Remission from addiction: erasing the wrong circuits or making new ones?

Chronic relapse is a hallmark of substance-use disorders (SUDs), but many people with SUDs do recover and eventually enter remission. Many preclinical studies in this field aim to identify interventions that can precipitate recovery by reversing or erasing the neuronal circuit changes caused by chronic drug use. A better understanding of remission from SUDs can also come from preclinical studies that model factors known to influence recovery in humans, such as the negative consequences of drug use and positive environmental influences.

The multiple faces of footshock punishment in animal research on addiction.

Continued drug use despite negative consequences is a hallmark of addiction commonly modelled in rodents using punished drug intake. Over the years, addiction research highlighted two subpopulations of punishment sensitive and resistant animals. While helpful to interrogate the neurobiology of drug-related behaviors, these procedures carry some weaknesses that need to be recognized and eventually defused.

A large-scale c-Fos brain mapping study on extinction of cocaine-primed reinstatement.

Individuals with cocaine addiction can experience many craving episodes and subsequent relapses, which represents the main obstacle to recovery. Craving is often favored when abstinent individuals ingest a small dose of cocaine, encounter cues associated with drug use or are exposed to stressors. Using a cocaine-primed reinstatement model in rat, we recently showed that cocaine-conditioned interoceptive cues can be extinguished with repeated cocaine priming in the absence of drug reinforcement, a phenomenon we called extinction of cocaine priming.

Knowledge by omission: the significance of omissions in the 5-choice serial reaction time task.

Rationale: The 5-choice serial reaction time task (5-CSRTT) is commonly used to assess attention in rodents. Manipulation of this task by decreasing the light stimulus duration is often used to probe attentional capacity and causes a decrease in accuracy and an increase in omissions. However, although a decrease in response accuracy is commonly interpreted as a decrease in attention, it is more difficult to interpret an increase in omissions in terms of attentional performance.

The importance of choice and agency in animal models of addiction.

The aim of this short commentary is twofold. First, it uncovers and outlines in broad strokes a historical, albeit oft-overlooked, trend toward a growing place for choice and agency in the design of animal models of addiction. Next, it tries to draw from this historical trend some perspectives and implications for future research.

Large-scale brain correlates of sweet versus cocaine reward in rats.

Cocaine induces many supranormal changes in neuronal activity in the brain, notably in learning- and reward-related regions, in comparison with nondrug rewards-a difference that is thought to contribute to its relatively high addictive potential. However, when facing a choice between cocaine and a nondrug reward (e.g.

Cocaine falls into oblivion during volitional initiation of choice trials.

When facing a choice, most animals quit drugs in favour of a variety of nondrug alternatives. We recently found, rather unexpectedly, that choice of the nondrug alternative is in fact inflexible and habitual. One possible contributing factor to habitual choice is the intermittency and uncontrollability of choice trials in previous studies.

Altered neuronal activity in the ventromedial prefrontal cortex drives nicotine intake escalation.

Nicotine addiction develops after prolonged drug use and escalation of drug intake. However, because of difficulties in demonstrating escalation of nicotine use in rats, its underlying neuroadaptations still remain poorly understood. Here we report that access to unusually high doses of nicotine (i.

Increased responsiveness to punishment of cocaine self-administration after experience with high punishment.

One behavioral feature of drug addiction is continued drug use despite awareness that this causes negative consequences. Attempts to model this feature in animals typically involve punishing drug self-administration with electrical footshock to identify individuals whose drug use is differently suppressed by punishment. Here we sought to further study individual responsiveness of drug use to punishment in rats self-administering intravenous cocaine.

Probing the decision-making mechanisms underlying choice between drug and nondrug rewards in rats.

Delineating the decision-making mechanisms underlying choice between drug and nondrug rewards remains a challenge. This study adopts an original approach to probe these mechanisms by comparing response latencies during sampling versus choice trials. While lengthening of latencies during choice is predicted in a deliberative choice model (DCM), the race-like response competition mechanism postulated by the Sequential choice model (SCM) predicts a shortening of latencies during choice compared to sampling.

Pharmacokinetics trumps pharmacodynamics during cocaine choice: a reconciliation with the dopamine hypothesis of addiction.

