Mesolimbic Research Articles

Structural mechanism of CB1R binding to peripheral and biased inverse agonists

The cannabinoid receptor 1 (CB1R) regulates synaptic transmission in the central nervous system, but also has important roles in the peripheral organs controlling cellular metabolism. While earlier generations of brain penetrant CB1R antagonists advanced to the clinic for their effective treatment of obesity, such molecules were ultimately shown to exhibit negative effects on central reward pathways that thwarted their further therapeutic development. The peripherally restricted CB1R inverse agonists MRI-1867 and MRI-1891 represent a new generation of compounds that retain the metabolic benefits of CB1R inhibitors while sparing the negative psychiatric effects. To understand the mechanism of binding and inhibition of CB1R by peripherally restricted antagonists, we developed a nanobody/fusion protein strategy for high-resolution cryo-EM structure determination of the GPCR inactive state, and used this method to determine structures of CB1R bound to either MRI-1867 or MRI-1891. These structures reveal how these compounds retain high affinity and specificity for CB1R’s hydrophobic orthosteric site despite incorporating polar functionalities that lead to peripheral restriction. Further, the structure of the MRI-1891 complex along with accompanying molecular dynamics simulations shows how differential engagement with transmembrane helices and the proximal N-terminus can propagate through the receptor to contribute to biased inhibition of β-arrestin signaling.

The Potential Role of Dopamine Pathways in the Pathophysiology of Depression: Current Advances and Future Aspects.

Depression is a serious mental health disorder that impacts more than 350 million individuals globally. While the roles of serotonin and norepinephrine in depression have been extensively studied, the importance of dopaminergic pathways-essential for mood, cognition, motor control, and endocrine function-often gets overlooked. This review focuses on four major dopamine (DA) circuits: the mesolimbic (MLP), mesocortical (MCP), nigrostriatal (NSP), and thalamictuberoinfundibular pathways (TTFP), and their roles in depression. The MLP, which is key to reward processing, is linked to anhedonia, a primary depression symptom. The MCP, projecting to the prefrontal cortex, affects cognitive issues like impaired attention and decision-making. The NSP, mainly responsible for motor control, is related to psychomotor retardation in depression, while the TTFP manages neuroendocrine responses, which are often disrupted in stress-related depressive conditions. Current antidepressant treatments mainly target serotonin and norepinephrine systems but tend to be less effective for patients with DArgic dysfunction, leading to treatment resistance. This review underscores emerging evidence that suggests targeting DArgic pathways could improve treatment outcomes, especially for symptoms like anhedonia and cognitive deficits that conventional therapies often fail to address. Future research should aim to combine advancements in neuroimaging, optogenetics, and genetic studies to better map DArgic pathways and create personalized treatment plans. This review highlights the potential for new therapies that focus on DA systems, which could pave the way for more effective and tailored approaches to treating depression.

Exploring the Genetic Contribution in Obesity: an overview of dopaminergic system genes.

Obesity is a widespread global health concern that affects a significant portion of the population and is associated with reduced quality of life, morbidity, and mortality. It is considered a pandemic, with its prevalence constantly rising in Western countries. As a result, numerous studies have focused on understanding the elements that contribute to obesity. Researchers have focused on neurotransmitters in the brain to develop weight management drugs that regulate food intake. This review explores the literature on genetic influences on dopaminergic processes to determine whether genetic variation has an association with obesity in reward-responsive regions, including mesolimbic efferent and mesocortical areas. Various neurotransmitters play an essential role in regulating food intake, such as dopamine which controls through mesolimbic circuits in the brain that modulate food reward. Appetite stimulation, including primary reinforcers such as food, leads to an increase in dopamine release in the reward centers of the brain. This release is related to motivation and reinforcement, which determines the motivational weighting of the reinforcer. Changes in dopamine expression can lead to hedonic eating behaviors and contribute to the development of obesity. Genetic polymorphisms have been investigated due to their potential role in modulating the risk of obesity and eating behaviors. Therefore, it is crucial to assess the impact of genetic alterations that disrupt this pathway on the obesity phenotype.

