key: cord-0982424-t10lf9ly
authors: Cisneros, I.E.; Cunningham, K.A.
title: Covid-19 interface with drug misuse and substance use disorders
date: 2021-08-26
journal: Neuropharmacology
DOI: 10.1016/j.neuropharm.2021.108766
sha: e4b05d756db282c2d8d4509a03d2abd485b9bde2
doc_id: 982424
cord_uid: t10lf9ly

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 resulting inflammatory outcomes may impact the functional status 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.

Coronavirus disease 2019 emerged as a world-historical pandemic which will change our lives for generations, and the end of this global crisis is not in sight. Covid-19 is the third coronavirus in the last 20 years to transmit from an animal reservoir to humans (Salajegheh Tazerji et al., 2020) . The causative virus has been designated severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV2), a single-strand RNA virus. SARS-CoV2 is genetically close, but a distinct version of the viruses which caused the outbreak of SARS in 2003 and Middle East respiratory syndrome (MERS) in 2012 (Viruses, 2020) . The epidemiology and clinical findings to date suggest that Covid-19 presents with a wide spectrum of disease characteristics. The virus devastates host cell function in the lung, resulting in respiratory damage as a primary cause of death in some cases, despite mechanical ventilation to achieve lung recovery (Hanidziar and Bittner, 2020) . Although the host risk factors are not yet completely clear, chronic comorbidities (e.g., diabetes, cardiovascular and pulmonary diseases) are thought to be key contributors to severe Covid-19 disease (Alhazzani et al., 2020; Qin et al., 2020; Zhao et al., 2020) , potentially due in part to the exuberant inflammatory response to infection ("cytokine storm") (Stebbing et al., 2020) . Additionally, neurological indicators of Covid-19 disease (e.g., confusion, delirium, dysphoria) have surfaced, suggesting that the central nervous system (CNS) involvement may contribute to the sustained pathophysiology of Covid-19 (Baig et al., 2020; Wu et al., 2020) .

The synergism between two or more health conditions within the context of both disease and societal factors has been used frequently to understand the morbidity and mortality associated with human immunodeficiency virus (HIV) transmission and substance use disorders (SUDs) Sil et al., 2021; Tyagi et al., 2016) . The syndemic concept is now relevant to the overlapping crises associated with the Covid-19 pandemic and the epidemic of abused drug misuse, overdose, and the incidence of SUDs.

The Center for Disease Control and Prevention (CDC) reports that more than 33 million people have contracted SARS-CoV2 and nearly 600,000 individuals in the U.S. have succumbed to Covid-19 ((NCHS), 2021; Statistics, 2021; System, 2021) . In parallel, drug overdose deaths claimed a reported 91,862 people in the U.S. in the 12month period ending in October of 2020; up by ~30% vs. the previous year (provisional data) (Ahmad et al., J o u r n a l P r e -p r o o f

The drug overdose crisis has resulted in the death of nearly 500,000 individuals between 1999-2018, the majority related to the opioid class of drugs [e.g., prescription pain relievers, synthetic opioids (fentanyl derivatives), heroin] (Upp and Waljee, 2020) . In addition to opioid overdoses, cocaine-and methamphetaminerelated fatalities increased nearly 30%, by approximately 10 deaths daily, between 1999 and 2018 (Hedegaard et al., 2020) . Alarmingly, the CDC reported that 30% of overdose deaths involved a combination of stimulants and opioids and 10% involved stimulants alone (O'Donnell et al., 2020) . Unfortunately, an 18.6% increase in non-fatal overdoses and an 11.4% increase in fatal overdose deaths have been observed during the stay-athome orders in 2020 (Alter and Yeager, 2020b; Niles et al., 2021) . Drug urine tests performed four months before and after the initiation of pandemic stay-at-home orders indicated increased prevalence of methamphetamine and cocaine use during the Covid-19 pandemic (Wainwright et al., 2020) . In fact, the CDC estimates that 13.3% of people began using or increased use of abused substances as of June 2020 (Czeisler et al., 2020 ) and a selfdescribed 34% increase in binge drinking by U.S. adults was also observed during the social isolation conditions of the pandemic (Weerakoon et al., 2021) . About 40% of individuals increased tobacco use during the pandemic at a time that 71% of individuals indicated a heightened motivation to quit smoking tobacco and/or electronic cigarettes to reduce harms from Covid-19 (Kowitt et al., 2020) . These indicators signal the potential for further elevations in drug overdoses and rises in the prevalence of SUDs.