Cocaine is known to increase brain dopamine at supranormal levels in comparison to alternative nondrug rewards. According to the dopamine hypothesis of addiction, this abnormally large dopamine response would explain why cocaine use is initially highly rewarding and addictive. Though resting on solid neuroscientific foundations, this hypothesis has nevertheless proven difficult to reconcile with research on cocaine choice in experimental animals.

Habitual Preference for the Nondrug Reward in a Drug Choice Setting.

For adaptive and efficient decision making, it must be possible to select between habitual alternative courses of action. However, research in rodents suggests that, even in the context of simple decision-making, choice behavior remains goal-directed. In contrast, we recently found that during discrete trial choice between cocaine and water, water-restricted rats preferred water and this preference was habitual and inflexible (i.

Animal Models of the Behavioral Symptoms of Substance Use Disorders.

To more effectively manage substance use disorders, it is imperative to understand the neural, genetic, and psychological underpinnings of addictive behavior. To contribute to this understanding, considerable efforts have been made to develop translational animal models that capture key behavioral characteristics of addiction on the basis of DSM5 criteria of substance use disorders. In this review, we summarize empirical evidence for the occurrence of addiction-like behavior in animals.

Reorganization of theta phase-locking in the orbitofrontal cortex drives cocaine choice under the influence.

Cortical theta oscillations of neuronal activity are a fundamental mechanism driving goal-directed behavior. We previously identified in the rat orbitofrontal cortex (OFC) a neuronal correlate of individual preferences between cocaine use and an alternative nondrug reward (i.e.

Relapse to cocaine use persists following extinction of drug-primed craving.

Craving often precedes relapse into cocaine addiction. This explains why considerable research effort is being expended to try to develop anti-craving strategies for relapse prevention. Recently, we discovered using the classic reinstatement model of cocaine craving that the reinstating or priming effect of cocaine can be extinguished with repeated priming in rats - a phenomenon dubbed extinction of cocaine priming because it is thought to involve extinction of the conditioned interoceptive cues of the drug.

Inflexible habitual decision-making during choice between cocaine and a nondrug alternative.

The concept of compulsive cocaine-seeking habits is difficult to reconcile with other evidence showing that humans and even rats remain able to shift their choice away from the drug and toward an alternative nondrug reward, when available. This paradox could dissolve if preference for the nondrug option reflected in fact inflexible habitual decision-making (i.e.

A neuronal population code for resemblance between drug and nondrug reward outcomes in the orbitofrontal cortex.

The orbitofrontal cortex (OFC) is implicated in choice and decision-making in both human and non-human animals. We previously identified in the rat OFC a mechanism that influences individual drug choices and preferences between a drug and a nondrug (i.e.

Non-pharmacological factors that determine drug use and addiction.

Based on their pharmacological properties, psychoactive drugs are supposed to take control of the natural reward system to finally drive compulsory drug seeking and consumption. However, psychoactive drugs are not used in an arbitrary way as pure pharmacological reinforcement would suggest, but rather in a highly specific manner depending on non-pharmacological factors. While pharmacological effects of psychoactive drugs are well studied, neurobiological mechanisms of non-pharmacological factors are less well understood.

A transdiagnostic dimensional approach towards a neuropsychological assessment for addiction: an international Delphi consensus study.

Background: The US National Institutes of Mental Health Research Domain Criteria (RDoC) seek to stimulate research into biologically validated neuropsychological dimensions across mental illness symptoms and diagnoses. The RDoC framework comprises 39 functional constructs designed to be revised and refined, with the overall goal of improving diagnostic validity and treatments. This study aimed to reach a consensus among experts in the addiction field on the 'primary' RDoC constructs most relevant to substance and behavioural addictions.

Pre-trial cocaine biases choice toward cocaine through suppression of the nondrug option.

Being under the influence during choice between drug and nondrug options can have a dramatic effect on choice outcomes. When rats face a choice between cocaine and sweet water and are not under the influence, they prefer sweet water. In contrast, when they are under the influence of cocaine, this causes them to shift their choice to cocaine nearly exclusively.