Promising immunomodulators for management of substance and alcohol use disorders.

INTRODUCTION: The neuroimmune system has emerged as a novel target for the treatment of substance use disorders (SUDs), with immunomodulation producing encouraging therapeutic benefits in both preclinical and clinical settings. AREAS COVERED: In this review, we describe the mechanism of action and immune response to methamphetamine, opioids, cocaine, and alcohol. We then discuss off-label use of immunomodulators as adjunctive therapeutics in the treatment of neuropsychiatric disorders, demonstrating their potential efficacy in affective and behavioral disorders. We then discuss in detail the mechanism of action and recent findings regarding the use of ibudilast, minocycline, probenecid, dexmedetomidine, pioglitazone, and cannabidiol to treat (SUDs). These immunomodulators are currently being investigated in clinical trials described herein, specifically for their potential to decrease substance use, withdrawal severity, central and peripheral inflammation, comorbid neuropsychiatric disorder symptomology, as well as their ability to improve cognitive outcomes. EXPERT OPINION: We argue that although mixed, findings from recent preclinical and clinical studies underscore the potential benefit of immunomodulation in the treatment of the behavioral, cognitive, and inflammatory processes that underlie compulsive substance use.

Methamphetamine and the Synthetic Cathinone 3,4-Methylenedioxypyrovalerone (MDPV) Produce Persistent Effects on Prefrontal and Striatal Microglial Morphology and Neuroimmune Signaling Following Repeated Binge-like Intake in Male and Female Rats.

Psychostimulants alter cellular morphology and activate neuroimmune signaling in a number of brain regions, yet few prior studies have investigated their persistence beyond acute abstinence or following high levels of voluntary drug intake. In this study, we examined the effects of the repeated binge-like self-administration (96 h/week for 3 weeks) of methamphetamine (METH) and 21 days of abstinence in female and male rats on changes in cell density, morphology, and cytokine levels in two addiction-related brain regions-the prefrontal cortex (PFC) and dorsal striatum (DStr). We also examined the effects of similar patterns of intake of the cocaine-like synthetic cathinone derivative 3,4-methylenedioxypyrovalerone (MDPV) or saline as a control. Robust levels of METH and MDPV intake (~500-1000 infusions per 96 h period) were observed in both sexes. We observed no changes in astrocyte or neuron density in either region, but decreases in dendritic spine densities were observed in PFC pyramidal and DStr medium spiny neurons. The microglial cell density was decreased in the PFC of METH self-administering animals, accompanied by evidence of microglial apoptosis. Changes in microglial morphology (e.g., decreased territorial volume and ramification and increased cell soma volume) were also observed, indicative of an inflammatory-like state. Multiplex analyses of PFC and DStr cytokine content revealed elevated levels of various interleukins and chemokines only in METH self-administering animals, with region- and sex-dependent effects. Our findings suggest that voluntary binge-like METH or MDPV intake induces similar cellular perturbations in the brain, but they are divergent neuroimmune responses that persist beyond the initial abstinence phase.

The dynamics of heroin and illicit opioid use disorder, casual use, treatment, and recovery: A mathematical modeling analysis.

A leading crisis in the United States is the opioid use disorder (OUD) epidemic. Opioid overdose deaths have been increasing, with over 100,000 deaths due to overdose from April 2020 to April 2021. This paper presents a mathematical model to address illicit OUD (IOUD), initiation, casual use, treatment, relapse, recovery, and opioid overdose deaths within an epidemiological framework. Within this model, individuals remain in the recovery class unless they relapse back to use and due to the limited availability of specialty treatment facilities for individuals with OUD, a saturation treatment function was incorporated. Additionally, a casual user class and its corresponding specialty treatment class were incorporated. We use both heroin and all-illicit opioids datasets to find parameter estimates for our models. Bistability of equilibrium solutions was found for realistic parameter values for the heroin-only dataset. This result implies that it would be beneficial to increase the availability of treatment. An alarming effect was discovered about the high overdose death rate: by 2046, the disorder-free equilibrium would be the only stable equilibrium. This consequence is concerning because it means the epidemic would end due to high overdose death rates. The IOUD model with a casual user class, its sensitivity results, and the comparison of parameters for both datasets, showed the importance of not overlooking the influence that casual users have in driving the all-illicit opioid epidemic. Casual users stay in the casual user class longer and are not going to treatment as quickly as the users of the heroin epidemic. Another result was that the users of the all-illicit opioids were going to the recovered class by means other than specialty treatment. However, the change in the relapse rate has more of an influence for those individuals than in the heroin-only epidemic. The results above from analyzing this model may inform health and policy officials, leading to more effective treatment options and prevention efforts.

