Effects of ambient temperature on locomotor activity and place conditioning elicited by abused psychostimulants in mice: Role of 3,4-methylenedioxy moiety.

BACKGROUND: Humans often administer psychostimulants in party or music festival settings characterized by warm ambient temperatures, which may impact drug effects; however, preclinical studies rarely investigate drug effects at multiple ambient temperatures. Work with 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxypyrovalerone (MDPV) suggests that the presence of a 3,4-methylenedioxy ring moiety may influence ambient temperature-dependent effects. METHODS: Locomotor activity and conditioned place preference dose-response curves were generated at 20±2°C for two amphetamine analogues (MDMA and methamphetamine [METH]) and two cathinone analogues (MDPV and α-pyrrolidinopentiophenone [αPVP]) in mice. Effects were then redetermined at 29±2°C for each drug and assay. RESULTS: All four drugs elicited dose-dependent locomotor stimulation at the cool ambient temperature. At the warm ambient temperature, MDMA and MDPV produced sensitization to stereotypy, whereas METH and αPVP produced sensitization to locomotor activity. Regarding place conditioning, the warm ambient environment potentiated place preference elicited by doses of METH and αPVP that were sub-threshold in the cool ambient environment, but attenuated the effects of analogous doses of MDMA and MDPV. CONCLUSIONS: These studies suggest that warmer ambient temperatures may potentiate typical stimulant effects for the drugs lacking the 3,4-methylenedioxy ring, but may potentiate the behaviorally toxic/adverse effects for the drugs containing a 3,4-methylenedioxy ring. Thus, preclinical abuse liability studies conducted at standard laboratory temperatures may not fully capture the effects of psychostimulants and highlight the need to model the environments in which drugs are typically used by humans.

Can internet use become addictive?

Problematic internet use parallels drug addiction, but the mechanisms are not yet clear.

Comparison of Pain in Male Drug Rehabilitees with and without Human Immunodeficiency Virus in Yunnan Province, China.

BACKGROUND The purpose of this study was to compare pain symptoms in drug rehabilitees with or without human immunodeficiency virus (HIV) in Yunnan Province, China. MATERIAL AND METHODS This was a retrospective single-center cohort study. A total of 120 male substance users, including 65 with HIV, were enrolled after admission to the Fifth Drug Rehabilitation Center in Yunnan Province. Individuals who were >18 years of age and who had illicit drugs detected in their urine, despite not having used drugs for at least 2 months, were included. The patients evaluated their average pain intensity for the previous 4 weeks using a visual analog scale. PainDETECT questionnaire scores were used to classify pain into nociceptive and mixed component subgroups. Sleep quality was also evaluated using the Pittsburgh Sleep Quality Index scale. RESULTS The prevalence and intensity of the pain symptoms were higher for the drug rehabilitees with HIV than for those without HIV. Moreover, the rehabilitees with HIV were more likely to experience neuropathic and nociceptive pain, whereas those without HIV reported only nociceptive pain. The sleep quality of the rehabilitees with HIV was also lower, regardless of the pain symptoms. CONCLUSIONS Our results showed that the drug rehabilitees with HIV in Yunnan Province, China, experienced more frequent and stronger pain (both nociceptive and neuropathic) than those without HIV. They also experienced poorer sleep quality, although it was unrelated to pain. Our results provide data to support clinical diagnosis and treatment.

Personal attributes and attitudes to substance use disorder: A study among Jordanian undergraduate medical majors students.

