Substance use disorder (SUD) is a chronic, relapsing disease with a highly multifaceted pathology that includes (but is not limited to) sensitivity to drug-associated cues, negative affect, and motivation to maintain drug consumption. SUDs are highly prevalent, with 35 million people meeting criteria for SUD. While drug use and addiction are highly studied, most investigations of SUDs examine drug use in isolation, rather than in the more prevalent context of comorbid substance histories. Indeed, 11.3% of individuals diagnosed with a SUD have concurrent alcohol and illicit drug use disorders. Furthermore, having a SUD with one substance increases susceptibility to developing dependence on additional substances. For example, the increased risk of developing heroin dependence is twofold for alcohol misusers, threefold for cannabis users, 15fold for cocaine users, and 40-fold for prescription misusers. Given the prevalence and risk associated with polysubstance use and current public health crises, examining these disorders through the lens of co-use is essential for translatability and improved treatment efficacy. The escalating economic and social costs and continued rise in drug use has spurred interest in developing preclinical models that effectively model this phenomenon. Here, we review the current state of the field in understanding the behavioral and neural circuitry in the context of co-use with common pairings of alcohol, nicotine, cannabis, and other addictive substances. Moreover, we outline key considerations when developing polysubstance models, including challenges to developing preclinical models to provide insights and improve treatment outcomes.
Past research with the Spontaneously Hypertensive Rat (SHR) model of Attention Deficit/Hyperactivity Disorder showed that adolescent methylphenidate treatment enhanced cocaine abuse risk in SHR during adulthood. Acquisition of cocaine self-administration was faster, and cocaine dose-response functions were shifted upward under fixed-ratio and progressive ratio schedules compared to adult SHR that received adolescent vehicle treatment or to control strains that received adolescent methylphenidate treatment. The current study determined if extending treatment beyond adolescence would ameliorate long-term consequences of adolescent methylphenidate treatment on cocaine abuse risk in adult SHR. Treatments (vehicle or 1.5 mg/kg/day oral methylphenidate) began on postnatal day 28. Groups of male SHR were treated with vehicle during adolescence and adulthood, with methylphenidate during adolescence and vehicle during adulthood, or with methylphenidate during adolescence and adulthood. The group receiving adolescent-only methylphenidate was switched to vehicle on P56. Cocaine self-administration began on postnatal day 77, and groups receiving methylphenidate during adolescence and adulthood were treated either 1-hr before or 1-hr after daily sessions. At baseline under a fixed-ratio 1 schedule, cocaine self-administration (2 hr sessions; 0.3 mg/kg unit dose) did not differ among the four treatment groups. Under a progressive ratio schedule (4.5 hr maximum session length; 0.01 – 1.0 mg/kg unit doses), breakpoints for self-administered cocaine in SHR receiving the adult methylphenidate treatment 1-hr pre-session were not different from the vehicle control group. However, compared to the vehicle control group, breakpoints for self-administered cocaine at the 0.3 and 1.0 mg/kg unit doses were greater in adult SHR that received adolescent-only methylphenidate or received methylphenidate that was continued into adulthood and administered 1-hr post-session. These findings suggest that extending methylphenidate treatment beyond adolescence does not ameliorate explicitly the long-term consequences of adolescent methylphenidate treatment. Pre-session methylphenidate may mask temporarily the detection of an increase in cocaine self-administration following chronic methylphenidate treatment.
Background Mild traumatic brain injury (mTBI) is common in civilians and highly prevalent among military service members. mTBI can increase health risk behaviors (e.g., sensation seeking, impulsivity) and addiction risk (e.g., for alcohol use disorder (AUD)), but how mTBI and substance use might interact to promote addiction risk remains poorly understood. Likewise, potential differences in single vs. repetitive mTBI in relation to alcohol use/abuse have not been previously examined. Methods Here, we examined how a history of single (1×) or repetitive (3×) blast exposure (blast‐mTBI) affects ethanol (EtOH)‐induced behavioral and physiological outcomes using an established mouse model of blast‐mTBI. To investigate potential translational relevance, we also examined self‐report responses to the Alcohol Use Disorders Identification Test‐Consumption questions (AUDIT‐C), a widely used measure to identify potential hazardous drinking and AUD, and used a novel unsupervised machine learning approach to investigate whether a history of blast‐mTBI affected drinking behaviors in Iraq/Afghanistan Veterans. Results Both single and repetitive blast‐mTBI in mice increased the sedative properties of EtOH (with no change in tolerance or metabolism), but only repetitive blast potentiated EtOH‐induced locomotor stimulation and shifted EtOH intake patterns. Specifically, mice exposed to repetitive blasts showed increased consumption “front‐loading” (e.g., a higher rate of consumption during an initial 2‐h acute phase of a 24‐h alcohol access period and decreased total daily intake) during an intermittent 2‐bottle choice condition. Examination of AUDIT‐C scores in Iraq/Afghanistan Veterans revealed an optimal 3‐cluster solution: “low” (low intake and low frequency), “frequent” (low intake and high frequency), and “risky” (high intake and high frequency), where Veterans with a history of blast‐mTBI displayed a shift in cluster assignment from “frequent” to “risky,” as compared to Veterans who were deployed to Iraq/Afghanistan but had no lifetime history of TBI. Conclusions Together, these results offer new insight into how blast‐mTBI may give increase AUD risk and highlight the increased potential for adverse health risk behaviors following repetitive blast‐mTBI.
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