Effects of repeated binge intake of the pyrovalerone cathinone derivative 3,4-methylenedioxypyrovalerone on prefrontal cytokine levels in rats - a preliminary study.

Drugs of abuse activate neuroimmune signaling in addiction-related regions of the brain, including the prefrontal cortex (PFC) which mediates executive control, attention, and behavioral inhibition. Traditional psychostimulants including methamphetamine and cocaine are known to induce PFC inflammation, yet the effects of synthetic cathinone derivatives are largely unexplored. In this study, we examined the ability of repeated binge-like intake of the pyrovalerone cathinone derivative 3,4-methylenedioxypyrovalerone (MDPV) to alter cytokine profiles in the PFC. Male and female rats were allowed to intravenously self-administer MDPV (0.05 mg/kg/infusion) or saline as a control under conditions of prolonged binge-like access, consisting of three 96 h periods of drug access interspersed with 72 h of forced abstinence. Three weeks following cessation of drug availability, PFC cytokine levels were assessed using antibody arrays. Employing the unsupervised clustering and regression analysis tool CytoMod, a single module of co-signaling cytokines associated with MDPV intake regardless of sex was identified. With regards to specific cytokines, MDPV intake was positively associated with PFC levels of VCAM-1/CD106 and negatively associated with levels of Flt-3 ligand. These findings indicate that prolonged MDPV intake causes changes in PFC cytokine levels that persist into abstinence; however, the functional ramifications of these changes remain to be fully elucidated.

Implications of starting antiepileptic treatment prior to electroencephalography in first epileptic seizures.

INTRODUCTION: This study aimed to determine whether the administration of antiepileptic drugs (AED) alters the likelihood of detecting epileptiform abnormalities in electroencephalographies (EEG) performed early after a first epileptic seizure. METHODS: We performed a retrospective, observational study including patients with a first seizure attended at our centre's emergency department between July 2014 and November 2019. We collected clinical data, as well as technical data on the acquisition and interpretation of the EEG performed within the first 72 hours after the seizure, and the factors related with seizure recurrence. RESULTS: We recruited 155 patients with a mean (SD) age of 48.6 (22.5) years; 61.3% were men. Regarding seizure type, 51% presented tonic-clonic seizures of unknown onset and 12% presented focal to bilateral tonic-clonic seizures. Thirty-nine patients (25.2%) received AED treatment before the EEG was performed: 33 received a non-benzodiazepine AED and 6 received a benzodiazepine. Epileptiform abnormalities were observed in 29.7% of patients. Previous administration of AEDs was not significantly associated with the probability of detecting interictal epileptiform abnormalities (P = .25) or with the risk of recurrence within 6 months (P = .63). CONCLUSIONS: Administration of AEDs before an early EEG following a first seizure does not decrease the likelihood of detecting epileptiform abnormalities. These findings suggest that starting AED treatment immediately in patients with a high risk of early recurrence does not imply a reduction in the diagnostic accuracy of the test.

Ocular axial length influence on peripapillary retinal nerve fiber layer thickness measurement with optical coherence tomography.

