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.

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.

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.

Ovarian Hormones Regulate Nicotine Consumption and Accumbens Glutamatergic Plasticity in Female Rats.

Women report greater cigarette cravings during the menstrual cycle phase with higher circulating levels of 17ß-estradiol (E2), which is metabolized to estrone (E1). Both E2 and E1 bind to estrogen receptors (ERs), which have been highly studied in the breast, uterus, and ovary. Recent studies have found that ERs are also located on GABAergic medium spiny neurons (MSNs) within the nucleus accumbens core (NAcore). Glutamatergic plasticity in NAcore MSNs is altered following nicotine use; however, it is unknown whether estrogens impact this neurobiological consequence. To test the effect of estrogen on nicotine use, we ovariectomized (OVX) female rats that then underwent nicotine self-administration acquisition and compared them to ovary-intact (sham) rats. The OVX animals then received either sesame oil (vehicle), E2, or E1+E2 supplementation for 4 or 20 d before nicotine sessions. While both ovary-intact and OVX females readily discriminated levers, OVX females consumed less nicotine than sham females. Further, neither E2 nor E1+E2 increased nicotine consumption back to sham levels following OVX, regardless of the duration of the treatment. OVX also rendered NAcore MSNs in a potentiated state following nicotine self-administration, which was reversed by 4 d of systemic E2 treatment. Finally, we found that E2 and E1+E2 increased ERα mRNA in the NAcore, but nicotine suppressed this regardless of hormone treatment. Together, these results show that estrogens regulate nicotine neurobiology, but additional factors may be required to restore nicotine consumption to ovary-intact levels.

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.

Early Life Stress Promotes Heroin Seeking But Does Not Alter the Excitability of Insular Pyramidal Cells Targeting the Nucleus Accumbens.

A number of retrospective studies have demonstrated adverse childhood experiences are associated with increased vulnerability to substance use disorders, including opioid use disorders (OUDs). These adverse childhood experiences, also referred to as early life stress (ELS), can be modeled in laboratory animals by various paradigms including limited bedding and nesting (LBN) procedures. Studies using rodent models of ELS have been shown to recapitulate various aspects of OUDs, including relapse propensity and perseverance of drug-seeking behavior. In the current study, we utilized the LBN paradigm to explore potential effects on heroin self-administration, extinction, and relapse-like behaviors in male and female rats. We also utilized in vitro whole-cell electrophysiology to examine the effects of LBN and repeated heroin administration on the excitability of pyramidal neurons in the anterior insular cortex (AIC) projecting to the nucleus accumbens core (NAc), as recent studies suggest that this circuit may mediate various aspects of OUDs and may be compromised as a result of either ELS or OUDs. We observed that compared to control animals, rats exposed to LBN conditions during postnatal days 2-9 showed increased breakpoints for heroin self-administration under a progressive ratio schedule of reinforcement, impaired extinction of heroin-seeking behavior, and increased reinstatement of heroin-seeking behavior induced by heroin-associated cues. No effect of LBN rearing conditions were observed on the acquisition and maintenance of heroin self-administration, and no sex differences in heroin intake were observed. LBN and control reared animals showed no differences in the excitability of AIC-NAc pyramidal neurons, but animals treated with repeated heroin showed decreased excitability of these neurons through a significant increase in rheobase and reduction in action potentials induced by depolarizing currents. Together, these results suggest that ELS exposure produces exacerbations of heroin seeking behavior without parallel effects on AIC-NAc excitability, although heroin itself reduces the excitability of these neurons.

Drugs of Abuse Differentially Alter the Neuronal Excitability of Prefrontal Layer V Pyramidal Cell Subtypes.