Substance use disorders are diagnosed in the U.S. with the Diagnostic and Statistical Manual of Mental Disorders-5 which outlines major SUD indicators (e.g., risky drug use, social/interpersonal difficulties linked to use, withdrawal/tolerance, failed efforts to control use, etc.) on a scale from mild to severe (Hasin et al., 2013) ; this nosology also includes craving (a strong desire or urge to take a drug) which is often triggered by cues associated with drug use (e.g., paraphernalia) and elevated stress levels (Koob, 2020; Koob and Volkow, 2016; Volkow et al., 2019) . The intoxication induced by a psychoactive drug, when perceived as pleasurable, motivates the user toward episodes of intake, punctuated with escalating misuse and abuse, craving and/or withdrawal effects. This cycle can devolve into a diagnosis of a SUD in susceptible individuals. Termination of drug use and efforts to sustain abstinence can be marked by a high recidivism rate and reversion to drug-using behavior which interrupts the progress of abstinence and rehabilitation. The magnifying disorder that advances from drug use to misuse to SUD is linked to CNS pathophysiology which engages an "expanding cycle of dysfunction" in cognition, J o u r n a l P r e -p r o o f learning, reward, and emotion (Koob, 2020; Koob and Volkow, 2016; Volkow et al., 2019) . Malfunctional synaptic plasticity in the CNS is a key pathological element in SUDs, which is dependent on the operational conversation across neurons, astrocytes, brain-resident microglia, and oligodendrocytes and is influenced by the neurovascular "unit" of endothelia and blood-born cells (leukocytes, platelets, erythrocytes) which carry peripheral immune cells and released pro-and anti-inflammatory cytokines and chemokines (Boulanger, 2009; He and Crews, 2008; Mahajan et al., 2008; Malaplate-Armand et al., 2005; Niu et al., 2019) . The status of CNS immunological function is impacted by exposure to life stressors, like those associated with Covid-19 during stayat-home orders and risk for contracting SARs-CoV2 infection, which evoke adaptations further impacting the experience of drug abuse (Clay and Parker, 2018; Koob and Kreek, 2007; Kreek et al., 2005; Vida et al., 2014; Wang et al., 2021b) . The accumulation of these components likely contributes to an increased risk for drug misuse, overdose, and escalation of SUDs during the pandemic and following recovery from Covid-19.

Disturbingly, 20% of respondents diagnosed with SUDs reported a consequent increase in drug use (Hulsey et al., 2020) , elevating the challenges in sustaining abstinence and recovery and complicating efforts to reduce drug overdoses.

Increased drug use and misuse during the Covid-19 pandemic is likely attributable to a multitude of stressors including the intense anxiety about the dangers of becoming infected, the trauma of deaths and disabilities in communities, and the socioeconomic impact of lost employment (Taylor et al., 2021; Volkow and Blanco, 2021) .

In addition, the probability of a synergistic interaction between the immunological and inflammatory aspects of Covid-19 and the pathophysiology of SUDs cannot be discounted (Tien et al., 2011) , especially given evidence to suggest that stress and drug misuse cycles promote the development of SUDs through elevated inflammatory cytokines (Blednov et al., 2015; Fox et al., 2012; Hueston et al., 2011; Loftis et al., 2013; Mandrekar et al., 2002; Truitt et al., 2016) . Neurological consequences of Covid-19 may contribute to these rises in drug use and misuse and are potentially uncaptured side effects of Covid-19 illness that impedes full recovery. Thus, activation of CNS resident immune cells and amplification of inflammation, have a reciprocal effect on stress and substance abuse, which may be additive during co-morbidity and neurological sequalae of Covid-19.