The Roles of Endogenous D2R Dopamine and μ-opioid Receptors of the Brain in Alcohol use Disorder.

Alcohol use disorder (AUD) affects millions of people worldwide. It is characterized by a strong physiological and psychological craving to consume large amounts of alcohol despite adverse consequences. Alcohol use disorder carries a large health and economic burden on society. Despite its prevalence, AUD is still severely undertreated. The precise molecular mechanisms of how alcohol addiction forms are yet unknown. However, previous studies on animal models show that along with the μ-opioid receptors, the D2R dopamine receptors may also be involved in alcohol craving and reward pathways. Currently, there is a limited number of treatment strategies for alcohol use disorder, which include several medications and therapy. By understanding the limitations of current treatment options and exploring new potential targets, it could be possible to find more effective ways of treating AUD in the future.

T-2 toxin triggers depression-like behaviors via upregulation of dopamine transporter in nucleus accumbens of male mice

The T-2 toxin is a frequent contaminant in the global environment and agricultural production. Existing evidence suggests that the ingested T-2 toxin can enter the brain and exhibit neurotoxicity. However, it is still unknown whether T-2 toxin causes the depression-like behaviors. In this study, the mice were orally administrated with 1.5 mg/kg T-2 toxin daily for 14 d, and the depression-like behaviors were assessed by the tail suspension test (TST) and sucrose preference test (SPT). Here, the results showed that T-2 toxin exposure induced depression-like behaviors, manifested as behavioral despair and anhedonia, without anxiety-like behaviors. In addition, the reduced dopamine (DA) level and elevated dopamine transporter (DAT) level were found in reward center nucleus accumbens (NAc) receiving DAergic projection from ventral tegmental area (VTA) in brain after T-2 toxin administration, while there was no significant alteration in DA synthesis-related tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC) in VTA and DA storage-related vesicle monoamine transporter 2 (VMAT2) in NAc. The local administration of DAT inhibitor AHN 1–055 hydrochloride into NAc alleviated T-2 toxin caused the depression-like behaviors. Importantly, the chemogenetic activation of the VTADA-NAc circuit increased the DA content in NAc and reversed the T-2 toxin-produced behavioral despair and anhedonia. Thus, our study for the first time illustrates DA dysregulation by upregulated DAT in NAc mediates T-2 toxin-triggered depression-like symptoms in mice. Meanwhile, this study establishes a novel causal relation between the neurotoxicant T-2 toxin exposure and the etiology of depression-like behaviors, and provides reference for the prevention and treatment for mycotoxin-induced depression-like symptoms.

Dysregulation of dopamine neurotransmission in drug addicts: implications for criminal behavior and corrective interventions.

Drug addiction often correlates with criminal behavior. When investigating criminal behavior among individuals grappling with drug addiction, it becomes crucial to scrutinize the influence of dopamine. Substances such as heroin, morphine, methamphetamine and other drugs can cause abnormal dopamine secretion when people are addicted to them, which promotes changes in the brain's reward circuit and emotional balance, thereby increasing susceptibility to criminal behavior. The pivotal role of dopamine within the reward pathway and its regulatory function in emotional processes exert profound influence on behavior following drug simulation. These influences are primarily manifested by three distinct attributes: a singular criminal motive and objective, lack of moral sense, and impulsive decision-making processes. Drawing upon the distinctive dopaminergic dynamics inherent in individuals afflicted by drug addiction, this study advocates for targeted corrective interventions. The preventive paradigm encompasses the cultivation of supportive community environments, the establishment of comprehensive databases, and providing legal education and protection, among other initiatives. In terms of treatment, along with judicial sanctions and protections, exercise regimens and psychotherapeutic interventions are advocated. The corrective endeavor necessitates a synergistic integration of community-based and legalistic frameworks. The objective is to furnish guiding principles for tackling criminal behavior precipitated by aberrant dopamine secretion, underpinned by a scientifically informed approach.

The therapeutic potential of low-intensity focused ultrasound for treating substance use disorder.