BACKGROUND: Optical coherence tomography (OCT) allows the measurement of the peripapillary optic nerve fiber layer (RNFL) thickness. The effect of ocular axial length (AL) on RNFL thickness measurement may be relevant in the interpretation of OCT results in diagnosing optic nerve diseases. PURPOSE: To assess the influence of ocular AL on RNFL thickness and on optic disc topographic parameters (optic disc area, rim area and cup volume) measured by OCT, in healthy individuals. METHODS: A sample of 109 healthy eyes classified into 3 groups according to AL (A: AL<22mm; B: AL 22-24.5mm; C: AL>24.5mm) was studied. RNFL thickness and optic disc topographic parameters were measured using Swept-Source OCT Triton (Topcon) and were compared between groups using a variance analysis. Correlation between the AL and the study variables was performed using a Pearson's correlation coefficient test. RESULTS: The RNFL thickness was lower in eyes with higher AL in the superior (r=-0.41; p<0.001), inferior (r=0.58; p<0.001) and nasal (r=-0.43; p<0.001) quadrants, in the mean value of the RNFL (r=-0.49; p<0.001), optic disc area (r=-0.40; p<0.001) and rim area (r=-0.25; p=0.01). CONCLUSIONS: AL is negatively correlated with RNFL thickness and optic disc topographic parameters measured by Swept-Source OCT Triton (Topcon).

Metabotropic glutamate receptors and cognition: From underlying plasticity and neuroprotection to cognitive disorders and therapeutic targets.

Metabotropic glutamate (mGlu) receptors are G protein-coupled receptors that play pivotal roles in mediating the activity of neurons and other cell types within the brain, communication between cell types, synaptic plasticity, and gene expression. As such, these receptors play an important role in a number of cognitive processes. In this chapter, we discuss the role of mGlu receptors in various forms of cognition and their underlying physiology, with an emphasis on cognitive dysfunction. Specifically, we highlight evidence that links mGlu physiology to cognitive dysfunction across brain disorders including Parkinson's disease, Alzheimer's disease, Fragile X syndrome, post-traumatic stress disorder, and schizophrenia. We also provide recent evidence demonstrating that mGlu receptors may elicit neuroprotective effects in particular disease states. Lastly, we discuss how mGlu receptors can be targeted utilizing positive and negative allosteric modulators as well as subtype specific agonists and antagonist to restore cognitive function across these disorders.

HIV gp120 impairs nucleus accumbens neuroimmune function and dopamine D3 receptor-mediated inhibition of cocaine seeking in male rats.

Cocaine Use Disorders (CUDs) are associated with an increased risk of human immunodeficiency virus (HIV) infection. Cocaine and the HIV envelope protein gp120 each induce distinct deficits to mesocorticolimbic circuit function and motivated behavior; however, little is known regarding how they interact to dysregulate these functions or how such interactions impact pharmacotherapeutic efficacy. We have previously shown that the selective, weak partial agonist of the dopamine D3 receptor (D3R), MC-25-41, attenuates cocaine-seeking behavior in male rats. Here, we sought to characterize changes in striatal neuroimmune function in gp120-exposed rats across abstinence from operant access to cocaine (0.75 mg/kg, i.v.) or sucrose (45 mg/pellet), and to examine the impact of gp120 exposure on MC-25-41-reduced cocaine seeking. After establishing a history of cocaine or sucrose self-administration, rats received intracerebroventricular gp120 infusions daily the first 5 days of abstinence and were sacrificed either on day 6 or after 21 days of forced abstinence and a cue-induced cocaine seeking test. We demonstrated that MC-25-41 treatment attenuated cue-induced cocaine seeking among control rats but not gp120-exposed rats. Moreover, postmortem analysis of nucleus accumbens (NAc) core neuroimmune function indicated cocaine abstinence- and gp120-induced impairments, and the expression of several immune factors within the NAc core significantly correlated with cocaine-seeking behavior. We conclude that cocaine abstinence dysregulates striatal neuroimmune function and interacts with gp120 to inhibit the effectiveness of a D3R partial agonist in reducing cocaine seeking. These findings highlight the need to consider comorbidities, such as immune status, when evaluating the efficacy of novel pharmacotherapeutics.

Current and emerging pharmacotherapies for opioid dependence treatments in adults: a comprehensive update.