J o u r n a l P r e -p r o o f

The Coronaviridae family of pathogen viruses present a clinical profile characterized primarily by respiratory involvement. However, SARs-CoV2 has the potential to be neuroinvasive based upon clinical, translational, and basic research conducted with SARS-CoV and the MERS-CoV (Arabi et al., 2015; Ng Kee Kwong et al., 2020) . Multiple studies demonstrate that, aside from SARS-CoV2 acute respiratory engagement, SARS-CoV2 is neuroinvasive with observed CNS manifestations of Covid-19 (Bullen et al., 2020; Cantuti-Castelvetri et al., 2020; Jacob et al., 2020; Puelles et al., 2020; Ramani et al., 2020; Solomon et al., 2020; Song et al., 2021; Yang et al., 2020a) . The mRNA for SARS-CoV2 was detected in human brain (Puelles et al., 2020; Solomon et al., 2020) and cortical neurons in autopsied patients who died of Covid-19 (Song et al., 2021) . Viral SARS-CoV2 proteins were also found in endothelial cells of the olfactory bulb in human Covid-19 autopsies (Cantuti-Castelvetri et al., 2020) . Several in vitro studies report SARS-CoV2 infection of human pluripotent stem cell-derived neural cells, human neurons of three-dimensional brain organoids, neural-perivascular assembloids, and neurospheres (Bullen et al., 2020; Jacob et al., 2020; Ramani et al., 2020; Song et al., 2021; Wang et al., 2021a; Yang et al., 2020a) ; however, the definitive routes of CNS infiltration for SARs-CoV2 remain to be identified. Thus, the virus invades neurons, and can be detected in CNS regions with direct connection to the point of entry in the olfactory mucosa, but other mechanisms and entry routes may allow trans-endothelial migration into brain parenchyma.

Neuroinvasive dissemination routes of SARS-CoV2 are proposed to include olfactory transmucosal invasion by retrograde transport along sensory and olfactory nerves, thereby bypassing the blood brain barrier (BBB) (Baig et al., 2020) . Alternatively, the hematogenous route via the systemic circulatory system may allow SARS-CoV2 to disseminate into the CNS via transcellular/paracellular migration or the Trojan horse strategy through host phagocytes (Perrin et al., 2021) . Moreover, SARS-CoV2 interacts with key human host factors including angiotensin-converting enzyme 2 (ACE2) receptor, transmembrane protease serine (TMPRSS) 2/4, cathepsin L (CTSL), two-pore channel subtype 2 (TPCN2), and neuropilin-1 (NRP-1) to trigger target cell and organ invasion (Matschke et al., 2020) . In silico analyses revealed the highest expression of ACE2 localizes to oligodendrocytes, NRP-1 and TPCN2 to astrocytes, CTSL to microglia, TMPRSS2/4 to neurons and NRP-1 to endothelial cells of the brain (Matschke et al., 2020) . These host factors are implicated in viral tropism to the J o u r n a l P r e -p r o o f CNS. In brain tissue collected from postmortem Covid-19 patients, common neuropathological findings included astrogliosis in multiple brain regions, microglial activation, and infiltration of cytotoxic T-lymphocytes in the brainstem and cerebellum which point to clinical findings suggestive of viral and autoimmune encephalitis (Matschke et al., 2020) . These authors also reported the detection of SARS-CoV2 RNA and viral proteins in the brains of 53% of the fatalities (Ludlow et al., 2016; Matschke et al., 2020) . Therefore, detection of SARS-CoV2 RNA, protein, and CNS localized host proteins including ACE2, TMPRSS2/4, CTSL, TPCN2 and NRP-1, suggest that SARS-CoV2 can infiltrate the CNS, activating neuroimmune signaling through host proteins.

Elevated levels of the circulating pro-and anti-inflammatory proteins (i.e. cytokines and chemokines), such as interleukin (IL)-1, IL-4, IL-6, IL-10, interferon (IFN)-, tumor necrosis factor (TNF)-, chemokine (C-X-C) ligand (CXCL)10, and monocyte chemoattractant (MCP)-1 have been measured during the clinical course of Covid-19 (Bouadma et al., 2020; Bronte et al., 2020; Han et al., 2020; La Rosée et al., 2020) . High concentrations of cytokines appear related to the more severe cases of Covid-19 based upon epidemiological evidence Ludlow et al., 2016) . Despite the identification of SARS-CoV2 RNA and viral proteins in the brains of patients who died of Covid-19, little clinical data are available to firmly establish the nature and extent of inflammatory-specific events in the CNS. However, recent findings suggest SARS-CoV2-associated CNS inflammation given observations of a high degree of astrogliosis, microglial activation and localization of microglial nodules in the brainstem and cerebellum in postmortem Covid-19 patients (Matschke et al., 2020) .