Substance use disorder (SUD) is a persistent public health issue that necessitates the exploration of novel therapeutic interventions. Low-intensity focused ultrasound (LIFU) is a promising modality for precise and invasive modulation of brain activity, capable of redefining the landscape of SUD treatment. The review overviews effective LIFU neuromodulatory parameters and molecular mechanisms, focusing on the modulation of reward pathways in key brain regions in animal and human models. Integration of LIFU with established therapeutics holds promise for augmenting treatment outcomes in SUD. The current research examines LIFU's efficacy in reducing cravings and withdrawal symptoms. LIFU shows promise for reducing cravings, modulating reward circuitry, and addressing interoceptive dysregulation and emotional distress. Selecting optimal parameters, encompassing frequency, burst patterns, and intensity, is pivotal for balancing therapeutic efficacy and safety. However, inconsistencies in empirical findings warrant further research on optimal treatment parameters, physiological action mechanisms, and long-term effects. Collaborative interdisciplinary investigations are imperative to fully realize LIFU's potential in revolutionizing SUD treatment paradigms and enhancing patient outcomes.

The Impact of Alcohol-Induced Epigenetic Modifications in the Treatment of Alcohol use Disorders.

Alcohol use disorders are responsible for 5.9% of all death annually and 5.1% of the global disease burden. It has been suggested that alcohol abuse can modify gene expression through epigenetic processes, namely DNA and histone methylation, histone acetylation, and microRNA expression. The alcohol influence on epigenetic mechanisms leads to molecular adaptation of a wide number of brain circuits, including the hypothalamus-hypophysis-adrenal axis, the prefrontal cortex, the mesolimbic-dopamine pathways and the endogenous opioid pathways. Epigenetic regulation represents an important level of alcohol-induced molecular adaptation in the brain. It has been demonstrated that acute and chronic alcohol exposure can induce opposite modifications in epigenetic mechanisms: acute alcohol exposure increases histone acetylation, decreases histone methylation and inhibits DNA methyltransferase activity, while chronic alcohol exposure induces hypermethylation of DNA. Some studies investigated the chromatin status during the withdrawal period and the craving period and showed that craving was associated with low methylation status, while the withdrawal period was associated with elevated activity of histone deacetylase and decreased histone acetylation. Given the effects exerted by ethanol consumption on epigenetic mechanisms, chromatin structure modifiers, such as histone deacetylase inhibitors and DNA methyltransferase inhibitors, might represent a new potential strategy to treat alcohol use disorder. Further investigations on molecular modifications induced by ethanol might be helpful to develop new therapies for alcoholism and drug addiction targeting epigenetic processes.

The Role of Dopamine in Impulsivity and Substance Abuse: A Narrative Review

Substance use disorder (SUD), based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), is defined by symptoms caused by utilizing a substance that a person continues taking despite its negative effects. Impulsive decision making is commonly defined as a reduced ability to choose a delayed large reward instead of a small immediate reward. Dopamine has been implicated as a prominent neurotransmitter implicated in the development and pattern of addiction and impulsivity, especially in regard to substance use disorder. Discovery as a key player in the development of addiction dates to the 1950s, with a study performed by Olds and Milner on rats placed in a Skinner box. Their original discovery is part of the beginning of what would become the search into the main mechanistic source of addiction, and how exactly it works at a cellular, physiological, and psychological level. The dopaminergic pathways of our brains are well-studied. It is well established that most of the dopaminergic neurons of the brain are located in the ventral mid-brain and consists of four main pathways: mesocortical, mesolimbic, nigrostriatal, and tuberoinfundibular pathways. Dopamine acts various receptors, with dopamine (D) receptors 1, 2, and 3 playing a major role in motor function and receptors D1 and D2 playing a major role in reward. There are additional studies warranted, especially finding ways to manipulate the dopaminergic system to treat addiction disorders of all varieties. The focus of the present investigation is to delve into the current literature regarding dopamine and its clinical implications in substance use disorder and impulsive behavior.

Does Incretin Agonism Have Sustainable Efficacy?