BACKGROUND: Emerging health professionals in undergraduate programs should be equipped to provide care to people with substance use disorder (SUD). The students' personal attributes may impact their attitude toward those with SUD. This study aims to evaluate the impact of personal attributes of Jordanian undergraduate health students on their attitudes toward SUD and examine the relationship between the personal attributes and their devaluation and discriminatory (stigmatory) behaviour toward those with SUD. METHOD: A cross-sectional descriptive design was used to examine the attitudes and stigmatory behaviours. The data were collected between May to October 2017 with a structured questionnaire that consisted of three parts: 1) a data sheet to collect the socio-demographic characteristics of the participants, 2) the Acute Mental Health Scale (ATAMHS), and 3) the Devaluation-Discrimination Scale (DDS). FINDINGS: Younger and females demonstrated a positive attitude toward those with SUD compared to older or male students. Age, gender, and previous experience with SUD are significant factors that affect their attitude. CONCLUSION: Identifying the attitude to people with SUD and personal attributes of emerging health professionals in Jordan will help identify the need to educate them prior to their entry into practice.

Closing the brain-heart loop: Towards more holistic models of addiction and addiction recovery.

Much research seeks to articulate the brain structures and pathways implicated in addiction and addiction recovery. Prominent neurobiological models emphasize the interplay between cortical and limbic brain regions as a main driver of addictive processes, but largely do not take into consideration sensory and visceral information streams that link context and state to the brain and behavior. Yet these brain-body information streams would seem to be necessary elements of a comprehensive model of addiction. As a starting point, we describe the overlap between one current model of addiction circuitry and the neural network that not only regulates cardiovascular system activity but also receives feedback from peripheral cardiovascular processes through the baroreflex loop. We highlight the need for neurobiological, molecular, and behavioral studies of neural and peripheral cardiovascular signal integration during the experience of internal states and environmental contexts that drive alcohol and other drug use behaviors. We end with a call for systematic, mechanistic research on the promising, yet largely unexamined benefits to addiction treatment of neuroscience-informed, adjunctive interventions that target the malleability of the cardiovascular system to alter brain processes.

Effects of substance misuse on inhibitory control in patients with attention-deficit/hyperactivity disorder.

Patients with attention-deficit/hyperactivity disorder (ADHD) are often diagnosed with comorbid substance misuse (SM), which is associated with poor treatment efficacy. Although literature indicates similar inhibitory control deficits in both conditions, it is unclear whether SM in ADHD exaggerates pre-existing deficits, with additive or distinct impairments in patients. Our aim was to examine SM effects on inhibitory control in ADHD. Behavioural and functional magnetic resonance imaging (fMRI) data from a stop-signal task were compared across ADHD patients with and without SM (ADHD + SM and ADHD-only, respectively) and controls (n = 33/group; 79 males, mean age 18.02 ± 2.45). To limit substance use disorder (SUD) trait effects, groups were matched for parental SUD. Overall, we found worse performance for ADHD-only and/or ADHD + SM compared with controls but no difference between the ADHD groups. Moreover, the ADHD groups showed decreased frontostriatal and frontoparietal activity during successful and failed stop trials. There were no differences between the ADHD groups in superior frontal nodes, but there was more decreased activation in temporal/parietal nodes in ADHD-only compared with ADHD + SM. During go-trials, ADHD + SM showed decreased activation in inferior frontal nodes compared with ADHD-only and controls. Findings during response inhibition showed deficits in inhibition and attentional processes for ADHD patients with and without SM. Despite no evidence for SM effects during response inhibition, results during go-trials suggest distinct effects on nodes that are associated with several executive functions. Future studies should investigate whether distinct deficits in ADHD + SM relate to poor treatment results and can direct development of distinct ADHD treatment strategies for these patients.

Association of prenatal substance use disorders with pregnancy and birth outcomes following bariatric surgery.

