Broadening sources of finance for health promotion and disease prevention: Smart capacitating investment.

Abuse of both psychostimulants and opioids represents a significant public health concern [–]. These drugs are often abused concurrently, and polysubstance abuse scenarios are of significant clinical interest []. Drug self-administration procedures are useful preclinical models of addiction []. Animals are trained to perform an operant response—e.g., pressing a lever—to earn an intravenous infusion of drug []. A large proportion of self-administration studies have used either psychostimulant (e.g., cocaine, methamphetamine) or opioid (e.g., heroin, morphine) reinforcers (e.g., [–]). Some have used a “speedball” (cocaine and heroin mix) reinforcer (e.g., [,]), but relatively few have specifically compared psychostimulant and opioid self-administration in a within-subjects design [–]. Thus, concurrent abuse of psychostimulants and opioids has received less study than single-drug use. Despite pronounced differences in the subjective effects of psychostimulants and opioids [], single-drug self-administration studies contribute to converging literature on drug addiction in general, due to evidence that overlapping circuitry, specifically within the nucleus accumbens (NAc) mediates the reinforcing effects of both drug classes [] and is necessary for self-administration []. NAc has been shown to be similarly involved in operant responding for non-drug rewards such as food, water, and juice [,]. At a single-cell level, however, multiple reward-seeking responses are heterogeneously represented within NAc. This functional heterogeneity has largely been characterized in comparisons of drug versus natural rewards [–], due to translational interest in examining drug vs. non-drug choice [,]. However, similar results have been found in comparisons of cocaine and heroin [,,], suggesting that despite similar overarching involvement of NAc, psychostimulant and opioid self-administration are likely represented by distinct ensembles. This perspective aligns with pharmacological evidence that psychostimulants and opioids produce different means to similar ends in terms of elevating NAc dopamine (DA) [,], and neuroadaptations such as the formation of silent synapses [], as well as behavioral evidence that common effects such as context-indued reinstatement involve overlapping, but not identical circuitry [,].