Recent clinical trials using synthetic incretin hormones, glucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists have demonstrated that these treatments ameliorated many complications related to obesity, emphasizing the significant impact of body weight on overall health. Incretins are enteroendocrine hormones secreted by gut endothelial cells triggered by nutrient ingestion. The phenomenon that oral ingestion of glucose elicits a much higher insulin secretion than intra-venous injection of equimolar glucose is known as the incretin effect. This also alludes to the thesis that food intake is the root cause of insulin resistance. Synthetic GLP-1 and GIP agonists have demonstrated unprecedented glucoregulation and body weight reduction. Also, randomized trials have shown their ability to prevent complications of obesity, including development of diabetes from prediabetes, reducing cardiovascular disease risks and renal complications in diabetic patients. Moreover, the benefits of these agonists persist among the patients who are already on metformin or insulin. The ultimate question is "Are these benefits of incretin agonism sustainable?" Chronic agonism of pancreatic β-cells may decrease the number of receptors and cause β-cell exhaustion, leading to β-cell failure. Unfortunately, the long-term effects of these drugs are unknown at the present because the longest duration in randomized trials is 3 years. Additionally, manipulation of the neurohormonal axis to control satiety and food intake may hinder the long-term sustainability of these treatments. In this review, we will discuss the incretins' mechanism of action, challenges, and future directions. We will briefly review other molecules involved in glucose homeostasis such as amylin and glucagon. Amylin is co-expressed with insulin from the pancreas β-cells but does not have insulinotropic function. Amylin suppresses glucagon secretion, slowing gastric emptying and suppressing the reward center in the central nervous system, leading to weight loss. However, amylin can self-aggregate and cause serious cytotoxicity and may cause β-cell apoptosis. Glucagon is secreted by pancreatic α-cells and participates in glucose homeostasis in a glucose-dependent manner. In hypoglycemia, glucagon increases the blood glucose level by glycogenolysis and gluconeogenesis and inhibits glycogenesis in the liver. Several triple agonists, in combination with dual incretins and glucagon, are being developed.

Multifunctional Neural Probes Enable Bidirectional Electrical, Optical, and Chemical Recording and Stimulation In Vivo.

Recording and modulation of neuronal activity enables the study of brain function in health and disease. While translational neuroscience relies on electrical recording and modulation techniques, mechanistic studies in rodent models leverage genetic precision of optical methods, such as optogenetics and fluorescent indicator imaging. In addition to electrical signal transduction, neurons produce and receive diverse chemical signals which motivate tools to probe and modulate neurochemistry. Although the past decade has delivered a wealth of technologies for electrophysiology, optogenetics, chemical sensing, and optical recording, combining these modalities within a single platform remains challenging. This work leverages materials selection and convergence fiber drawing to permit neural recording, electrical stimulation, optogenetics, fiber photometry, drug and gene delivery, and voltammetric recording of neurotransmitters within individual fibers. Composed of polymers and non-magnetic carbon-based conductors, these fibers are compatible with magnetic resonance imaging, enabling concurrent stimulation and whole-brain monitoring. Their utility is demonstrated in studies of the mesolimbic reward pathway by interfacing with the ventral tegmental area and nucleus accumbens in mice and characterizing the neurophysiological effects of a stimulant drug. This study highlights the potential of these fibers to probe electrical, optical, and chemical signaling across multiple brain regions in both mechanistic and translational studies.

Genomic Insights into Drug Abuse: The Role of DNA and Protein-Coding Regions in Addiction and Genetic Mutation

Abstract This paper explores the genetic and epigenetic impacts of drug abuse, focusing on how chronic drug use can induce mutations in DNA, particularly within protein-coding regions, and alter gene expression through mechanisms such as DNA methylation. The study highlights the significant role of these genetic changes in the brain's reward pathways, which contribute to the development and persistence of addiction. Through a comprehensive literature review, the paper identifies key genetic factors associated with addiction susceptibility and the long-term effects of drug-induced epigenetic modifications. A proposed research framework is presented, emphasizing the need for longitudinal studies to track epigenetic changes over time, targeted genomic analysis to identify critical mutations, and the integration of multi-omics approaches to provide a holistic understanding of drug abuse's impact on the genome. The paper also addresses ethical considerations, including the importance of protecting genetic privacy and preventing stigmatization based on genetic findings. The study concludes that advancing our understanding of the genetic and epigenetic mechanisms underlying addiction can lead to more effective, personalized treatment strategies and inform public health policies aimed at mitigating the effects of drug abuse.