BACKGROUND/OBJECTIVES: While an increased risk for substance use disorders (SUD) and also for several adverse pregnancy and birth outcomes in patients who have undergone bariatric surgery have been well documented when considered separately, an association between these important risk factors has not been investigated. This study explored the potential dependence of these two bariatric surgery-related risks. SUBJECTS/METHODS: This study was a retrospective cohort study with adult women (18-45) who underwent bariatric surgery between 1996 and 2016 and who gave birth after surgery between 1996 and 2018. The study population consisted of 1849 post-bariatric surgery women with 3010 reported post-surgical births. Subjects with post-surgical, prenatal SUD were identified based on diagnosis codes extracted within the 10 months prior to delivery. Using random-effects logistic regression with retrospective cohort data, preterm birth, low birth weight, macrosomia, Caesarian delivery, congenital anomalies, and neonatal intensive care unit admission were considered as outcomes. RESULTS: About 10% (n = 289) of women had an SUD diagnosis within 10 months prior to child delivery. Women with SUD during pregnancy had significantly more pregnancy and birth complications compared to women without SUD: preterm birth (OR = 2.08, p = 0.03, 95% CI: 1.07-4.03), low birth weight (OR = 3.41, p < 0.01, 95% CI: 1.99-5.84), Caesarian delivery (OR = 9.71, p < 0.01, 95% CI: 2.69-35.05), and neonatal intensive care unit admission (OR = 3.87, p < 0.01, 95% CI: 2.04-7.34). Women with SUD had lower risk for macrosomia than women without SUD (OR = 0.07, p = 0.02, 95% CI: 0.01-0.70). CONCLUSION: Results from this study demonstrated that post-bariatric surgery women who had SUD during pregnancy had significantly more pregnancy- and birth-related complications than post-surgery pregnant women without SUD, despite the reduction in macrosomia. Where possible, greater prenatal surveillance of post-surgery women with SUD should be considered.

Role of Nociceptin/Orphanin FQ-NOP Receptor System in the Regulation of Stress-Related Disorders.

Nociceptin/orphanin FQ (N/OFQ) is a 17-residue neuropeptide that binds the nociceptin opioid-like receptor (NOP). N/OFQ exhibits nucleotidic and aminoacidics sequence homology with the precursors of other opioid neuropeptides but it does not activate either MOP, KOP or DOP receptors. Furthermore, opioid neuropeptides do not activate the NOP receptor. Generally, activation of N/OFQ system exerts anti-opioids effects, for instance toward opioid-induced reward and analgesia. The NOP receptor is widely expressed throughout the brain, whereas N/OFQ localization is confined to brain nuclei that are involved in stress response such as amygdala, BNST and hypothalamus. Decades of studies have delineated the biological role of this system demonstrating its involvement in significant physiological processes such as pain, learning and memory, anxiety, depression, feeding, drug and alcohol dependence. This review discusses the role of this peptidergic system in the modulation of stress and stress-associated psychiatric disorders in particular drug addiction, mood, anxiety and food-related associated-disorders. Emerging preclinical evidence suggests that both NOP agonists and antagonists may represent a effective therapeutic approaches for substances use disorder. Moreover, the current literature suggests that NOP antagonists can be useful to treat depression and feeding-related diseases, such as obesity and binge eating behavior, whereas the activation of NOP receptor by agonists could be a promising tool for anxiety.

Barreiras para a prática de atividades físicas entre usuários de substâncias psicoativas / Barreras para la actividad física en consumidores de sustancias psicoactivas / Barriers to physical activity among users of psychoactive substances

Objetivo: Verificar as barreiras que influenciam a não realização de atividade física no tempo livre entre usuários de substâncias psicoativas.Método: 144 indivíduos com média de idade de 44.3±12.6 anos foram entrevistados respondendo um questionário que verifica as barreiras para a prática de atividades físicas. Foi aplicado o teste Qui-quadrado de independência aceitando um p<0.05 como significativo.Resultados: Os dados mostraram que há associação entre as sentenças do questionário e o padrão de resposta dos indivíduos [x2(13)=193.88; p≤0.001]. Foi encontrada significância como barreira para prática de atividade física o cansaço físico, falta de companhia, falta de incentivo familiar e acometimento de dores leves ou mal-estar. Por outro lado, a falta de tempo, fator climático, não disponibilidade no ambiente, não disponibilidade de equipamento e falta de habilidade física foram apontados, significativamente, como não serem barreiras para a prática de atividade física em usuários de substâncias psicoativas.Conclusão: A partir destes dados será possível estabelecer estratégias mais efetivas para a promoção da prática de atividade física nesta população. (AU)