Magnetic resonance imaging scans revealed reactive astrogliosis in postmortem brains (Coolen et al., 2020; Kanberg et al., 2020) and increased glial fibrillary acidic protein levels in plasma of patients who succumbed to Covid-19 (Coolen et al., 2020; Kanberg et al., 2020) , indicating pathological events occurring in the CNS (Brommeland et al., 2007; Nylén et al., 2006; Quddusi and (Reynolds and Mahajan, 2021) . Considering previous evidence of activated CNS immune signaling associated with SARS and MERS infection, this cross-section of recent findings illustrates that SARs-CoV2 profoundly impacts immunological function in the brain.

The amino acid protein l-tryptophan is an essential amino acid precursor for the biosynthesis of the small endogenous molecules serotonin and melatonin as well as for numerous important CNS and immune system proteins. The kynurenine pathway is a major route of degradation of ingested l-tryptophan not used for protein synthesis which accounts for ~95% of the dietary tryptophan disposal (Yu et al., 1999) . During tryptophan degradation, the bioactive compound kynurenic acid is produced and accounts for diverse biological functions, including regulation of the immune responsivity and involvement in immune-mediated disorders (Huang et al., 2020b) . Several viral infections, including human immunodeficiency virus (HIV) (Huengsberg et al., 1998) Therefore, it is possible that the kynurenine pathway is a driving factor in the development of Covid-19 neurological sequelae given that the kynurenine pathway is activated in patients with Covid-19. In two separate metabolomic studies, Covid-19 patients had significantly reduced serum levels of tryptophan and serotonin and elevated serum levels of L-kynurenine (Shen et al., 2020; Thomas et al., 2020) . In another study, severely ill Covid-19 patients showed significantly higher L-kynurenine levels compared to Covid-19 negative or control patients (Fraser et al., 2020) . These studies did not evaluate CNS levels of kynurenine or kynurenic acid; however, transgenic mice devoid of ACE2, which binds the SARS-CoV2 spike protein, uptake less tryptophan from the gut compared to their wild-type controls (Schwarcz, 2016; Singer et al., 2012) and exhibit significantly lower levels of serotonin in blood and brain (Klempin et al., 2018) , implicating ACE2 as modulator in serotonin synthesis. The dopamine synthetic pathway also engages ACE2 mechanisms (Attademo and Bernardini, 2021) .

Employing a multi-experiment matrix web tool that utilizes microarray datasets to merge information from J o u r n a l P r e -p r o o f different datasets and mine for co-expression, dopa decarboxylase (DDC), an enzyme which converts l-3,4dihydroxyphenylalanine (l-DOPA) into dopamine and l-5-hydroxytryptophan into serotonin, exhibits the highest statistically significant co-expression link with ACE2 (Nataf, 2020) . These findings suggest an association between ACE2 function and dopamine/serotonin synthesis by DDC.

Kynurenic acid, a product of l-tryptophan metabolism, also inhibits dopamine release and reduces extracellular dopamine levels in the rat striatum (Borland and Michael, 2004; Wu et al., 2007) . This is in part through kynurenic acid-induced antagonism of glutamate receptors and therefore kynurenic acid is also considered a major regulator of glutamatergic activity in the CNS strongly linking the kynurenine pathway to glutamate imbalance (Borland and Michael, 2004; Meier et al., 2016) . Alleviating kynurenic acid accumulation in the CNS is thought to positively impact mental health (Wu et al., 2007) . Although kynurenine, or its pathway metabolites have not been measured in the CNS of Covid-19 patients, cumulatively, these finding suggest the potential importance of ACE2-kynurenine interactions with serotonin, dopamine, and glutamate systems in normal brain function, and implicates kynurenine dysregulation in the neuropsychiatric and neurological consequences associated with Covid-19.

The bidirectional relationship between innate immunity and the kynurenine pathway provides further evidence for the potential progression of neuropsychiatric disorders during and following recovery from Covid-19. For example, immune signaling, like that induced by Covid-19, impacts downstream metabolism of the kynurenine pathway, including quinolinic and kynurenic acid and the neurotransmitters serotonin, dopamine, and glutamate Capuron and Miller, 2011; Maes et al., 2002) . Inflammation stimulates the activity and expression of the enzyme indoleamine dioxygenase (IDO) which metabolizes tryptophan to kynurenine rather than to serotonin (Badawy, 2017; Kiank et al., 2010; O'Connor et al., 2009; Yisireyili et al., 2018) , decreasing the availability of the primary amino acid precursor for the synthesis of serotonin, setting the stage for the disorders mediated by the serotonin system, including the cascade into depression which is resistant to treatment with selective serotonin reuptake inhibitors (for review) (Roman and Irwin, 2020) .

