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EDITORIAL

Addiction

etiology and therapeutics

doi: 10.1097/FBP.0000000000000232
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Public views on recreational drug use have changed dramatically over the past decades. For example, attitudes in the USA have evolved from the mid-20th century view of any illicit drug use as a sure sign of moral depravity to the ‘just say no’ days of the Reagan presidency to the current movements that portend a widespread legitimization of the recreational or medicinal use of marijuana. Throughout this time and regardless of prevailing views on the recreational drug use, however, drug addiction – loosely defined as the habitual, often self-destructive, use of drugs in a manner that pre-empts personally or socially desirable behavior – has presented an unremitting public health challenge throughout the world. We have learned much about pharmacological, biological, and environmental determinants of drug addiction, and we can invoke theories of neurobiological derangement and point to the potentially remedial power of pharmacological or behavioral interventions. Yet, the sad reality is that, notwithstanding scientific advances, addiction persists as a chronic recurring disorder across many societies and the fundamental questions of ‘how did I get here?’ and ‘how do I get out?’ remain largely unanswered. This Special Issue of Behavioural Pharmacology entitled ‘Addiction: etiology and therapeutics’ was conceived to spotlight these latter questions and, as briefly summarized below, it includes a wide range of reviews and original reports from investigators committed to answering them.

The Special Issue opens with an article by Sun and colleagues that reviews recent developments in genetic approaches to both the diagnosis and the treatment of alcoholism. They argue persuasively that these developments bring us ever closer to the use of precision medicine in redressing genetic vulnerabilities to alcoholism. Next, Katz et al. broadly review compelling evidence for the intimate and singular interactions of dopamine and sigma-1 (σ1) receptor mechanisms in the reinforcing effects of both dopamine uptake inhibitors and σ1 agonists. The authors point out that these advances in our fundamental understanding of the reinforcing effects of psychomotor stimulants have led to a new therapeutic avenue – combination medications that target both systems – for the management of stimulant addiction. The third review, by Roger-Sanchez and co-workers, tackles the question of which mechanisms mediate the rewarding effects of MDMA in laboratory subjects. The answer provided in this review is that different neurochemical systems mediate different aspects of MDMA reward and, optimistically, the rational design of new pharmacotherapy for MDMA dependence will benefit from an appreciation of its complexity.

Empirical reports in this Special Issue begin with a consideration of etiology. First, several papers address organismic variables in the etiology of different types of drug addiction. Radke and colleagues exploit rat strain differences in saccharin consumption to study genetic factors in cocaine reward. Their data elegantly show that subjects bred for high levels of saccharin intake show a greater reduction in the ICSS threshold after cocaine injection, providing a motivational basis for the higher levels of cocaine intake that are also observed. Bertz et al. examine sex-related factors in remifentanil-induced conditioned reinforcement. Their data, showing differences in the acquisition and expression of opioid-conditioned reinforcement in male and female rats, show not only the fundamental role of conditioned reinforcement in drug-seeking behavior but also the complex – and not well understood – interactions of sex and drug-related reinforcement. Still with a focus on etiological factors in opioid addiction, the next paper by Maguire and his co-workers focuses on the role of impulsivity by measuring the delay discounting of opioid reward; their findings are consistent with the idea that delays in the delivery of a large-magnitude reinforcer may enhance the value of a reinforcer of lesser value and, in this way, contribute toward drug abuse and addiction. In a separate report, Maguire and colleagues extend their work to examine how opioids modify the delay discounting of food reward. Their findings show that, although there are definite opioid effects on the discounting of food reward, the direction of these effects is highly individual and complexly determined. Wilcockson and Pothos round out this part of the Special Issue with another approach to understanding etiological factors in drug addiction. In this work, they use a novel cognitive task in which human participants are presented with several categories of stimuli and are asked to estimate the percentage of appetitive stimuli during the session. Here, the authors provide intriguing data showing that the results of this test correlate well with attentional bias and, perhaps, can be used to identify vulnerability to drug addiction.