Objetivo: Verificar las barreras que influyen en los usuarios de sustancias psicoactivas para no utilizar su tiempo libre para practicar actividad física.Método: 144 personas, con edad de 44.3 ± 12.6 años, respondieron a un cuestionario sobre las barreras para la practica de actividad física. Se aplicó el test de independencia de chi-cuadrado, aceptando como significativa um valor de p<0.05.Resultados: Los datos muestran que existe asociación entre las sentencias del cuestionario y el patrón de respuesta de los individuos [x2(13)=193.88; p≤0.001]. Se consideró significativa la existencia de barreras para la práctica de actividad física como el cansancio físico, la falta de un compañero y motivación familiar, padecimiento de dolores o malestar ligeros. Por otro lado, la falta de tiempo, el factor climático, la indisponibilidad en el medio ambiente, la falta de equipos y de entrenamiento físico no fueron señalados de manera significativa como barreras para la práctica de actividad física en usuarios de sustancias psicoactivas.Conclusión: En base a estos datos, será posible establecer estrategias más efectivas para promover la práctica de actividad física en esta población. (AU)

Objective: To verify the barriers that influence the non-performance of physical activity in free time among users of psychoactive substances.Methods: 144 individuals with a mean age of 44.3±12.6 years were interviewed by answering a questionnaire that checks the barriers to physical activity. The Chi-square test of independence was applied accepting a p<0.05 as significant.Results: The data showed that there is an association between the sentences of the questionnaire and the response pattern of individuals [x2(13)=193.88; p≤0.001]. Significance was found as a barrier to physical activity the physical tiredness, lack of company, lack of family incentive and involvement of mild pain or discomfort. On the other hand, lack of time, climatic factor, non-availability in the environment, non-availability of equipment, and lack of physical ability were significantly pointed out as not being barriers to the practice of physical activity in users of psychoactive substances.Conclusion: From these data it will be possible to establish more effective strategies for the promotion of physical activity in this population. (AU)

Nonclinical evaluation of abuse liability of the dual orexin receptor antagonist lemborexant.

Lemborexant is a dual orexin receptor antagonist (DORA) approved in multiple countries including the United States, Japan, Canada and Australia for the treatment of adults with insomnia. As required for marketing approval of new compounds with central nervous system activity with sedating effects, the abuse potential of lemborexant was assessed in accordance with regulatory guidelines, which included three nonclinical studies. These assessments comprised physical dependence and drug discrimination studies in rats and a self-administration study in rhesus monkeys. There was no evidence of withdrawal signs following abrupt drug discontinuation, indicating that lemborexant does not induce physical dependence. In the drug discrimination study, lemborexant at doses up to 1000 mg/kg administered orally did not cross-generalize to the zolpidem training stimulus, although another DORA included in the same experiment, suvorexant, showed partial generalization with zolpidem. In rhesus monkeys, lemborexant treatment did not induce any gross behavioral changes, and there was no increase in self-administration rates compared with control, indicative of a lack of reinforcing effects of lemborexant. Collectively, these nonclinical studies support the position that lemborexant, which has been placed in Schedule IV by the United States Drug Enforcement Administration, has a low risk of abuse in humans.

Effects of adolescent substance use disorders on central cholinergic function.

Adolescence is a transitional period between childhood and adulthood, in which the individual undergoes significant cognitive, behavioral, physical, emotional, and social developmental changes. During this period, adolescents engage in experimentation and risky behaviors such as licit and illicit drug use. Adolescents' high vulnerability to abuse drugs and natural reinforcers leads to greater risk for developing substance use disorders (SUDs) during adulthood. Accumulating evidence indicates that the use and abuse of licit and illicit drugs during adolescence and emerging adulthood can disrupt the cholinergic system and its processes. This review will focus on the effects of peri-adolescent nicotine and/or alcohol use, or exposure, on the cholinergic system during adulthood from preclinical and clinical studies. This review further explores potential cholinergic agents and pharmacological manipulations to counteract peri-adolescent nicotine and/or alcohol abuse.

