Controversies in translational research: drug self-administration

Abstract

Rationale Laboratory animal and human models of drug self-administration are used to evaluate potential pharmacotherapies for drug abuse, yet the utility of these models in predicting clinically useful medications is variable. Objective The objective of this study was to track how antagonist, agonist, and partial agonist medication approaches influence heroin and cocaine self-administration by rodents, non-human primates, and humans and to compare these results to clinical outcomes. Results Across species, heroin self-administration was decreased by all three medication approaches, paralleling their demonstrated clinical utility. The heroin data emphasize the importance of assessing a medication's abuse liability preclinically to predict medication abuse and compliance and of considering subject characteristics (e.g., opioid dependence) when interpreting medication effects. For cocaine, the effects of ecopipam, modafinil, and aripiprazole were consistent in the laboratory and clinic, provided that the medications were administered repeatedly before self-administration sessions. Modafinil attenuated cocaine's reinforcing effects in the human laboratory and improved treatment outcome, while ecopipam and aripiprazole increased the reinforcing effects of cocaine and do not appear promising in the clinic. Conclusions The self-administration model has reliably identified medications to treat opioid dependence, and the recent data with modafinil suggest that the human laboratory model also identifies medications to treat cocaine dependence. There have been numerous false positives when subjective effects are the primary outcome measure, but not when self-administration is the outcome. Factors relevant to the predictive validity of self-administration procedures include medication maintenance and the concurrent assessment of a range of behaviors to determine abuse liability and the specificity of effect.Keywords Cocaine . Opioid . Naloxone . Dopamine receptor . Drug abuse . Model . Monkey . Human . Reinforcement Laboratory testing of potential pharmacotherapies for drug abuse is an essential component of medication development. Although well-designed clinical trials are the standard by which the efficacy of a new medication is assessed, clinical trials test the effects of a potential treatment medication on a broad sample of patients, which is both costly and potentially risky. Before exposing a large number of treatment seekers to a medication, there needs to be both a strong scientific rationale for combining the medication with a drug of abuse as well as a demonstration that the co-administration of the medication and the abused drug is safe and selectively modifies the behavior of interest: drug taking.Models of drug self-administration in rodents, nonhuman primates, and humans have been used to evaluate the effects of candidate medications for the treatment of drug dependence. The self-administration model provides Psychopharmacology (2008) meaningful behavioral data on the safety and efficacy of potentia...

Oral Cannabidiol does not Alter the Subjective, Reinforcing or Cardiovascular Effects of Smoked Cannabis

“…The present multi-site study, testing a range of CBD doses using a statistically powerful within-subject design, provides no evidence that acute administration of oral CBD reduces the reinforcing or positive subjective effects of cannabis in current cannabis smokers. It is possible that chronic rather than acute CBD administration would have produced different results, as the duration of medication administration can have an important impact on outcome in medication development (eg, Haney and Spealman, 2008). It is also possible that different results would have been obtained if CBD or THC were given by another route of administration or if participants were not cannabis smokers.…”

An fMRI-Based Neural Signature of Decisions to Smoke Cannabis

“…Laboratory models may therefore be particularly valuable for studying substance abuse. Indeed, laboratory drug self-administration models, although they differ from naturalistic drug use in several ways, have predictive validity in terms of clinical outcomes (Haney and Spealman, 2008). The current approach, combining laboratory self-administration with fMRI-based decision making, is thus well suited to assess the neural processes underlying the key behavioral pathology in substance abuse, decisions to self-administer drugs.…”

Interaction Between Behavioral and Pharmacological Treatment Strategies to Decrease Cocaine Choice in Rhesus Monkeys

“…First, a main goal of any treatment strategy should be to not only decrease drug-taking behavior, but also reallocate behavior to activities maintained by more adaptive reinforcers (Vocci, 2007). Thus, in preclinical studies that aspire to evaluate pharmacological or behavioral treatment strategies for drug dependence, choice procedures can play a critical role in the preclinical evaluation process to determine whether a given experimental manipulation produces this critical reallocation of behavior (Haney and Spealman, 2008;Negus et al, 2011). Second, although dopamine/norepinephrine-selective releasers have consistently demonstrated efficacy to decrease cocaine choice in nonhuman primates Negus, 2003;present study), human laboratory studies (Greenwald et al, 2010;Rush et al, 2010), and clinical trials (Grabowski et al, 2001;Mooney et al, 2009), the magnitude of this therapeutic effect is limited by untoward effects and lower than the magnitude of effect that can potentially be achieved with behavioral economic approaches.…”