Invited reviewPredicting abuse potential of stimulants and other dopaminergic drugs: Overview and recommendations
Introduction
The Controlled Substances Act (CSA) was passed in the United States in 1970 and established five schedules of controlled substances (Title 21 and 21USC801,, Title 21 and 21USC812,). The scheduling of a controlled substance is based on its potential for abuse where schedule I indicates no currently accepted medical use and high abuse potential (Title 21USC812). Schedule II through V drugs include those with currently accepted medical use and are categorized within this range (i.e., II–V) based on their abuse potential (Title 21USC812). The Food and Drug Administration (FDA) defines a drug as having abuse potential if it “… is used in nonmedical situations, repeatedly or even sporadically, for the positive psychoactive effects it produces” (FDA/Center for Drug Evaluation and Research; CDER, 2010, p. 4) or by O'Connor et al. (2011) as “…the potential for repeated taking of a drug for its reinforcing or subjective-effects, or the avoidance of associated negative effects” (p. 913).
Abuse-potential assessment predates the CSA and is an essential component to regulation of controlled substances (Balster and Bigelow, 2003). A complete assessment of abuse potential includes data collected at several levels, from cellular action to whole-organism behavior to collection of epidemiological data (Balster and Bigelow, 2003, FDA and CDER, 2010, Horton et al., 2013). The compounds being assessed may be putative therapeutics or emerging “street” drugs that are anecdotally abused but too new to have been characterized empirically. Readers are encouraged to refer to Calderon and Klein (Neuropharmacology, this issue), for a review of US regulatory procedures for evaluating abuse potential of central nervous system (CNS) stimulants. In this review, we focused on behavioral research with nonhuman animals in the characterization of abuse potential of CNS stimulants. The term “CNS stimulant” has been broadly defined as a centrally acting drug with actions on monoamine neurotransmitter systems that increases alertness, attention, energy, blood pressure, and heart and respiration rate (National Institute on Drug Abuse; NIDA, 2001). We focused on therapeutics including stimulant medications (i.e., those for attention-deficit/hyperactivity disorder (ADHD) and other dopamine uptake inhibitors) and illicit compounds such as methamphetamine, cocaine, and synthetic cathinones often referred to as “bath salts”. While dopamine agonists like those developed as potential therapies for stimulant abuse and Parkinson's disease often lack some of the physiological characteristics associated with CNS stimulants, we reviewed these drugs because they are typically compared to illicit stimulants in assessment of their abuse potential.
The FDA/CDER (2010) describes five types of procedures typically used in assessment of abuse potential in nonhuman subjects: drug self-administration, conditioned place preference, drug discrimination, psychomotor tests, and dependence potential. We reviewed drug self-administration and drug discrimination experiments because they are regarded as “gold-standard” procedures in abuse-potential testing, perhaps because they are good predictors of CSA scheduling status and abuse-potential measures obtained with humans (e.g., Horton et al., 2013, Kamien et al., 1993, Rush et al., 2001). With drug self-administration, we reviewed species differences and the importance of reinforcing effectiveness relative to known and well-characterized drugs of abuse. With drug discrimination, we reviewed the role of training stimulus in obtaining false positives. Finally, we discussed the nature of physical dependence with this drug class and whether it should be included in assessments of abuse potential of CNS stimulants.
The use of nonhuman animals in preclinical assessments of abuse potential offers distinct advantages compared with human participants, and there are ethical and safety reasons for understanding drug effects in nonhuman animals prior to their study in humans. Newly developed compounds can be characterized relatively early in the drug-development process, often as part of the safety/toxicology profile of the compound. A wider range of doses can be examined for a longer period of time. Studies with nonhuman animals can be conducted with greater experimental control than is feasible with humans because the investigator can control many of the environmental conditions such as drug history, enrichment, nutrition, and so on. In some cases with nonhuman primates (NHP), but particularly with rodents, each organism's history is known and can be controlled by the experimenter. With rodents, subjects with similar genetic composition (e.g., inbred strains) or specific genetic modifications (e.g., knockout mice) can be selected and used depending on the experimental question. On the other hand, it is impossible to test drugs on naïve humans, and when conducting inpatient studies with drug abusers, extra-experimental events and genetic differences are extremely difficult, if not impossible, to control.
An important consideration in abuse-potential testing is the choice of animal model. Rodents and NHPs each have advantages and disadvantages (discussed below). In the current review, we distinguished between studies with rodents and NHPs to highlight the common and unique attributes of each model in characterizing abuse potential of CNS stimulants.
Section snippets
Drug self-administration
Drug self-administration is a procedure used to determine whether behavior can be maintained by the administration of a drug, a characteristic that defines a drug as a reinforcer. The drug is generally delivered intravenously (though other routes have been used, e.g., oral; Lemaire and Meisch, 1985, Meisch, 2001) contingent on a specific behavior, such as a lever press, or a pattern of lever presses (see Ator and Griffiths, 2003 for a methodological review). For a drug to be considered a
Drug discrimination
Drug discrimination is a procedure used to determine whether the interoceptive nature of a drug will generalize to or substitute for other drugs. That is, comparisons can be made between centrally acting drugs to determine whether different drugs induce comparable interoceptive effects (see Ator and Griffiths, 2003 for a methodological review). These studies allow for behavioral and pharmacological characterization of drugs into different classes based on their discriminative-stimulus effects
Physical dependence and withdrawal
The FDA broadly defines dependence potential as “…the propensity of a substance, as a consequence of its pharmacological effects on physiological or psychological functions, to give rise to a need for repeated doses of the substance” (FDA/CDER, 2010, p. 11). A state of physical dependence can be identified when administration of the drug is abruptly ceased (i.e., spontaneous withdrawal) or induced pharmacologically by an antagonist (i.e., precipitated withdrawal) following a protracted period
Conclusions
We have reviewed studies examining stimulant and other dopaminergic drugs in assessment of abuse potential with drug self-administration, drug discrimination, and physical dependence. We believe drug self-administration and drug discrimination are valuable in predicting abuse potential of these types of drugs, and rarely do these procedures fail to detect true positives. On the other hand, both procedures yielded many false positives, and we made recommendations for each procedure that may help
Acknowledgments
Preparation of this manuscript was supported by R01 DA027666 and R03 DA031835 to K.B.F and by R01 DA033795, R01 DA011792, and R01 AG035361 to J.K.R.
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