Characteristic changes in EEG spectral powers of patients with opioid-use disorder as compared with those with methamphetamine- and alcohol-use disorders.

Electroencephalography (EEG) likely reflects activity of cortical neurocircuits, making it an insightful estimation for mental health in patients with substance use disorder (SUD). EEG signals are recorded as sinusoidal waves, containing spectral amplitudes across several frequency bands with high spatio-temporal resolution. Prior work on EEG signal analysis has been made mainly at individual electrodes. These signals can be evaluated from advanced aspects, including sub-regional and hemispheric analyses. Due to limitation of computational techniques, few studies in earlier work could conduct data analyses from these aspects. Therefore, EEG in patients with SUD is not fully understood. In the present retrospective study, spectral powers from a data house containing opioid (OUD), methamphetamine/stimulants (MUD), and alcohol use disorder (AUD) were extracted, and then converted into five distinct topographic data (i.e., electrode-based, cortical subregion-based, left-right hemispheric, anterior-posterior based, and total cortex-based analyses). We found that data conversion and reorganization in the topographic way had an impact on EEG spectral powers in patients with OUD significantly different from those with MUD or AUD. Differential changes were observed from multiple perspectives, including individual electrodes, subregions, hemispheres, anterior-posterior cortices, and across the cortex as a whole. Understanding the differential changes in EEG signals may be useful for future work with machine learning and artificial intelligence (AI), not only for diagnostic but also for prognostic purposes in patients with SUD.

Gray areas: Neuropeptide circuits linking the Edinger-Westphal and Dorsal Raphe nuclei in addiction.

The circuitry of addiction comprises several neural networks including the midbrain - an expansive region critically involved in the control of motivated behaviors. Midbrain nuclei like the Edinger-Westphal (EW) and dorsal raphe (DR) contain unique populations of neurons that synthesize many understudied neuroactive molecules and are encircled by the periaqueductal gray (PAG). Despite the proximity of these special neuron classes to the ventral midbrain complex and surrounding PAG, functions of the EW and DR remain substantially underinvestigated by comparison. Spanning approximately -3.0 to -5.2 mm posterior from bregma in the mouse, these various cell groups form a continuum of neurons that we refer to collectively as the subaqueductal paramedian zone. Defining how these pathways modulate affective behavioral states presents a difficult, yet conquerable challenge for today's technological advances in neuroscience. In this review, we cover the known contributions of different neuronal subtypes of the subaqueductal paramedian zone. We catalogue these cell types based on their spatial, molecular, connectivity, and functional properties and integrate this information with the existing data on the EW and DR in addiction. We next discuss evidence that links the EW and DR anatomically and functionally, highlighting the potential contributions of an EW-DR circuit to addiction-related behaviors. Overall, we aim to derive an integrated framework that emphasizes the contributions of EW and DR nuclei to addictive states and describes how these cell groups function in individuals suffering from substance use disorders. This article is part of the special Issue on 'Neurocircuitry Modulating Drug and Alcohol Abuse'.

The rostromedial tegmental (RMTg) "brake" on dopamine and behavior: A decade of progress but also much unfinished work.

Between 2005 and 2009, several research groups identified a strikingly dense inhibitory input to midbrain dopamine neurons arising from a previously uncharted region posterior to the ventral tegmental area (VTA). This region is now denoted as either the rostromedial tegmental nucleus (RMTg) or the "tail of the VTA" (tVTA), and is recognized to express distinct genetic markers, encode negative "prediction errors" (inverse to dopamine neurons), and play critical roles in behavioral inhibition and punishment learning. RMTg neurons are also influenced by many categories of abused drugs, and may drive some aversive responses to such drugs, particularly cocaine and alcohol. However, despite much progress, many important questions remain about RMTg molecular/genetic properties, diversity of projection targets, and applications to addiction, depression, and other neuropsychiatric disorders. This article is part of the special Issue on 'Neurocircuitry Modulating Drug and Alcohol Abuse'.