The remaining studies of etiological factors in this Special Issue focus on the examination of environmental and pharmacological variables that can contribute toward different types of drug addiction. Didone et al. report on the role of the context in which drug exposure occurs. Their work shows that the influence of environmental factors can differ qualitatively across drug class; here, cocaine sensitization is context dependent, whereas the expression of sensitization to ethanol is context independent and, perhaps, lessened by context familiarity. The next two papers delve into the role of early life experience in drug addiction: Lewis and colleagues identify early life stress in rats as a contributing factor in vulnerability to methamphetamine’s reinforcing effects, especially when stress is later re-experienced. On the same theme, but focused on another type of drug addiction, Cortes-Patino et al. show how early social isolation can be a key determinant of alcohol-seeking behavior later in life. Together, these papers make the implicit point that addiction processes are dynamic throughout life and indicate the tremendous value of longitudinally designed drug addiction research. The next series of papers turn to the role of pharmacological variables in drug addiction that can be explored with well-established drug-discrimination techniques. In the first two articles in this series, Banks and his colleagues report on therapeutics that act by monoaminergic mechanisms, but are not widely abused. In the first paper, they find that the anorectic agent phendimetrazine, like its amphetamine-like metabolic product phenmetrazine, produces cocaine-like effects, which suggests that, depending on the conditions of availability, the parent compound may pose a drug abuse problem in its own right. In the second study, Banks et al. show that the antidepressant and smoking cessation agent bupropion and one of its metabolites (2S,3S-hydroxybupropion) produce methamphetamine-like discriminative-stimulus effects, most likely due to their monoamine transport blocking actions. Bupropion previously has been shown to have strong reinforcing effects in laboratory animals and these results suggest that will be the case for its active metabolite. Perhaps because of pharmacokinetic factors, bupropion has not been a widely abused drug and it may be that such factors also constrain the abuse potential of its metabolite. Focusing on the more recently identified antidepressant ketamine in the next article, Chiamulera and colleagues use drug-discrimination techniques in rats to show that methoxetamine, a chemical analog of ketamine and originally proposed as a fast-acting antidepressant, produces ketamine-like discriminative-stimulus effects that also are fully reproduced by MK-801 and partially reproduced by lysergic acid or methamphetamine. The authors provide an optimistic perspective but, clearly, the extent to which the potential therapeutic and addiction-related effects of ketamine-like drugs can be separated remains a major challenge to the development of novel antidepressants. In the last paper in this series, drug-discrimination procedures also are expertly used – this time to investigate novel compounds found in the widely popular but illicit designer drugs that are sold as ‘Spice’. In this paper, Jarbe et al. show that ‘Spice’ compounds including AM2201 and its structural analogs fully substitute for the THC discriminative-stimulus in laboratory animals and, moreover, that these effects can be fully antagonized by the CB1 antagonist rimonabant. Although these experiments firmly establish these compounds as CB1 agonists, additional information is needed to understand whether the popularity of ‘Spice’ compound – when THC often is readily available – reflects differences in pharmacological action as well as legality.

The second set of empirical studies in the Special Issue focuses on the treatment of drug addiction. The majority of articles examine pharmacotherapeutic approaches to different types of drug addiction. First, Lile and colleagues investigate the mechanisms that may mediate the use of gabapentin to maintain abstinence from cannabis use. Their studies, carried out in human participants, surprisingly indicate that gabapentin can produce THC-like discriminative-stimulus and subjective effects, pointing to this commonality of behavioral effect as an important therapeutic feature of gabapentin. In the next article, Jayarajan et al. evaluate the ability of a 5-HT6 antagonist, administered chronically, to modulate a variety of effects produced by ethanol. 5-HT6 antagonists, which influence multiple neurotransmitter systems, are reported to produce procognitive effects in various learning paradigms, and have been developed for the management of Alzheimer’s disease; this paper provides evidence that the wide-ranging neurochemical sequelae of 5-HT6 receptor antagonism may also include actions that counter behavioral and neurochemical consequences of ethanol exposure. The question of whether analogs of the neuropeptide neurotensin – previously forwarded as potentially novel antipsychotics – can also be advantageous in treating cocaine addiction is addressed by Boules and her co-workers in the next article. Their research shows that a neurotensin agonist blocks cocaine-induced conditioned place preference and its reinstatement by a priming dose of cocaine, supporting the possibility that such ligands may yet fill a therapeutic role in the management of cocaine addiction. In the next report, deMoura and McMahon use classical pharmacology to examine the mechanisms that mediate the behavioral effects of nicotine and other nicotinic agonists including the tobacco cessation agents (varenicline, cytisine). Their results unexpectedly indicate that multiple receptor subtypes are likely involved in the pharmacological actions of drugs that are often considered to act primarily through the α4β2 subtype of the nicotinic receptor. By improving our understanding of nicotinic pharmacology, these results can help foster novel approaches to the development of pharmacotherapies for smoking cessation. The last two reports that focus on pharmacology return the reader to cannabinoids – but in very different ways. Maguire and France present the results of research on the modulation of heroin’s reinforcing effects by THC. Their data largely show that daily exposure to the cannabinoid did not alter heroin self-administration – an important set of findings that argues against the idea of synergy in the reinforcing effects of opioid and cannabinoid agonists. In the last paper in this series, Gueye and colleagues find that another cannabinoid agonist, WIN 55,212–2, can alter behavior in a gambling task in laboratory animals. Interestingly, the CB1 agonist preferentially enhanced suboptimal performance by improving choice strategy and increasing choice latency. These results show that the effects of cannabinoids, like those of many psychoactive drugs, can depend considerably on rates and patterns of ongoing behavior.