The medial prefrontal cortex (mPFC) plays an important role in regulating executive functions including reward seeking, task flexibility, and compulsivity. Studies in humans have demonstrated that drugs of abuse, including heroin, cocaine, methamphetamine, and alcohol, alter prefrontal function resulting in the consequential loss of inhibitory control and increased compulsive behaviors, including drug seeking. Within the mPFC, layer V pyramidal cells, which are delineated into two major subtypes (type I and type II, which project to subcortical or commissurally to other cortical regions, respectively), serve as the major output cells which integrate information from other cortical and subcortical regions and mediate executive control. Preclinical studies examining changes in cellular physiology in the mPFC in response to drugs of abuse, especially in regard to layer V pyramidal subtypes, are relatively sparse. In the present study, we aimed to explore how heroin, cocaine, methamphetamine, ethanol, and 3,4-methylenedioxypyrovalerone (MDPV) alter the baseline cellular physiology and excitability properties of layer V pyramidal cell subtypes. Specifically, animals were exposed to experimenter delivered [intraperitoneal (i.p.)] heroin, cocaine, the cocaine-like synthetic cathinone MDPV, methamphetamine, ethanol, or saline as a control once daily for five consecutive days. On the fifth day, whole-cell physiology recordings were conducted from type I and type II layer V pyramidal cells in the mPFC. Changes in cellular excitability, including rheobase (i.e., the amount of injected current required to elicit action potentials), changes in input/output curves, as well as spiking characteristics induced by each substance, were assessed. We found that heroin, cocaine, methamphetamine, and MDPV decreased the excitability of type II cells, whereas ethanol increased the excitability of type I pyramidal cells. Together, these results suggest that heroin, cocaine, MDPV, and methamphetamine reduce mPFC commissural output by reducing type II excitability, while ethanol increases the excitability of type I cells targeting subcortical structures. Thus, separate classes of abused drugs differentially affect layer V pyramidal subtypes in the mPFC, which may ultimately give rise to compulsivity and inappropriate synaptic plasticity underlying substance use disorders.

Natural and synthetic estrogens specifically alter nicotine demand and cue-induced nicotine seeking in female rats.

Women have more difficulty maintaining smoking cessation than men, and experience greater withdrawal symptomatology as well as higher prevalence of relapse. Further, currently available treatments for smoking cessation, such as the nicotine patch and varenicline, have been shown to be less effective in women. Fluctuations in ovarian hormones across the menstrual cycle can affect craving and smoking relapse propensity. In addition, many women who smoke use some form of oral contraceptives, which most often contain ethinyl estradiol (EE), a synthetic, orally bio-available estrogen that is currently prescribed to women chronically and has been shown to alter smoking reward in women. The current study examined the impact of 17ß-estradiol (E2), the prominent endogenous form of the steroid hormone estrogen, as well as EE, on nicotine self-administration, demand, and reinstatement following ovariectomy (OVX) or sham surgery. OVX vehicle-treated female rats consumed less nicotine, had lower intensity of demand, and reinstated less compared to sham vehicle-treated female rats. OVX-E2 and OVX-EE treatment groups showed a rebound of nicotine intake later in training, and Q0 levels of consumption were partially rescued in both groups. Further, E2 but not EE reversed the abolishment of reinstated nicotine seeking induced by OVX. Taken together, these results demonstrate that natural and synthetic estrogens play a critical role in mediating the neurobehavioral effects of nicotine, and future studies are essential for our understanding of how synthetic hormones contained within oral contraceptives interact with smoking.

Alcohol consumption preferentially activates a subset of pro-opiomelanocortin (POMC) producing neurons targeting the amygdala.

BACKGROUND: Alcohol abuse is a worldwide public health concern and leads to an estimated 90,000 alcohol-related deaths in the United States annually. Alcohol may promote its euphoric and motivational effects, in part, by activating the endogenous opioid system. Pro-opiomelanocortin (POMC) producing neurons located within the arcuate nucleus (ArcN) of the hypothalamus make up one circuit of the endogenous opioid system, and heavily projects to reward-related brain areas such as the amygdala, nucleus accumbens (NAc) and ventral tegmental area (VTA). POMC producing neurons release ß-endorphin and other peptides that target opioid receptors within reward areas to elicit their associated rewarding effects. Here we explore ArcN POMC neuronal activation, as assessed via FosB expression, following alcohol consumption to determine whether activation varied within subsets of ArcN POMC projection neurons targeting different reward-related areas. METHODS: Fluorescent retrobeads were used to label ArcN POMC projection neurons targeting the NAc, amygdala and VTA in POMC-cre mice expressing the reporter tdTomato. Animals (n = 57) were then allowed to voluntarily consume alcohol or water using the drinking-in-the-dark (DID) paradigm, and sacrificed for immunohistochemistry to examine FosB expression within ArcN POMC neurons. RESULTS: Female mice displayed escalation of alcohol intake across DID sessions, whereas males did not. A greater percent of ArcN POMC neurons target the amygdala over the NAc and VTA, and alcohol consumption preferentially activated ArcN POMC neurons targeting the amygdala over other areas. CONCLUSION: These findings highlight a novel aspect alcohol-induced activation of the endogenous opioid system, whereby alcohol activates a specific subpopulation of ArcN POMC producing neurons that project primarily to the amygdala.