Covid-19 interface with drug misuse and substance use disorders.

The coronavirus disease 2019 (Covid-19) pandemic intensified the already catastrophic drug overdose and substance use disorder (SUD) epidemic, signaling a syndemic as social isolation, economic and mental health distress, and disrupted treatment services disproportionally impacted this vulnerable population. Along with these social and societal factors, biological factors triggered by intense stress intertwined with incumbent overactivity of the immune system and the resulting inflammatory outcomes may impact the functional status of the central nervous system (CNS). We review the literature concerning SARS-CoV2 infiltration and infection in the CNS and the prospects of synergy between stress, inflammation, and kynurenine pathway function during illness and recovery from Covid-19. Taken together, inflammation and neuroimmune signaling, a consequence of Covid-19 infection, may dysregulate critical pathways and underlie maladaptive changes in the CNS, to exacerbate the development of neuropsychiatric symptoms and in the vulnerability to develop SUD. This article is part of the special Issue on 'Vulnerabilities to Substance Abuse'.

CalDAG-GEFI mediates striatal cholinergic modulation of dendritic excitability, synaptic plasticity and psychomotor behaviors.

CalDAG-GEFI (CDGI) is a protein highly enriched in the striatum, particularly in the principal spiny projection neurons (SPNs). CDGI is strongly down-regulated in two hyperkinetic conditions related to striatal dysfunction: Huntington's disease and levodopa-induced dyskinesia in Parkinson's disease. We demonstrate that genetic deletion of CDGI in mice disrupts dendritic, but not somatic, M1 muscarinic receptors (M1Rs) signaling in indirect pathway SPNs. Loss of CDGI reduced temporal integration of excitatory postsynaptic potentials at dendritic glutamatergic synapses and impaired the induction of activity-dependent long-term potentiation. CDGI deletion selectively increased psychostimulant-induced repetitive behaviors, disrupted sequence learning, and eliminated M1R blockade of cocaine self-administration. These findings place CDGI as a major, but previously unrecognized, mediator of cholinergic signaling in the striatum. The effects of CDGI deletion on the self-administration of drugs of abuse and its marked alterations in hyperkinetic extrapyramidal disorders highlight CDGI's therapeutic potential.

A systematic review of the effect of ovarian sex hormones on stimulant use in females.

Stimulant use disorder is associated with significant global health burden. Despite evidence for sex differences in the development and maintenance of stimulant use disorder, few studies have focused on mechanisms underpinning distinct trajectories in females versus males, including the effect of the ovarian sex hormones estrogen and progesterone. This review aimed to identify and synthesise the existing preclinical and clinical literature on the effect of ovarian sex hormones on stimulant consumption in females. A systematic search of peer-reviewed literature identified 1593 articles, screened using the following inclusion criteria: (1) adult female humans or animals, (2) using stimulant drugs, (3) ovarian sex hormones were administered exogenously OR were measured in a validated manner and (4) with stimulant consumption as an outcome measure. A total of 50 studies (3 clinical and 47 preclinical) met inclusion criteria. High-estrogen (low progesterone) phases of the menstrual/estrus cycle were associated with increased stimulant use in preclinical studies, while there were no clinical studies examining estrogen and stimulant consumption. Consistent preclinical evidence supported progesterone use reducing stimulant consumption, which was also identified in one clinical study. The review was limited by inconsistent data reporting across studies and different protocols across preclinical laboratory paradigms. Importantly, almost all studies examined cocaine use, with impact on methamphetamine use a significant gap in the existing evidence. Given the safety and tolerability profile of progesterone, further research is urgently needed to address this gap, to explore the potential therapeutic utility of progesterone as a treatment for stimulant use disorder.

Real time monitoring of dopamine release evoked by mitragynine (Kratom): An insight through electrochemical sensor.

