Substance use disorders are global health problems with few effective treatment options. Unfortunately, most potential pharmacological treatments are hindered by abuse potential of their own, limited efficacy, or adverse side effects. As a consequence, there is a pressing need for the development of addiction treatments with limited abuse potential and fewer off target effects. Given the difficulties in developing new pharmacotherapies for substance use disorders, there has been growing interest in medications that act on non-traditional targets. Recent evidence suggests a role for dysregulated immune signaling in the pathophysiology of multiple psychiatric diseases. While there is evidence that immune responses in the periphery and the central nervous system are altered by exposure to drugs of abuse, the contributions of neuroimmune interactions to addictive behaviors are just beginning to be appreciated. In this review, we discuss the data on immunological changes seen in clinical populations with substance use disorders, as well as in translational animal models of addiction. Importantly, we highlight those mechanistic findings showing causal roles for central or peripheral immune mediators in substance use disorder and appropriate animal models. Based on the literature reviewed here, it is clear that brain-immune system interactions in substance use disorders are much more complex and important than previously understood. While much work remains to be done, there are tremendous potential therapeutic implications for immunomodulatory treatments in substance use disorders.

Aims: Drug withdrawal is suggested to play a role in precipitating mood disorders in individuals with familial predisposition. Age-related differences in affective responses to withdrawal might explain the increased risk of mental illnesses when drug use begins during adolescence. Since there is a lack of animal research examining the effects of opioid withdrawal during adolescence, the present study examined whether there are age-related differences in affective responses to opioid withdrawal.Main methods: Adolescent and adult mice were injected with two different morphine regimens, namely low and high, which differed in the dosage. Three and nine days following discontinuation of morphine administration, immobility time in the forced swim test (FST) and locomotion (total distance traveled) were evaluated.Key findings: On withdrawal day 3 (WD3), adolescent mice exhibited a decrease in immobility as compared to controls. No significant differences in immobility were observed on withdrawal day 9 (WD9). This effect on FST behaviors was not due to changes in overall motor activity, since no differences in locomotion were observed on either WD3 or WD9 in adolescent mice. In adults, no differences in either FST or locomotor behaviors were observed on WD3. As expected, on WD9, adult mice exhibited an increase in immobility and a decrease in locomotion.Significance: This study demonstrates age-dependent differences in both FST scores and locomotor behaviors during opioid withdrawal. FST behaviors are classically used to evaluate mood in rodents, thus this study suggests that opioid withdrawal might affect mood differentially across age.

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Opioid withdrawal is known to be anxiogenic in humans and, using the elevated plus maze (EPM), was demonstrated to also be anxiogenic in rats. Thus, this study characterizes EPM behaviors of mice during naloxone-precipitated morphine withdrawal. Naloxone did not significantly change EPM behaviors of drug-naïve mice. Additionally, morphine-dependent mice in which withdrawal was not precipitated (i.e. morphine-dependent mice receiving saline) spent less time in the open-arms compared to the controls. Surprisingly, increased open-arm time was observed in morphine-dependent mice undergoing naloxone-precipitated withdrawal. This increase was not because of total motor activity, as no significant differences in total activity were observed. Moreover, morphine dependency was necessary, given that there was not a significant increase in open-arm time for mice undergoing withdrawal from acute morphine. Increased open-arm time during withdrawal is unexpected, given that opioid withdrawal is usually associated with anxiety. Additionally, even in mice, naloxone-precipitated morphine withdrawal is known be aversive and increases plasma corticosterone levels. In conclusion, this study demonstrates somewhat unexpected EPM behavior in mice undergoing naloxone-precipitated morphine withdrawal. Possible interpretations of these EPM results, though somewhat speculative, raise the possibility that EPM behaviors might not be driven exclusively by anxiety levels but rather by other withdrawal-induced behaviors.