Review
Insights from Preclinical Choice Models on Treating Drug Addiction

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Trends

Substance-use disorders (i.e., drug addiction) are increasingly being conceptualized as disorders of behavioral misallocation between drug and nondrug reinforcers.

Preclinical drug versus food choice procedures are increasingly being utilized to elucidate environmental, pharmacological, and biological mechanisms associated with this behavioral misallocation.

Preclinical drug versus food choice procedures provide distinct dependent measures that dissociate drug reinforcement (i.e., allocation of behavior) from motor competence (i.e., rate of behavior).

Alternative nondrug reinforcer availability and temporal delivery impact behavioral allocation.

Preclinical drug versus food choice procedures are being developed for abused drugs other than cocaine.

Biological variables are an emerging as important determinants of behavioral allocation between drug and nondrug reinforcers.

Substance-use disorders are a global public health problem that arises from behavioral misallocation between drug use and more adaptive behaviors maintained by nondrug alternatives (e.g., food or money). Preclinical drug self-administration procedures that incorporate a concurrently available nondrug reinforcer (e.g., food) provide translationally relevant and distinct dependent measures of behavioral allocation (i.e., to assess the relative reinforcing efficacy of the drug) and behavioral rate (i.e., to assess motor competence). In particular, preclinical drug versus food ‘choice’ procedures have produced increasingly concordant results with both human laboratory drug self-administration studies and double-blind placebo-controlled clinical trials. Accordingly, here we provide a heuristic framework of substance-use disorders based on a behavioral-centric perspective and recent insights from these preclinical choice procedures.

Section snippets

Drug Addiction

Drug addiction is an insidious and global public health problem. Estimates from the most recent World Drug Report indicate that 246 million adults aged 15–64 have used at least one illicit drug within the past year and, since 2008, this number of individuals has increased year on year [1]. Although both scientists and clinicians agree that drug addiction is a significant public health issue, there are disagreements regarding the operational definition of drug addiction 2, 3. For example, both

Preclinical Drug Choice

The development of preclinical drug self-administration procedures has been critical for improving our understanding of substance-use disorders. All drug self-administration procedures are founded on the principles of operant conditioning related to the three-term contingency [13] as follows (Equation 1):SDRSC,where SD denotes the discriminative stimulus (see Glossary), R denotes the response by the organism, and SC denotes the consequent stimulus. For example, in a simple type of drug

Concurrent Availability of an Alternative Reinforcer

To date, preclinical drug versus nondrug choice procedures have been established for the abused drugs cocaine 20, 21, 22, methamphetamine 23, 24, 3,4-methylenedioxymethamphetamine [25], heroin 26, 27, remifentanil [28], secobarbital and chlordiazepoxide [29], and nicotine [30] in either nonhuman primates or rats. With the exception of one heroin versus electrical brain stimulation choice study [31], all other preclinical drug versus nondrug choice procedures have used some food variant as the

Pharmacological Determinants

One area of scientific discovery where preclinical choice procedures have emerged as having translational utility is in the development and evaluation of candidate pharmacotherapies for substance-use disorders. Examples of recent pharmacological variables that have either decreased or increased drug versus food choice are listed in Table 1. Preclinical drug versus food choice procedures evaluating subchronic pharmacological treatments have produced concordant results with both human laboratory

Biological Determinants

Emerging preclinical evidence has implicated sex as a biological determinant of both substance-use initiation and progression to substance-use disorders (recently reviewed in 100, 101). The role of sex as a determinant of preclinical drug versus nondrug choice has been recently investigated in both rats 65, 102, 103, 104 and monkeys [105], and these results suggest two main findings. First, there was no effect of estrous cycle on intravenous cocaine versus food choice in rats or an effect of

Concluding Remarks

Substance-use disorders occur in the context of numerous competing alternative nondrug reinforcers. The diagnosis of substance-use disorders is founded in part on the maladaptive allocation of behavior toward drug use at the expense of other more adaptive behaviors maintained by nondrug alternative reinforcers. This diagnosis implies that the treatment of substance-use disorders seeks not only to decrease behaviors maintained by the abused substance, but also to increase behaviors maintained by

Acknowledgments

The authors’ research related to this topic has been supported by the National Institute on Drug Abuse of the National Institutes of Health under award numbers R01DA031718 (M.L.B.), R01DA033364 (M.L.B. and S.S.N.), and R01DA026946 (S.S.N.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We also acknowledge the artistic assistance of Megan Jo Moerke.

Glossary

Concurrent schedule of reinforcement
one category of reinforcement schedules where two different schedules of reinforcement are presented to the organism simultaneously or concurrently. Responding on one operant manipulandum to obtain one of the concurrently available reinforcers implies a ‘choice’ and subsequent forfeiture of the other reinforcer available during that particular experimental trial or session.
Consequent stimulus (SC)
one category of stimuli in operant terminology; defined as a

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