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.

Rationale.-The number of synthetic derivatives of cathinone, the primary psychoactive alkaloid found in Catha edulis (khat), has risen exponentially in the past decade. Synthetic cathinones (frequently referred to as "bath salts") produce adverse cognitive and behavioral sequelae, share similar pharmacological mechanisms of action with traditional psychostimulants, and may therefore trigger similar cellular events that give rise to neuroinflammation and neurotoxicity Objectives.-In this review, we provide a brief overview of synthetic cathinones, followed by a summary of cognitive deficits in animals and humans that have been documented following acute or repeated exposure. We also summarize growing evidence from in vitro and in vivo studies for synthetic cathinone-induced neurotoxicity, and provide a working hypothetic model of potential cellular mechanisms. Results.-Synthetic cathinones produce varying effects on markers of monoaminergic terminal function, and can increase the formation of reactive oxygen and nitrogen species, induce apoptotic signaling, and cause neurodegeneration and cytotoxicity. We hypothesize that these effects result from biochemical events similar to those induced by traditional psychostimulants. However, empirical evidence for the ability of synthetic cathinones to induce neuroinflammatory processes is currently lacking. Conclusions.-Like their traditional psychostimulant counterparts, synthetic cathinones appear to induce neurocognitive dysfunction and cytotoxicity, which are dependent on drug type, dose, frequency, and time following exposure. However, additional studies on synthetic cathinoneinduced neuroinflammation are clearly needed, as are investigations into the neurochemical and neuroimmune mechanisms underlying their neurotoxic effects. Such endeavors may lead to novel therapeutic avenues to promote recovery in habitual synthetic cathinone users.

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Synthetic cathinones are designer psychostimulants that are derivatives of the natural alkaloid cathinone, and produce effects similar to more traditional illicit stimulants such as cocaine and methamphetamine. The pyrovalerone cathinones methylenedioxypyrovalerone (MDPV) and α-pyrrolidinopropiophenone (α-PPP) exert their effects via inhibition of presynaptic dopamine and norepinephrine reuptake transporters. While the reinforcing effects of MDPV in rodents are well-established, very few studies have examined self-administration patterns of α-PPP. Users of synthetic cathinones often engage in repeated binge episodes of drug intake that last several days. We therefore sought to determine the reinforcing effects of three doses of α-PPP (0.05, 0.1 and 0.32 mg/kg/infusion) under conditions of prolonged binge-like access conditions, with three 96-h periods of drug access interspersed with 72 h of abstinence. MDPV (0.05 mg/kg/infusion) was used as a comparison drug. Our results show that both MDPV and the high (0.32 mg/kg/infusion) dose of α-PPP are readily self-administered at high levels across all three extended access periods, whereas lower doses of α-PPP produce variable and less robust levels of self-administration. These results indicate that higher doses of α-PPP have reinforcing effects under conditions of extended access, suggesting the potential for abuse and a need for consideration in drug control policies.

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.

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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 β‐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.