Neuroimmune Mechanisms as Novel Treatment Targets for Substance Use Disorders and Associated Comorbidities.

Recent studies examining the neurobiology of substance abuse have revealed a significant role of neuroimmune signaling as a mechanism through which drugs of abuse induce aberrant changes in synaptic plasticity and contribute to substance abuse-related behaviors. Immune signaling within the brain and the periphery critically regulates homeostasis of the nervous system. Perturbations in immune signaling can induce neuroinflammation or immunosuppression, which dysregulate nervous system function including neural processes associated with substance use disorders (SUDs). In this review, we discuss the literature that demonstrates a role of neuroimmune signaling in regulating learning, memory, and synaptic plasticity, emphasizing specific cytokine signaling within the central nervous system. We then highlight recent preclinical studies, within the last 5 years when possible, that have identified immune mechanisms within the brain and the periphery associated with addiction-related behaviors. Findings thus far underscore the need for future investigations into the clinical potential of immunopharmacology as a novel approach toward treating SUDs. Considering the high prevalence rate of comorbidities among those with SUDs, we also discuss neuroimmune mechanisms of common comorbidities associated with SUDs and highlight potentially novel treatment targets for these comorbid conditions. We argue that immunopharmacology represents a novel frontier in the development of new pharmacotherapies that promote long-term abstinence from drug use and minimize the detrimental impact of SUD comorbidities on patient health and treatment outcomes.

Strain and sex matters: Differences in nicotine self-administration between outbred and recombinase-driver transgenic rat lines.

Preclinical studies of nicotine self-administration provide important value for the field as they are highly rigorous, controlled, can be conducted quickly, and are generalizable to humans. Given the translational value of the nicotine self-administration model, and the relatively new guidelines of the National Institutes of Health to include sex as a biological variable, strain and sex differences in nicotine acquisition were examined here in two outbred rat strains. Sprague-Dawley (SD) and Long-Evans (LE; wildtype and cholinergic acetyltransferase cre-recombinase transgenic) rats of each sex were implanted with indwelling intravenous jugular catheters. Rats were trained to self-administer nicotine (0.02 mg/kg per infusion, paired with contingent light + tone stimuli). Acquisition criteria were set at a minimum active:inactive response ratio of 2:1 and a minimum of 10 infusions per session, both of which had to be met for a minimum of 10 sessions. Across 10 sessions, male SD rats self-administered significantly more nicotine than female SD rats (p < .05), indicating a sex difference in this strain. LE females self-administered more nicotine than SD females indicative of a strain difference between females (p < .05). SD males increased nicotine infusions across sessions compared to LE males and SD females (p < .05). No strain or sex differences were observed in the number of sessions to reach criteria. No differences between wildtype and transgenic LE rats were observed. These results demonstrate sex and strain differences in nicotine self-administration between SD and LE rats and may lend insight into development of other nicotine self-administration models, where sex and strain may impact acquisition. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Accumbens Cholinergic Interneurons Mediate Cue-Induced Nicotine Seeking and Associated Glutamatergic Plasticity.