Preclinical studies demonstrate that a lipopolysaccharide (LPS) challenge which activates the immune system, J o u r n a l P r e -p r o o f increases IDO activity and expression (Dobos et al., 2012) which likely activates the metabolism of l-tryptophan to kynurenine, initiating an excitotoxic imbalance, based on the strong link of kynurenine to glutamate dysregulation (Borland and Michael, 2004; Meier et al., 2016) . Decreased levels of tryptophan and serotonin and increased levels of kynurenine were correlated to levels of IL-6 in Covid-19 patients, associated inflammation, and kynurenine (Thomas et al., 2020) . Similarly, several studies observed reduced levels of tryptophan and serotonin and elevated levels of L-kynurenine in serum collected from Covid-19 patients (Shen et al., 2020; Thomas et al., 2020) , likely via increased IDO activity dictated by inflammatory cytokines and chemokines generated during infection with SARS-CoV2. In line with these studies, patients suffering from HCV-induced cognitive impairments, have increased IDO expression in liver and peripheral monocytes, and increased blood levels of kynurenine that correlate to cognitive dysfunction (Larrea et al., 2007; Schulz et al., 2015; Weinstein et al., 2019) . Moreover, patients suffering from HIV-associated dementia had increased IDO activity when compared to HIV patients without dementia (Sardar and Reynolds, 1995) . In preclinical studies, HIV significantly increase extracellular glutamate concentrations in an in vitro astrocyte model that corresponds to clinical studies demonstrating increased excitotoxicity in patients suffering from HIV-associate neurocognitive disorders (Cisneros and Ghorpade, 2014; Cisneros et al., 2020; Fields et al., 2013) . Although, IDO levels and activity have not been measured in Covid-19 patients, it is likely that triggering of the immune system by SARS-CoV2 increases IDO activity and kynurenine levels thereby decreasing serotonin and dopamine levels and increasing glutamate excitotoxicity in Covid-19. Thus, dysregulation of the host factor ACE2, inflammation, and altered synthesis and levels of serotonin, dopamine, and glutamate via the kynurenine pathway, during Covid-19 is strongly related to neurological sequalae (Schematic 2).

Glutamate, dopamine, and serotonin crosstalk with the immune system and maladaptive changes induced by inflammation may certainly contribute to increased vulnerability to SUDs, although direct and clear experimental designs for definitive studies are difficult to develop. For instance, TNF- and IL-1, classical proinflammatory cytokines, inhibit glutamate uptake in astrocytes and increase ionotropic glutamate receptor expression at the synapse Ghorpade, 2012, 2014; Cisneros et al., 2020; Olmos and Lladó, 2014; Pickering et al., 2005) and activating glutamate transporters in glial cells reduces cocaine and methamphetamine J o u r n a l P r e -p r o o f induced CPP and significantly decreases cocaine self-administration (Nakagawa et al., 2005; Northcutt et al., 2015) . Reduced clearance and increased levels of synaptic glutamate is a central mechanism underlying SUD pathophysiology and associated cocaine-and heroin-seeking behaviors. In vitro, in vivo, and ex vivo studies demonstrate that proinflammatory cytokines, including IL-1, TNF-, and downstream signaling pathways that include p38 mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-B) can modulate the functional activity of serotonin, which is involved in the transition to compulsive drug use behaviors (Bubar and Cunningham, 2006; Cunningham and Anastasio, 2014; Howell and Cunningham, 2015; Müller and Homberg, 2015; Nic Dhonnchadha and Cunningham, 2008; Schwamborn et al., 2016; Steiner et al., 2008; Walsh and Cunningham, 1997; Zhu et al., 2010) . Chronic inflammation is characterized to decrease dopamine levels in the CNS which aligns with a similar observation for chronic drug use (Lacagnina et al., 2017; Treadway et al., 2019) , supporting the interactive relationship between these system in control of SUD behaviors and implications for CNS mechanisms underlying drug reward (Di Chiara, 2002) .

