal damages in animal model and in vitro model and investigated its underlying mechanisms. Materials and methodsMice epilepsy model was induced by pilocarpine following seizures assessed by Racine classification. Hippocampus tissues were obtained for genetic, protein, and histological investigation. Furthermore, lipopolysaccharide (LPS)-activated BV2 microglial cells were utilized to validate the anti-inflammatory and microglia polarization regulation effects of Sal A. ResultsSal A treatment significantly prolonged the latency to status epileptics (SE) and shortened the duration of SE in the pilocarpine-induced model. It also alleviated neuronal damages via activation of the AMPK/JNK/p-38 MAPK pathway and inhibition of apoptosis-related protein in hippocampus tissues. Furthermore, Sal A dose-dependently reduced microglia-mediated expression of pro-inflammatory cytokines and increased anti-inflammatory factors levels in SE mice and LPS-activated BV2 microglial cells by regulating microglia polarization. In addition, the effect of Sal A in vitro was totally blocked by KOR antagonist nor-BNI. ConclusionSal A treatment protects against epileptic seizures and neuronal damages in pilocarpine-induced models by suppressing the inflammation response through regulating microglial M1/M2 polarization. This study might serve as a theoretical basis for clinical applications of Sal A and its analogs and provide a new insight into the development of anti-seizure drugs.

Sub-chronic nicotine exposure influences methamphetamine self-administration and dopamine overflow in a sex-and genotype-dependent manner in humanized CHRNA6 3'-UTR SNP (rs2304297) adolescent rats.

Introduction: The rewarding effects of drugs of abuse are associated with the dopaminergic system in the limbic circuitry. Nicotine exposure during adolescence is linked to increased use of drugs of abuse with nicotine and methamphetamine (METH) commonly used together. Nicotine acts on neuronal nicotinic acetylcholine receptor (nAChR) systems, critical for reward processing and drug reinforcement, while METH leads to a higher dopamine (DA) efflux in brain reward regions. A human single nucleotide polymorphism (SNP) in the 3'-untranslated region (UTR) of the α6 nicotinic receptor subunit gene (CHRNA6, rs2304297), has been linked with tobacco/nicotine and general substance use during adolescence. Using CRISPR-Cas9 genomic engineering, our lab recapitulated the CHRNA6 3'UTRC123G SNP, generating α6CC and α6GG allele carriers in Sprague Dawley rats. We hypothesized the CHRNA6 3'UTRC123G SNP would sex- and genotype-dependently enhance nicotine-induced METH self-administration as well as nicotine-induced DA overflow in the nucleus accumbens shell of adolescent α6GG and α6CC carriers. Methods: Adolescent male and female rats underwent a 4-day sub-chronic, low-dose (0.03mg/kg/0.1mL, x2) nicotine pretreatment paradigm to assess intravenous METH (0.02mg/kg/0.1mL) self-administration as well as nicotine- and METH (0.02mg/kg/0.1mL)-induced DA overflow in the nucleus accumbens shell (NAcS) using in vivo microdialysis coupled with high-performance liquid-chromatography-electrochemical detection (HPLC-ECD). Results: Nicotine pretreatment sex- and genotype-dependently enhanced subsequent METH self-administration in adolescent CHRNA6 3'UTRC123G SNP rats. Further nicotine and METH-induced DA overflow is observed in α6CC females as compared to α6GG females, with METH-induced DA overflow enhanced in α6GG males when compared to α6CC males. Conclusion: These findings demonstrate that the CHRNA6 3'-UTRC123G SNP can sex- and genotype-dependently impact adolescent nicotine-induced effects on METH self-administration and stimulant-induced DA overflow in reward regions of the brain.

Transient frequency preference responses in cell signaling systems

Ligand–receptor systems, covalent modification cycles, and transcriptional networks are the fundamental components of cell signaling and gene expression systems. While their behavior in reaching a steady-state regime under step-like stimulation is well understood, their response under repetitive stimulation, particularly at early time stages is poorly characterized. Yet, early-stage responses to external inputs are arguably as informative as late-stage ones. In simple systems, a periodic stimulation elicits an initial transient response, followed by periodic behavior. Transient responses are relevant when the stimulation has a limited time span, or when the stimulated component’s timescale is slow as compared to the timescales of the downstream processes, in which case the latter processes may be capturing only those transients. In this study, we analyze the frequency response of simple motifs at different time stages. We use dose-conserved pulsatile input signals and consider different metrics versus frequency curves. We show that in ligand–receptor systems, there is a frequency preference response in some specific metrics during the transient stages, which is not present in the periodic regime. We suggest this is a general system-level mechanism that cells may use to filter input signals that have consequences for higher order circuits. In addition, we evaluate how the described behavior in isolated motifs is reflected in similar types of responses in cascades and pathways of which they are a part. Our studies suggest that transient frequency preferences are important dynamic features of cell signaling and gene expression systems, which have been overlooked.

Kappa-opioid receptor antagonism in the nucleus accumbens shell distinguishes escalated alcohol consumption and negative affective-like behavior from physiological withdrawal in alcohol-dependence

Alcohol use disorder (AUD) is a chronic relapsing disease that is deleterious at individual, familial, and societal levels. Although AUD is one of the highest preventable causes of death in the USA, therapies for the treatment of AUD are not sufficient given the heterogeneity of the disorder and the limited number of approved medications. To provide better pharmacological strategies, it is important to understand the neurological underpinnings of AUD. Evidence implicates the endogenous dynorphin (DYN)/κ-opioid receptor (KOR) system recruitment in dysphoric and negative emotional states in AUD to promote maladaptive behavioral regulation. The nucleus accumbens shell (AcbSh), mediating motivational and emotional processes that is a component of the mesolimbic dopamine system and the extended amygdala, is an important site related to alcohol's reinforcing actions (both positive and negative) and neuroadaptations in the AcbSh DYN/KOR system have been documented to induce maladaptive symptoms in AUD. We have previously shown that in other nodes of the extended amygdala, site-specific KOR antagonism can distinguish different symptoms of alcohol dependence and withdrawal. In the current study, we examined the role of the KOR signaling in the AcbSh of male Wistar rats in operant alcohol self-administration, measures of negative affective-like behavior, and physiological symptoms during acute alcohol withdrawal in alcohol-dependence. To induce alcohol dependence, rats were exposed to chronic intermittent ethanol vapor for 14 h/day for three months, during which stable escalation of alcohol self-administration was achieved and pharmacological AcbSh KOR antagonism ensued. The results showed that AcbSh KOR antagonism significantly reduced escalated alcohol intake and negative affective-like states but did not alter somatic symptoms of withdrawal. Understanding the relative contribution of these different drivers is important to understand and inform therapeutic efficacy approaches in alcohol dependence and further emphasis the importance of the KOR/DYN system as a target for AUD therapeutics.