Nicotine, the primary addictive substance in tobacco, is widely abused. Relapse to cues associated with nicotine results in increased glutamate release within nucleus accumbens core (NAcore), modifying synaptic plasticity of medium spiny neurons (MSNs), which contributes to reinstatement of nicotine seeking. However, the role of cholinergic interneurons (ChIs) within the NAcore in mediating these neurobehavioral processes is unknown. ChIs represent less than 1% of the accumbens neuronal population and are activated during drug seeking and reward-predicting events. Thus, we hypothesized that ChIs may play a significant role in mediating glutamatergic plasticity that underlies nicotine-seeking behavior. Using chemogenetics in transgenic rats expressing Cre under the control of the choline acetyltransferase (ChAT) promoter, ChIs were bidirectionally manipulated before cue-induced reinstatement. Following nicotine self-administration and extinction, ChIs were activated or inhibited before a cue reinstatement session. Following reinstatement, whole-cell electrophysiology from NAcore MSNs was used to assess changes in plasticity, measured via AMPA/NMDA (A/N) ratios. Chemogenetic inhibition of ChIs inhibited cued nicotine seeking and resulted in decreased A/N, relative to control animals, whereas activation of ChIs was unaltered, demonstrating that ChI inhibition may modulate plasticity underlying cue-induced nicotine seeking. These results demonstrate that ChI neurons play an important role in mediating cue-induced nicotine reinstatement and underlying synaptic plasticity within the NAcore.

Direct administration of ifenprodil and citalopram into the nucleus accumbens inhibits cue-induced nicotine seeking and associated glutamatergic plasticity.

Nicotine use disorder has been associated with glutamatergic alterations within the basal ganglia that might contribute to relapse. Specifically, initiation of cue-induced nicotine seeking produces rapid, transient synaptic potentiation (t-SP) in nucleus accumbens core (NAcore) medium spiny neurons (MSNs), defined as increases in spine head diameter and AMPA to NMDA current ratios (A/N). Ifenprodil, which inhibits nicotine reinstatement when administered systemically, antagonizes GluN2B-containing NMDA receptors, has affinity for serotonin receptors, and blocks serotonin transporters (SERT). The mechanisms underlying its therapeutic efficacy, however, remain unknown. Using pharmacological and genetic approaches, the current study examined the role of NAcore GluN2B receptors as well as SERT in mediating cue-induced nicotine seeking and associated MSN structure and physiology. Prior to reinstatement, rats received intra-NAcore injections of either ifenprodil, citalopram or artificial cerebral spinal fluid (15 min prior), or GluN2B or control siRNAs (3 consecutive days prior). Rats were sacrificed after a 15-min cue-induced reinstatement session for dendritic spine analysis, western blotting or whole-cell electrophysiology. Intra-NAcore ifenprodil blocked nicotine-seeking behavior and promoted a higher frequency of shorter spines on MSN dendrites. However, a decrease in membrane-bound GluN2B receptor expression did not prevent cue-induced nicotine seeking or associated MSN cell physiology. Interestingly, intra-NAcore citalopram, an SSRI, prevented cue-induced nicotine seeking. Together, these results indicate that the therapeutic effects of ifenprodil on cue-induced nicotine seeking may, in part, be due to its actions at SERT rather than GluN2B, which may be specific to nicotine-seeking as opposed to other drugs of abuse.

Ethanol has concentration-dependent effects on hypothalamic POMC neuronal excitability.

Alcohol abuse is a worldwide public health concern, yet the precise molecular targets of alcohol in the brain are still not fully understood. Alcohol may promote its euphoric and motivational effects, in part, by activating the endogenous opioid system. One particular component of this system consists of pro-opiomelanocortin (POMC) -producing neurons in the arcuate nucleus (ArcN) of the hypothalamus, which project to reward-related brain areas. To identify the physiological effects of ethanol on ArcN POMC neurons, we utilized whole cell patch-clamp recordings and bath application of ethanol (5-40 mM) to identify alterations in spontaneous baseline activity, rheobase, spiking characteristics, or intrinsic neuronal properties. We found that 10 mM ethanol increased the number of depolarization-induced spikes in the majority of recorded cells, whereas higher concentrations of ethanol (20-40 mM) decreased the number of spikes. Interestingly, we found that basal firing rates of ArcN POMC neurons may predict physiological responding to ethanol. Rheobase and spontaneous activity, measured by spontaneous excitatory post-synaptic potentials (EPSPs) at rest, were unchanged after exposure to ethanol, regardless of concentration. These results suggest that ethanol has concentration-dependent modulatory effects on ArcN POMC neuronal activity, which may be relevant to treatments for alcohol use disorders that target endogenous opioid systems.

Restoration of prosocial behavior in rats after heroin self-administration via chemogenetic activation of the anterior insular cortex.