Substances of abuse additionally dysregulate immune signaling driving the complexity associated with understanding maladaptive changes that increase vulnerability to SUDs. Although both TNF- and IL-1, cytokines that modulate the activity of serotonin, dopamine, and glutamate, are canonically increased during viral infections, such as HIV (Chivero et al., 2017; Vartak-Sharma et al., 2014) and Covid-19 (McElvaney et al., 2020; , substances of abuse can be both immunostimulatory and immunosuppressive. For instance, inflammatory cytokines and chemokines are increased and decreased following exposure to cocaine (Atluri et al., 2016; Kovalevich et al., 2015; Montesinos et al., 2020; Souza et al., 2021) , methamphetamine (Karimi-Haghighi et al., 2020; Kays and Yamamoto, 2019; Wang et al., 2018; Yang et al., 2020b) and/or alcohol (Barr et al., 2016; Crews et al., 2006) and dysregulated following opioid exposure (Cisneros and Cunningham, 2021; Ezeomah et al., 2020) . For example, we demonstrated increased and decreased inflammation in the nucleus accumbens relative to the hippocampus in rats withdrawn from chronic self-administration of the opioid fentanyl; these outcomes positively correlated to expression of specific host pattern recognition receptors that trigger inflammatory cascades (Cisneros and Cunningham, 2021; Ezeomah et al., 2020) . An unanswered question remains as to the impact of such drug-induced inflammatory changes to perpetuate fentanyl selfadministration; if this is the case, there may be the potential anti-inflammatory therapeutics to help mitigate J o u r n a l P r e -p r o o f continuing opioid abuse. For instance, opiate antagonists which are used to treat alcohol and opiate use disorders also block induction of innate immune cytokine and chemokine generation, and prevent LPS-induced immune responses (Liu et al., 2000a; Liu et al., 2000b) . Perhaps, prevention of inflammatory cytokine and chemokine cascades may reduce alcohol and opiate use. Although statistical significance was not achieved, the TNF- inhibitor pentoxifylline tended to decrease cocaine use in clinical studies conducted in cocaine-dependent individuals relative to placebo (Ciraulo et al., 2005) . Further studies are also required to evaluate whether the immune-kynurenine pathway is directly involved in mediating inflammation evoked by cocaine or other abused drugs. Based on the evidence presented, we speculate that inflammation-induced dysregulation of serotonin, dopamine and glutamate may trigger interacting aspects of underlying the pathophysiology of SUDs and compulsive drug-seeking behaviors (Koob et al., 2014; Koob and Volkow, 2016) . Taken together, inflammation and its relationship to this pathophysiology of SUD development and maintenance is undoubtedly complex and worthy of further investigation.

SARS-CoV2, the virus that causes Covid-19, activates the host immune system, thereby impacting the onset of neurological sequelae. The severity of neuropsychiatric and neurocognitive symptoms of Covid-19 are directly associated with the levels of circulating inflammatory cytokines and chemokines Ludlow et al., 2016) . Based on the evidence presented in this review, we suspect that inflammation in the CNS, initiated by host immune responses to SARS-CoV2, results in dysregulation in tryptophan metabolism, dually triggered by IDO activity and ACE2 functionality. Increased levels of peripheral kynurenine and CNS kynurenic acid are predicted to destabilize normal serotonin, dopamine and glutamate function vital for normal brain functioning.

Alterations in these neurotransmitters are strongly related to drug use and misuse and the vulnerability to develop SUD (Schematic 3). More research is needed to further dissect (1) the CNS inflammatory response to  (2) the causal relationship of the immune-kynurenine pathway with Covid-19 neurological sequalae; (3) the impact of Covid-19-related inflammation on IDO activity and interruption of serotonin, dopamine and glutamate metabolism; (4) the role of Covid-19 CNS inflammation in the evolution of drug misuse and SUD; and (5) the regulation of CNS-expressed Covid-19 host factors (e.g., ACE2, TMPRSS2/3, CTSL, NRP-1, TPCN2) following exposure to drugs of abuse and how impaired host factors contribute to sustained clinical challenges during J o u r n a l P r e -p r o o f recovery. In summary, as the research field continues to explore these questions and the Covid-19 pandemic continues, we hope that gains in knowledge will frame the means through which we can mitigate suffering of those co-morbid for SUDs and the sequela of Covid-19. The identification of specific targets related to SARS-CoV2-induced inflammation may help guide novel therapeutics approaches to alleviate the future SUD burdens.

Acknowledgements: This work was supported by the National Institute on Drug Abuse (DA050317-S1; KAC, IEC) and R01 DA052263 (IEC, KAC).

J o u r n a l P r e -p r o o f SCHEMATICS Schematic 1: Relationship between Covid-19, inflammation and SUDs. Inflammation and neuroimmune signaling related to Covid-19 infection underlay maladaptive changes within key brain regions involved in the formation of drug abuse and SUD behaviors.