Functional Adaptation in the Brain Habenulo-Mesencephalic Pathway During Cannabinoid Withdrawal.

The mesolimbic reward system originating from dopamine neurons in the ventral tegmental area (VTA) of the midbrain shows a profound reduction in function during cannabinoid withdrawal. This condition may underlie aversive states that lead to compulsive drug seeking and relapse. The lateral habenula (LHb) exerts negative control over the VTA via the GABA rostromedial tegmental nucleus (RMTg), representing a potential convergence point for drug-induced opponent processes. We hypothesized that the LHb-RMTg pathway might be causally involved in the hypodopaminergic state during cannabinoid withdrawal. To induce Δ9-tetrahydrocannabinol (THC) dependence, adult male Sprague-Dawley rats were treated with THC (15 mg/kg, i.p.) twice daily for 6.5-7 days. Administration of the cannabinoid antagonist rimonabant (5 mg/kg, i.p.) precipitated a robust behavioral withdrawal syndrome, while abrupt THC suspension caused milder signs of abstinence. Extracellular single unit recordings confirmed a marked decrease in the discharge frequency and burst firing of VTA dopamine neurons during THC withdrawal. The duration of RMTg-evoked inhibition was longer in THC withdrawn rats. Additionally, the spontaneous activity of RMTg neurons and of LHb neurons was strongly depressed during cannabinoid withdrawal. These findings support the hypothesis that functional changes in the habenulo-mesencephalic circuit are implicated in the mechanisms underlying substance use disorders.

Interaction between corticotropin-releasing factor, orexin, and dynorphin in the infralimbic cortex may mediate exacerbated alcohol-seeking behavior

A major challenge for the treatment of alcohol use disorder (AUD) is relapse to alcohol use, even after protracted periods of self-imposed abstinence. Stress significantly contributes to the chronic relapsing nature of AUD, given its long-lasting ability to elicit intense craving and precipitate relapse. As individuals transition to alcohol dependence, compensatory allostatic mechanisms result in insults to hypothalamic-pituitary-adrenal axis function, mediated by corticotropin-releasing factor (CRF), which is subsequently hypothesized to alter brain reward pathways, influence affect, elicit craving, and ultimately perpetuate problematic drinking and relapse vulnerability. Orexin (OX; also called hypocretin) plays a well-established role in regulating diverse physiological processes, including stress, and has been shown to interact with CRF. Interestingly, most hypothalamic cells that express Ox mRNA also express Pdyn mRNA. Both dynorphin and OX are located in the same synaptic vesicles, and they are co-released. The infralimbic cortex (IL) of the medial prefrontal cortex (mPFC) has emerged as being directly involved in the compulsive nature of alcohol consumption during dependence. The IL is a CRF-rich region that receives OX projections from the hypothalamus and where OX receptor mRNA has been detected. Although not thoroughly understood, anatomical and behavioral pharmacology data suggest that CRF, OX, and dynorphin may interact, particularly in the IL, and that functional interactions between these three systems in the IL may be critical for the etiology and pervasiveness of compulsive alcohol seeking in dependent subjects that may render them vulnerable to relapse. The present review presents evidence of the role of the IL in AUD and discusses functional interactions between CRF, OX, and dynorphin in this structure and how they are related to exacerbated alcohol drinking and seeking.