The anterior insular cortex (AIC) mediates various social, emotional, and interoceptive components of addiction. We recently demonstrated a disruption of prosocial behavior following heroin self-administration in rats, as assessed by examining the animals' propensity to rescue its cagemate from a plastic restrainer while having simultaneous access to heroin. To examine the possibility that heroin-induced deficits in prosocial function are mediated by the AIC, the present study examined the effects of chemogenetic activation or inhibition of excitatory AIC pyramidal neurons on heroin-induced prosocial deficits. After establishment of baseline rescuing behavior, rats received bilateral infusions of viral vectors encoding either a control virus (AAV-CaMKIIα-GFP), stimulatory DREADD (AAV-CaMKIIα-hM3Dq-mCherry) (Experiment 1), or inhibitory DREADD (AAV-CaMKIIα-hM4Di-mCherry) (Experiment 2), into the AIC. Rats were then allowed to self-administer heroin (0.06 mg/kg/infusion) 6 hr/day for 2 weeks. Prior to re-assessment of prosocial behavior, animals were administered clozapine-N-oxide (1.5 mg/kg, i.p.) to assess the effects of chemogenetic activation or inhibition of the AIC. Relative to control animals, chemogenetic activation of the AIC reversed deficits in rescuing behavior induced by heroin, whereas chemogenetic inhibition of the AIC had no effect. We hypothesize that stimulatory neuromodulation of the AIC may be a novel approach for restoring prosociality in opiate abuse.

Pharmacotherapeutic management of co-morbid alcohol and opioid use.

Opioid use disorder (OUD) and alcohol use disorder (AUD) are two highly prevalent substance-related disorders worldwide. Co-use of the substances is also quite prevalent, yet there are no pharmacological treatment approaches specifically designed to treat co-morbid OUD and AUD. Here, the authors critically summarize OUD, AUD and opioid/alcohol co-use and their current pharmacotherapies for treatment. They also review the mechanisms of action of opioids and alcohol within the brain reward circuitry and discuss potential combined mechanisms of action and resulting neuroadaptations. Pharmacotherapies that aim to treat AUD or OUD that may be beneficial in the treatment of co-use are also highlighted. Preclinical models assessing alcohol and opioid co-use remain sparse. Lasting neuroadaptations in brain reward circuits caused by co-use of alcohol and opioids remains largely understudied. In order to fully understand the neurobiological underpinnings of alcohol and opioid co-use and develop efficacious pharmacotherapies, the preclinical field must expand its current experimental paradigms of 'single drug' use to encompass polysubstance use. Such studies will provide insights on the neural alterations induced by opioid and alcohol co-use, and may help develop novel pharmacotherapies for individuals with co-occurring alcohol and opioid use disorders.

N-acetylcysteine yields sex-specific efficacy for cue-induced reinstatement of nicotine seeking.

Women report greater craving during certain phases of the menstrual cycle. As well, research indicates that pharmacotherapies for smoking may be less efficacious in women compared with men, which may be due to interactions with natural fluctuations in ovarian hormone levels. N-Acetylcysteine (NAC) is a glutamatergic compound that has shown some efficacy in treating substance use disorders and aids in the prevention of relapse. However, it is unclear whether NAC has sex-specific effectiveness for nicotine relapse treatment. Given that NAC has shown promise to reduce nicotine reinstatement in preclinical models using male rats, the exploration of potential sex differences in the efficacy of NAC is warranted. Using a rat model, we first investigated the ability of NAC treatment (100 mg/kg, ip) during nicotine withdrawal with extinction training to reduce cue-induced nicotine seeking in male and female rats. Next, we assessed whether NAC's effects were estrous cycle-dependent for female rats. Results show that following NAC treatment during extinction, reinstatement of nicotine seeking was significantly decreased in males but not females, indicating a sex-specific effect of NAC. Furthermore, for females, both vehicle- and NAC-treated groups significantly reinstated nicotine-seeking behavior compared with extinction, regardless of estrous cycle phase. These results suggest that NAC is inefficacious in reducing nicotine relapse in females regardless of estrous cycle phase at the dose evaluated here. These collective findings could have important clinical implications for use and efficacy of NAC as a pharmacotherapy for freely cycling women smokers.