Schematic 2: SARS-CoV2 host factors and inflammation in the regulation serotonin, dopamine, and glutamate. We propose that SARS-CoV2 may activate host factors and increase peripheral levels of inflammatory cytokines and chemokines with the potential to reduce tryptophan and serotonin functionality while while kynurenine is increased in Covid-19 patients. With increased IDO activity upon Covid-19-evoked inflammation, tryptophan metabolism may be diverted from maintaining serotonin function into increased levels of kynurenine and kynurenic acid. Given that kynurenic acid antagonizes glutamate receptors and increases glutamate concentrations, excitotoxicity may become a challenge. Kynurenic acid also inhibits dopamine release thereby reducing dopamine levels in the brain.

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Cocaine induces nuclear export and degradation of neuronal retinoid X receptor-γ via a TNF-α/JNK-mediated mechanism

Tobacco Quit Intentions and Behaviors among Cigar Smokers in the United States in Response to COVID-19

Genetic influences on impulsivity, risk taking, stress responsivity and vulnerability to drug abuse and addiction

Accelerated Overdose Deaths Linked With COVID-19

The Janus kinase 1/2 inhibitor ruxolitinib in COVID-19 with severe systemic hyperinflammation

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

Upregulation of indoleamine 2,3-dioxygenase in hepatitis C virus infection

Glial mechanisms underlying substance use disorders

Naloxone protects rat dopaminergic neurons against inflammatory damage through inhibition of microglia activation and superoxide generation

Systemic infusion of naloxone reduces degeneration of rat substantia nigral dopaminergic neurons induced by intranigral injection of lipopolysaccharide

Partial MHC/neuroantigen peptide constructs: a potential neuroimmune-based treatment for methamphetamine addiction

The role of gut-immune-brain signaling in substance use disorders

Neurotropic virus infections as the cause of immediate and delayed neuropathology

Depressive and anxiety symptoms in the early puerperium are related to increased degradation of tryptophan into kynurenine, a phenomenon which is related to immune activation

Methamphetamine alters blood brain barrier permeability via the modulation of tight junction expression: Implication for HIV-1 neuropathogenesis in the context of drug abuse

Effect of acute and chronic psychostimulant drugs on redox status, AP-1 activation and pro-enkephalin mRNA in the human astrocyte-like U373 MG cells

Inhibition of NF-kappa B binding correlates with increased nuclear glucocorticoid receptor levels in acute alcohol-treated human monocytes

Cytokine Storms: Understanding COVID-19

Neuropathology of patients with COVID-19 in Germany: a post-mortem case series

Anxiety and depression in COVID-19 survivors: Role of inflammatory and clinical predictors

Relationship between neurotoxic kynurenine metabolites and reductions in right medial prefrontal cortical thickness in major depressive disorder

Cocaine-induced changes in CX

Addiction and the kynurenine pathway: A new dancing couple?

The role of serotonin in drug use and addiction

Effect of MS-153, a glutamate transporter activator, on the conditioned rewarding effects of morphine, methamphetamine and cocaine in mice

An alteration of the dopamine synthetic pathway is possibly involved in the pathophysiology of COVID-19

The Role of NFkB in Drug Addiction: Beyond Inflammation

COVID-19, SARS and MERS: A neurological perspective

Serotonergic mechanisms in addiction-related memories

The Opioid Epidemic Within the COVID-19 Pandemic: Drug Testing in 2020

Cocaine-induced release of CXCL10 from pericytes regulates monocyte transmigration into the CNS

DAT isn't all that: cocaine reward and reinforcement require Toll-like receptor 4 signaling

Increased serum-GFAP in patients with severe traumatic brain injury is related to outcome

Interferon-gamma and tumor necrosis factor-alpha mediate the upregulation of indoleamine 2,3-dioxygenase and the induction of depressive-like behavior in mice in response to bacillus Calmette-Guerin

Vital signs: Characteristics of drug overdose deaths involving opioids and stimulants -24 states and the District of Columbia

Tumor necrosis factor alpha: a link between neuroinflammation and excitotoxicity

Cytokine release syndrome-associated encephalopathy in patients with COVID-19

Actions of TNF-alpha on glutamatergic synaptic transmission in the central nervous system