INTRODUCTION: Opioid use disorder (OUD) is characterized by compulsive opioid seeking and taking, intense drug craving, and intake of opioids despite negative consequences. The prevalence of OUDs has now reached an all-time high, in parallel with peak rates of fatal opioid-related overdoses, where 15 million individuals worldwide meet the criteria for OUD. Further, in 2020, 120,000 opioid-related deaths were reported worldwide with over 75,000 of those deaths occurring within the United States. AREAS COVERED: In this review, we highlight pharmacotherapies utilized in patients with OUDs, including opioid replacement therapies, and opioid antagonists utilized for opioid overdoses and deterrent of opioid use. We also highlight newer treatments, such as those targeting the neuroimmune system, which are potential new directions for research given the recently established role of opioids in activating neuroinflammatory pathways, as well as over the counter remedies, including kratom, that may mitigate withdrawal. EXPERT OPINION: To effectively treat OUDs, a deeper understanding of the current therapeutics being utilized, their additive effects, and the added involvement of the neuroimmune system are essential. Additionally, a complete understanding of opioid-induced neuronal alterations and therapeutics that target these abnormalities - including the neuroimmune system - is required to develop effective treatments for OUDs.

Patients with initial nodal involvement due to breast cancer who have received neoadjuvant chemotherapy: Combined sentinel node-radioguided surgery of the pathological node.

OBJECTIVE: To study the feasibility and usefulness of ultrasound-guided pre-chemotherapy marking of pathologic lymph node followed by sentinel lymph node biopsy (SLNB)-pathologic node radioguided biopsy (ROLL) combined technique, in axillary involvement breast cancer patients undergoing neoadjuvant chemotherapy (NACT). MATERIAL AND METHODS: Prospective diagnostic study of 30 patients with breast cancer and cN1 axillary staging with NACT indication. Before NACT, the biopsied node was marked with a clip (MBN). After NACT an ultrasound was performed and in case of good response a SLNB (99mTc-nanocolloids) plus targeted axillary dissection MBN ROLL biopsy (99mTc-albumin macroaggregates) was performed. Axillary lymph node dissection (ALND) was performed if SLNB and/or MBN were positive for tumor cells. The localization-removal rate of the sentinel lymph node (SLN) and MBN were evaluated. False-negative rate (FNR) and positive predictive value (PPV) of SLNB alone were also evaluated. RESULTS: Thirty patients were included in the study. SLN could be detected in all patients while MBN was successfully removed in 27 (90%). The SLN coincided with MBN in 15 patients (50%). In 12 patients SLNB was negative while MBN positive, leading to a FNR of 44.4% for SLNB alone. We found a PPV of 37% for the SLNB. In 5 patients (18.5%) both SLNB and MBN were negative, avoiding ALND. CONCLUSIONS: SLNB-MBN radioguided biopsy ROLL combined technique is a useful and accessible procedure for accurate axillary restaging after NACT, avoiding the high rate of FNR of SLNB alone in this group of patients and avoiding a great number of ALND.

Sex differences and the lack of effects of chemogenetic manipulation of pro-opiomelanocortin (POMC) neurons on alcohol consumption in male and female mice.

The endogenous opioid system has been implicated in the rewarding and reinforcing effects of alcohol. Pro-opiomelanocortin (POMC) neurons located within the arcuate nucleus of the hypothalamus (ArcN) secrete multiple peptides associated with alcohol consumption, including ß-endorphin (ß-END), α-melanocyte stimulating hormone (α-MSH), and adrenocorticotropic hormone (ACTH). In this study, we utilized chemogenetics to bidirectionally modulate ArcN POMC neurons to determine their role in alcohol and saccharin consumption and regional levels of POMC-derived peptides. Male and female POMC-cre mice were infused with viral vectors designed for cre-dependent expression of either excitatory and inhibitory DREADDs or a control vector into the ArcN. Following recovery, animals were allowed to consume alcohol or saccharin using the drinking-in-the-dark (DID) paradigm of binge-like intake for 4 consecutive days. Prior to the final test session, animals were injected with clozapine-N-oxide (2.5 mg/kg, i.p.) for DREADD activation. Following the last DID session, animals were euthanized and the ArcN, VTA, amygdala and NAc were dissected and assessed for POMC peptide expression utilizing western blotting. We found that female mice consumed more alcohol than males during DID sessions 2-4, and that chemogenetic activation had no effect on alcohol or saccharin consumption in either sex. We found that ß-END expression within the ArcN positively correlated with alcohol consumption. Given the molecular and functional heterogeneity of ArcN POMC neurons, future studies are needed to assess the effects of modulation of specific subpopulations of these neurons within the ArcN on consumption of rewarding substances such as alcohol and saccharin.