Effect of Raha syrup on the motivational effects of morphine and CSF serotonin levels in rats

Opiates may influence motivational processes by a dysregulation of brain reward pathways that play a role in context-induced reinstatement of drug seeking. Raha syrup as herbal bioactive compounds with anti-anxiety/depressant effects may be prevented morphine-induced reward and motivation effects. Therefore, the aim of this study was to investigate the effect of Raha syrup on the rewarding effects of morphine and motivational aspects of morphine-seeking behavior in morphine-induced conditioned place preference (CPP) model and also the cerebrospinal fluid (CSF) serotonin levels following the extinction and reinstatement in rats. In this study, adult male Wistar rats received Raha syrup via oral gavage to assess of the acquisition, extinction and reinstatement of the morphine-induced CPP and as well as measurement of the CSF serotonin levels. Administration of Raha syrup during the conditioning period significantly attenuated the acquisition of morphine-induced CPP, and increased the CSF serotonin level, 6 days after cessation of treatment during extinction, while did not affect the duration of the extinction period. Also, Raha syrup during the extinction period did not affect the reinstatement of morphine-induced CPP and the CSF serotonin levels in rats. We conclude that Raha syrup attenuated the acquisition of morphine reward probably through an increase in CSF serotonin, while could not maintain the extinguished CPP and had no effect on the reinstatement. Therefore, Raha syrup as a useful adjunctive therapeutic strategy may exert a protective effect against opiate-related rewards, while it may be ineffective to prevention of motivation or drug-seeking reinstatement (relapse).

5-HT2C receptors in the nucleus accumbens constrain the rewarding effects of MDMA.

MDMA is a promising adjunct to psychotherapy and has well-known abuse liability, although less than other amphetamine analogs. While the reinforcing dopamine (DA)-releasing properties of MDMA are on par with methamphetamine (METH), MDMA is a far more potent serotonin (5-HT) releaser, via the 5-HT transporter (SERT). MDMA-mediated 5-HT release in a major reward center, the nucleus accumbens (NAc), drives prosocial behaviors via 5-HT1BR activation. We hypothesized that this prosocial mechanism contributes to the reduced reinforcing properties of MDMA compared to METH and used a platform of assays to predict the balance of prosocial and abuse-linked effects of (R)-MDMA, a novel entactogen in clinical development. NAc DA release, measured by GRAB-DA photometry in vivo, increased in proportion to MDMA (7.5 and 15 mg/kg, i.p.) and METH (2 mg/kg i.p.)-conditioned place preference (CPP). Using conditional knockouts (cKOs) for DAT and SERT, microdialysis, and photometry, we found that MDMA-released 5-HT limited MDMA-released DA through actions in the NAc, rather than at ventral tegmental area DAergic cell bodies. SERT cKO reduced the MDMA dose required for CPP three-fold. This enhanced MDMA-CPP and increased DA release were replicated by intra-NAc infusion of either a 5-HT reuptake inhibitor (escitalopram) to prevent MDMA interaction with SERT, or a 5-HT2CR antagonist (SB242084), but not by the 5-HT1BR antagonist NAS-181. These data support separate mechanisms for the low abuse potential versus prosocial effect of MDMA. Using this platform of assays, (R)-MDMA is predicted to have prosocial effects and low abuse potential.

Behavioral changes and transcriptional regulation of mesolimbic dopaminergic genes in a mouse model of binge eating disorder by diet intermittent access

Binge Eating Disorder (BED) is among the most prevalent eating disorders worldwide. It is characterized by recurrent episodes of excessive consumption of palatable foods in short periods, accompanied by a sense of loss of control and distress around the episode, which tends to worsen over time. The mesolimbic dopaminergic system influences on reinforcement and reward-seeking behaviors is implicated in the disorder's pathogenesis. Animal models that replicate the clinical conditions observed in humans, including the disorder progression, are essential for understanding the underlying physiological mechanisms of BED. This study aimed to evaluate binge eating behavior induced by intermittent High Sugar and Butter (HSB) diet access in mice, their phenotypes, transcriptional regulation of mesolimbic dopaminergic system genes, and behavior. Thus, mice were subdivided into three groups: CHOW (maintenance diet only), HSB-i (maintenance diet with thrice-weekly access to HSB), and HSB (continuous access to HSB). Animals were subjected to marble-burying and light-dark box behavioral tests, and transcriptional regulation was evaluated by RT-qPCR. The results indicated that the HSB-i group established a feeding pattern of significantly more kilocalories on days when HSB was available and reduced intake on non-HSB days similar to human binge eating. Over time, binge episodes intensified, potentially indicating a tolerance effect. Additionally, these animals behave differently towards preferring the HSB diet and exhibited altered transcriptional regulation of the Drd1, Slc6a3, and Lrrk2 genes. Our study provides a mouse model that reflects human BED, showing a progression in binge episodes and mesolimbic dopamine pathway involvement, suggesting targets for future therapeutic interventions.