The next two articles in the Special Issue are centered on the question of non-pharmacological treatment of drug addiction. In the first report, Hammami – Abrand Abadi et al. show that environmental enrichment, an approach that has gained considerable attention, can decrease the severity of morphine dependence and withdrawal and also voluntary morphine consumption. These findings are generally consistent with previous reports of the positive effects of environmental enrichment in reducing the reinforcing effects of other drugs (e.g. cocaine). In the next article, Pinheiro et al. present data from their efforts to develop a model for studying the effectiveness of social alternatives in promoting drug abstinence. Their findings show that dyadic social interactions between mice are rewarding, as measured by conditioned place preference, but that substrain differences must be considered in optimizing the model. Although these studies are still in their early stages, this report highlights the types of concerns that must be addressed in developing behavioral models to study addiction.

Finally, it is well understood that drug addiction is driven by multiple factors that actively mitigate against abstinence. The last three papers address this aspect of drug addiction. First, Kearns and Silberberg present a short report that elegantly presents a methodology for quickly evaluating the reinforcing strength of self-administered drugs in laboratory animals. Using demand analysis to study cocaine self-administration in rats, they show that the elasticity of demand is greater for intermediate to high doses than for low doses of self-administered cocaine. This is a well-established behavioral economic approach with great promise for understanding the relative elasticity of demand of different classes, as well as doses, of drugs and other reinforcers. Next, Weiss and Kearns formally analyze factors that influence the effectiveness of stimuli that have been conditioned to inhibit cocaine-seeking behavior. Their results provide strong evidence that a history of drug experience significantly reduces the effectiveness of conditioned inhibition – suggesting, by extension, the need for especially powerful behavioral therapeutic approaches to overcome such historical influences. The last article in the Special Issue, an evaluation of the comparative value of conventional cigarettes and high-dose E-cigarettes by McPherson et al., serves as another reminder of the ability of previous experience to control drug-taking behavior. Notwithstanding the high dose of nicotine in the E-cigarette, participants in this study generally chose the conventional cigarette over the E-cigarette, perhaps reflecting the positive feature of familiar cues associated with the conventional cigarette and, in a way, indicating the difficulty in changing well-established addictive behavior.

Overall, the diversity of topics in the more than two dozen articles published in this Special Issue speaks to the broad range of approaches to understanding the etiology of drug addiction and to its management and treatment. Clearly, the study of the determinants and treatment of drug addiction is an active field of research and we believe that advances in the laboratory can and will be translated into real-life progress in how we address the challenges of drug addiction on personal and societal levels. Yet, drug addiction is only one of the behavioral addictions– for example, compulsive gambling and certain eating disorders, –that have emerged into the light of contemporary public discussion, and that are now widely thought to share common features. Surely, advances in our understanding of drug addiction are also likely to benefit our understanding of other types of addiction and the development of therapeutic programs for their management.

Jack Bergman,

Paul Willner,

Louk Vanderschuren and

Bart Ellenbroek February 2016

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