Ethanol consumption activates a subset of arcuate nucleus pro-opiomelanocortin (POMC)-producing neurons: a c-fos immunohistochemistry study.

Ethanol activates various opioid peptide-containing circuits within the brain that may underlie its motivational and rewarding effects. One component of this circuitry consists of neurons located in the arcuate nucleus (ArcN) of the hypothalamus which express pro-opiomelanocortin (POMC), an opioid precursor peptide that is cleaved to form bioactive fragments including ß-endorphin and α-melanocyte stimulating hormone. In this study, we sought to determine if ethanol intake activates ArcN POMC neurons as measured by expression of the immediate early gene c-fos. Male and female POMC-EGFP mice underwent drinking-in-the-dark (DID) procedures for 3 consecutive days (2 h/day) and were allowed to consume either ethanol (20% v/v), saccharin (0.2% w/v), or water. On the fourth day of DID procedures, animals were allowed to consume their respective solutions for 20 min, and 1 h following the session brains were harvested and processed for c-fos immunohistochemistry and co-localization with EGFP. Our results indicate that ethanol intake activates a subset (~15-20%) of ArcN POMC neurons, whereas saccharin or water intake activates significantly fewer (~5-12%) of these neurons. The percent of activated POMC neurons did not correlate with blood ethanol levels at the time of tissue collection, and activation appeared to be distributed throughout the rostrocaudal axis of the ArcN. No sex differences were observed in the degree of neuronal activation across drinking solutions. These findings indicate a preferential activation of ArcN POMC neurons by ethanol consumption, strengthening the notion that ethanol activates endogenous opioid systems in the brain which may underlie its motivational properties.

Nuclear factor kappa B signaling within the rat nucleus accumbens core sex-dependently regulates cue-induced cocaine seeking and matrix metalloproteinase-9 expression.

Chronic drug self-administration and withdrawal are associated with distinct neuroimmune adaptations that may increase drug craving and relapse vulnerability in humans. The nuclear factor kappa-B (NF-κB) pathway is a critical regulator of many immune- and addiction-related genes such as the extracellular matrix enzyme matrix metalloproteinase-9 (MMP-9), which is a known modulator of learning, memory, and synaptic plasticity. While some studies suggest striatal NF-κB signaling may regulate drug-conditioned behavior, no studies to date have examined whether NF-κB signaling within the nucleus accumbens core (NAc core) alters downstream neuroimmune function and cue-motivated cocaine seeking following a period of forced abstinence, whether any effects are specific to cocaine over other reinforcers, or whether sex differences exist. Here, we examined whether viral-mediated knockdown of the p65 subunit of NF-κB within the NAc core would alter MMP-9 expression and cue-induced cocaine- and sucrose-seeking behavior following a period of forced abstinence in male and female rats. We demonstrate that NAc core p65 knockdown results in a significant decrease in cue-induced cocaine seeking in males but not females. This effect was specific to cocaine, as p65 knockdown did not significantly affect cue-induced sucrose seeking in either males or females. Moreover, we demonstrate that males express higher levels of MMP-9 within the NAc core and nucleus accumbens shell (NAcSh) compared to females, and that p65 knockdown significantly decreases MMP-9 in the NAc core of males but not females among cocaine cue-exposed animals. Altogether, these results suggest that NAc core NF-κB signaling exerts modulatory control over cue-motivated drug-seeking behavior and downstream neuroimmune function in a sex-specific manner. These findings highlight the need to consider sex as an important biological variable when examining immunomodulatory mechanisms of cocaine seeking.