Investigating the Interrelationship between the Desire for a Cohesive Community and Opioid Abuse: A Neuropsychological Study of Demon Copperhead

Abstract Foregrounding the increasing global crisis of opioids as the “leading cause of deaths in fatal overdoses,” the World Drug Report 2023, published by the United Nations Office on Drugs and Crime (UNODC), mentioned that in 2021 more than 80,000 people died due to opioid overdose in the United States of America. The Centers for Disease Control and Prevention (CDC), the national public health protection agency in the United States, has reported that “the predicted number of drug overdose deaths showed an increase of 0.5% from the 12 months ending in December 2021 to the 12 months ending in December 2022, from 109,179 to 179,680” (“Provisional Data”). Although the trajectory of opioid use disorders (OUDs) has affected different sociodemographic groups in the country since its first wave in the 1990s, teenagers in poverty-stricken rural areas are more vulnerable to such addiction (Keyes et al.). Poor parental guidance, impoverishment, troubled childhoods, detrimental familial structure, scarce opportunities, and accessibility to opioids are often considered to be the primary risk factors for unprivileged teenagers to develop a psychic reliance on opioids for engendering a perpetual sense of contentment. According to the incentive sensitization theory, the persistent desire to transcend physical and psychical limitations for a sense of relief, triggered by chronic drug misuse, often evokes a sense of “wanting” or incentive salience, a compulsive inclination towards drug-associated stimuli (Berridge and Robinson, “Drug Addiction” 22). This intense desire of “wanting” often generates a perpetual sensitization of the mesolimbic systems in the brain which is also activated by mental representations of drug-associated cues (Robinson and Berridge 3139). Focusing on drug-induced changes in the brain such as hypersensitization and neuroadaptation, this study analyzes Barbara Kingsolver’s Demon Copperhead, a modern reimagining of David Copperfield by Charles Dickens. The selected text addresses primarily some pertinent socio-political crises, such as the poor foster care system, poverty, and the engrossing opioid endemic in Southern Appalachia. However, this study attempts to analyze the precarious state of some characters, who become addicted to opioids seeking recognition from peer groups and perpetual psychic stability, in the selected text from a neuropsychological perspective.

7173 Cabergoline Induced Psychosis in a Patient with no Previous History of Psychiatric Disorder

Abstract Disclosure: B. Aryal: None. K. Kim: None. A. Shafi: None. M. Ganesh: None. Introduction: Cabergoline is a dopamine agonist (DA) used to treat prolactinomas. It is well established that DAs may cause psychotic symptoms. However, very few cases report cabergoline-associated psychosis in patients without personal or family history of psychiatric disorders. We report a rare case of cabergoline-induced psychosis in a patient with a prolactinoma without any underlying psychiatric disorder, which was managed with the addition of olanzapine. Case: A 41 year old male with no history of psychiatric disorder was started on cabergoline 0.5mg twice a week for a newly diagnosed prolactinoma. 4 weeks later, he presented to the emergency room for aggressive behavior and confusion for the past 2 weeks. He endorsed visual and auditory hallucinations. Cabergoline was discontinued. During hospitalization, he attempted suicide and required 1:1 observation. He was started on olanzapine per the inpatient psychiatry team. Surgical resection of the prolactinoma was considered given his acute psychosis associated with cabergoline. However, complete resection of the tumor was deemed impossible given encasement of the internal carotid arteries. After discussion with the patient, he underwent re-challenge with cabergoline 0.25mg weekly while on olanzapine under 1:1 observation in the ICU. He was monitored for 2 weeks and eventually discharged home on cabergoline 0.25mg twice a week and olanzapine with improvement in prolactin levels to 4973.7 ng/mL after 4 weeks. He continued to remain free of psychotic symptoms upon follow up as an outpatient. Discussion: Psychosis is a rare side effect of DA mediated via D2/D3 receptors in the mesocortical and mesolimbic pathways. Several cases report psychosis associated with cabergoline in patients with a history of psychiatric disorders. However only one case reports de novo psychosis. Our patient developed severe psychosis while on low-dose cabergoline for 4 weeks. This rare case of de novo cabergoline-associated psychosis re-emphasizes that psychosis may occur regardless of previous history of psychiatric disorder and independent of the dose or duration of cabergoline. Treatment of a prolactinoma in the setting of cabergoline-associated psychosis requires a multidisciplinary approach. Alternative treatment of surgical resection was considered for our patient. However surgical resection was not plausible given difficult surgical anatomy. Therefore he was monitored closely to re-initiate cabergoline while on olanzapine. Several cases report successful use of clozapine, aripiprazole, and quetiapine for patients with psychiatric symptoms while on cabergoline. Patients who are on cabergoline should be closely monitored for any psychotic symptoms. Further studies are warranted to identify patients at risk of developing psychosis while on cabergoline to tailor an individualized approach to therapy and monitoring. Presentation: 6/2/2024