BACKGROUND: Mitragynine, the major indole alkaloid from Mitragyna speciosa has been reported previously to possess abuse liability. However, there are insufficient data suggesting the mechanism through which this pharmacological agent causes addiction. AIMS: In this study, we investigated the effects of mitragynine on dopamine (DA) level and dopamine transporter (DAT) expression from the rat's frontal cortex. METHODS: DA level was recorded in the brain samples of animals treated with acute or repeated exposure for 4 consecutive days with either vehicle or mitragynine (1 and 30 mg/kg) using electrochemical sensor. Animals were then decapitated and the brain regions were removed, snap-frozen in liquid nitrogen and immediately stored at -80 °C. DA level was quantified using Enzyme linked immunosorbent assay (ELISA) kits and DAT gene expression was determined using quantitative real time polymerase chain reaction (RT-qPCR). RESULTS/OUTCOME: Mitragynine (1 and 30 mg/kg) did not increase DA release following acute treatment, however, after repeated exposure at day 4, mitragynine significantly and dose dependently increased DA release in the frontal cortex. In this study, we also observed a significant increase in DAT mRNA expression at day 4 in group treated with mitragynine (30 mg/kg). CONCLUSION/INTERPRETATION: Data from this study indicates that mitragynine significantly increased DA release when administered repeatedly, increased in DAT mRNA expression with the highest tested dose (30 mg/kg). Therefore, the rewarding effects observed after mitragynine administration could be due to its ability to increase DA content in certain areas of the brain especially the frontal cortex.

Emerging Benefits: Pathophysiological Functions and Target Drugs of the Sigma-1 Receptor in Neurodegenerative Diseases.

The sigma-1 receptor (Sig-1R) is encoded by the SIGMAR1 gene and is a nonopioid transmembrane receptor located in the mitochondrial-associated endoplasmic reticulum membrane (MAM). It helps to locate endoplasmic reticulum calcium channels, regulates calcium homeostasis, and acts as a molecular chaperone to control cell fate and participate in signal transduction. It plays an important role in protecting neurons through a variety of signaling pathways and participates in the regulation of cognition and motor behavior closely related to neurodegenerative diseases. Based on its neuroprotective effects, Sig-1R has now become a breakthrough target for alleviating Alzheimer's disease and other neurodegenerative diseases. This article reviews the most cutting-edge research on the function of Sig-1R under normal or pathologic conditions and target drugs of the sigma-1 receptor in neurodegenerative diseases.

Circuit and neuropeptide mechanisms of the paraventricular thalamus across stages of alcohol and drug use.

The paraventricular nucleus of the thalamus (PVT) is a midline thalamic brain region that has emerged as a critical circuit node in the regulation of behaviors across domains of affect and motivation, stress responses, and alcohol- and drug-related behaviors. The influence of the PVT in this diverse array of behaviors is a function of its ability to integrate and convey information about salience and valence through its connections with cortical, hypothalamic, hindbrain, and limbic brain regions. While understudied to date, recent studies suggest that several PVT efferents play critical and complex roles in drug and alcohol-related phenotypes. The PVT is also the site of signaling for many neuropeptides released from the synaptic terminals of distal inputs and local neuropeptidergic neurons within. While there is some evidence that neuropeptides including orexin, neurotensin, substance P, and cocaine and amphetamine-related transcript (CART) signal in the PVT to regulate alcohol/drug intake and reinstatement, there remains an overall lack of understanding of the roles of neuropeptides in the PVT in addiction-related behaviors, especially in a circuit-specific context. In this review, we present the current status of preclinical research regarding PVT circuits and neuropeptide modulation of the PVT in three aspects of the addiction cycle: reward/acquisition, withdrawal, and relapse, with a focus on alcohol, opioids (particularly morphine), and psychostimulants (particularly cocaine). Given the PVT's unique position within the broader neural landscape, we further discuss the potential ways in which neuropeptides may regulate these behaviors through their actions upon PVT circuits. This article is part of the special Issue on 'Neurocircuitry Modulating Drug and Alcohol Abuse'.