Drug overdose deaths

Multiorgan and Renal Tropism of SARS-CoV-2

Dysregulation of Immune Response in Patients With Coronavirus

Serum biomarkers for glioblastoma multiforme

SARS-CoV-2 targets neurons of 3D human brain organoids

SARS-COV2 Alters Blood Brain Barrier Integrity Contributing to Neuro-Inflammation

Novel neuroimmunologic therapeutics in depression: A clinical perspective on what we know so far

Frontal cortex indoleamine-2,3-dioxygenase activity is increased in HIV-1-associated dementia

Indolamine 2,3-dioxygenase expression by monocytes and dendritic cell populations in hepatitis C patients

Elevation of cortical serotonin transporter activity upon peripheral immune challenge is regulated independently of p38 mitogen-activated protein kinase activation and transporter phosphorylation

Kynurenines and Glutamate: Multiple Links and Therapeutic Implications

Proteomic and Metabolomic Characterization of COVID-19

HIV-1 and drug abuse comorbidity: Lessons learned from the animal models of NeuroHIV

Defective intestinal amino acid absorption in Ace2 null mice

Neuropathological Features of Covid-19

Neurological infection with SARS-CoV-2 -the story so far

Histopathological and inflammatory response in multiple organs of rats exposed to crack

Provisional death counts for Covid-19

COVID-19: combining antiviral and anti-inflammatory treatments

Going with the flow: trafficking-dependent and -independent regulation of serotonin transport

Provisional death counts for Covid-19

Substance use and abuse, COVID-19-related distress, and disregard for social distancing: A network analysis

Neonatal exposure to lipopolysaccharide enhances methamphetamine-induced reinstated behavioral sensitization in adult rats

Can't or Won't? Immunometabolic Constraints on Dopaminergic Drive

Mechanisms of HIV Transcriptional Regulation by Drugs of Abuse

The Opioid Epidemic

Astrocyte elevated gene-1 is a novel modulator of HIV-1-associated neuroinflammation via regulation of nuclear factor-κB signaling and excitatory amino acid transporter-2 repression

Increase of oxidation and inflammation in nervous and immune systems with aging and anxiety

The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2

The changing opioid crisis: development, challenges and opportunities

Prevention and Treatment of Opioid Misuse and Addiction: A Review

Analysis of Drug Test Results Before and After the US Declaration of a National Emergency Concerning the COVID-19 Outbreak

Serotonergic mechanisms involved in the discriminative stimulus, reinforcing and subjective effects of cocaine

Methamphetamine modulates the production of interleukin-6 and tumor necrosis factor-alpha via the cAMP/PKA/CREB signaling pathway in lipopolysaccharide-activated microglia

A human three-dimensional neural-perivascular 'assembloid' promotes astrocytic development and enables modeling of SARS-CoV-2 neuropathology

COVID-19 risk and outcomes in patients with substance use disorders: analyses from electronic health records in the United States

Serum GFAP and neurofilament light as biomarkers of disease activity and disability in NMOSD

Longer time spent at home during COVID-19 pandemic is associated with binge drinking among US adults

Relationships among neurotransmitters, cytokines and cognitive performance for individuals with hepatitis C achieving sustained virologic response: A pilot study

Kynurenic acid leads, dopamine follows: a new case of volume transmission in the brain?

Nervous system involvement after infection with COVID-19 and other coronaviruses

A Human Pluripotent Stem Cell-based Platform to Study SARS-CoV-2 Tropism and Model Virus Infection in Human Cells and Organoids

Methamphetamine induced neuroinflammation in mouse brain and microglial cell line BV2: Roles of the TLR4/TRIF/Peli1 signaling axis

Angiotensin receptor blocker irbesartan reduces stress-induced intestinal inflammation via AT1a signaling and ACE2-dependent mechanism in mice

Immunohistochemical localization of tryptophan hydroxylase in the human and rat gastrointestinal tracts

COVID-19 and gender-specific difference: Analysis of public surveillance data in Hong Kong

Interleukin-1 receptor activation by systemic lipopolysaccharide induces behavioral despair linked to MAPK regulation of CNS serotonin transporters

J o u r n a l P r e -p r o o f  Co-morbidities contribute to severe Covid-19, potentially due to inflammation  Inflammation and the kynurenine pathway during SUD may add to Covid-19 severity  Neuroimmune signaling during Covid-19 dysregulates tryptophan metabolism  Increased levels of kynurenine destabilize normal neurotransmitter levels  Altered neurotransmitters are related to drug use and misuse and increased SUDs J o u r n a l P r e -p r o o f