8684 Lifetime Duration of Amenorrhea Is Associated With Monetary Decision-Making and Hedonic Eating In Females With a Low-Weight Eating Disorder

Abstract Disclosure: F. Plessow: None. M. Wronski: None. M. Rogers: None. M.G. Turley: None. E.R. Golden: None. M. Slattery: None. J.J. Thomas: None. E.A. Lawson: None. M. Misra: None. K.T. Eddy: None. Background: Low estrogen levels and oligomenorrhea are common characteristics in females with a low-weight eating disorder (LWED). In animal models, estrogen status is associated with neural activity in dopaminergic reward pathways affecting reward processing and decision-making. Whether a similar link exists in humans is unknown but important to understand, as reduced reward-driven behavior and an increased delay of gratification driving decision-making hinder recovery from a LWED. To fill this knowledge gap, we studied the relationship between lifetime duration of amenorrhea and hedonic eating and monetary decision-making in a group of females with a LWED. We hypothesized that longer lifetime duration of amenorrhea is associated with reduced hedonic food intake and a smaller delay discounting rate (indicating an increased delay of gratification) in females with a LWED (independent of age and illness severity). Methods: Fifty-six females with a LWED (mean age±SD: 19.84±2.98 years, range: 13.6-23.5 years) and 34 female healthy controls (HC; 19.08±2.41 years, 13.4-22.2 years) underwent a menstrual history to determine the number of missed menses since menarche, Eating Disorder Examination (EDE) to assess ED psychopathology, anthropometric measurements to calculate body mass index (BMI), Cookie Taste Test as a laboratory-based assessment of reward-related eating beyond satiety, and a monetary Delay Discounting Task to determine their delay discounting rate. Between-group differences were tested using Mann-Whitney U-tests, and associations between duration of amenorrhea and caloric intake at the Cookie Taste Test and delay discounting rate in the LWED group were examined using partial Spearman correlations adjusted for age and BMI as a marker for illness severity. Results: By study design, females with a LWED had a lower BMI (17.97±2.16 vs. 21.71±2.57 kg/m2, U=1,802.50, p<0.001, r=0.75) and more pronounced ED psychopathology (EDE Global Score: 2.38±2.50 vs. 0.00±0.00, U=22.50, p<0.001, r=0.83) than HC. They had missed 16.50±22.64 menses since menarche. When controlling for age and BMI, longer lifetime duration of amenorrhea was correlated with lower caloric intake in the Cookie Taste Test (rs=-0.34, p=0.011) and a smaller delay discounting rate indicating an increased delay of gratification (rs=-0.40, p=0.004). Conclusions: This is the first demonstration that lifetime duration of amenorrhea is associated with hedonic food intake and monetary decision-making in females with a LWED, pointing towards a potential role of cumulative estrogen status in reward processing and decision-making in this population. Future research avenues include investigating whether estrogen replacement can increase reward responsiveness and reduce delay of gratification to promote a faster recovery from a LWED. Presentation: 6/1/2024