Elsevier

The Lancet Psychiatry

Volume 3, Issue 8, August 2016, Pages 760-773
The Lancet Psychiatry

Review
Neurobiology of addiction: a neurocircuitry analysis

https://doi.org/10.1016/S2215-0366(16)00104-8Get rights and content

Summary

Drug addiction represents a dramatic dysregulation of motivational circuits that is caused by a combination of exaggerated incentive salience and habit formation, reward deficits and stress surfeits, and compromised executive function in three stages. The rewarding effects of drugs of abuse, development of incentive salience, and development of drug-seeking habits in the binge/intoxication stage involve changes in dopamine and opioid peptides in the basal ganglia. The increases in negative emotional states and dysphoric and stress-like responses in the withdrawal/negative affect stage involve decreases in the function of the dopamine component of the reward system and recruitment of brain stress neurotransmitters, such as corticotropin-releasing factor and dynorphin, in the neurocircuitry of the extended amygdala. The craving and deficits in executive function in the so-called preoccupation/anticipation stage involve the dysregulation of key afferent projections from the prefrontal cortex and insula, including glutamate, to the basal ganglia and extended amygdala. Molecular genetic studies have identified transduction and transcription factors that act in neurocircuitry associated with the development and maintenance of addiction that might mediate initial vulnerability, maintenance, and relapse associated with addiction.

Section snippets

Conceptual framework, definitions, and animal models

Drug addiction can be defined as a chronically relapsing disorder, characterised by compulsion to seek and take the drug, loss of control in limiting intake, and emergence of a negative emotional state (eg, dysphoria, anxiety, irritability) when access to the drug is prevented. From a diagnostic perspective, the term addiction is now encompassed by the term substance use disorders. In 2013, DSM-51 combined what was previously conceptualised as two separate and hierarchical disorders (substance

Drug reward

Drugs of abuse activate brain reward systems, and research on drug addiction has in large part defined the neurocircuitry of reward. This line of investigation is fundamental because changes to how the drug-induced reward system is activated are key to the understanding of the development of addiction.4 Reward is defined herein as any event that increases the probability of a response with a positive hedonic component. A principal focus of research on the neurobiology of the rewarding effects

Neurobiological mechanisms of the withdrawal/negative affect stage

The withdrawal/negative affect stage consists of key motivational elements, such as chronic irritability, emotional pain, malaise, dysphoria, alexithymia, states of stress, and loss of motivation for natural rewards. Across all major drugs of abuse, this stage is characterised in laboratory animals by elevations in reward thresholds (ie, decreased reward) during withdrawal. In animal models of the transition to addiction, elevations in brain reward thresholds occur that temporally precede and

Neurobiological mechanisms of the preoccupation/anticipation stage

The preoccupation/anticipation stage has long been hypothesised to be a key element of relapse in humans, and defines addiction as a chronic relapsing disorder. Although this stage has often been linked to the construct of craving, craving in itself has been difficult to measure in human clinical studies and does not always correlate with relapse.89 Nevertheless, the stage in which the individual reinstates drug-seeking behaviour after abstinence remains a focus for identifying neurobiological

Molecular and genetic treatment targets within brain circuits associated with addiction

The neuroplastic changes outlined previously are triggered and sustained by molecular and cellular adaptations that can presumably also interact with genetic and environmental vulnerability to addiction. In the binge/intoxication stage, both signal transduction mechanisms and changes in gene transcription have been identified. For example, chronic exposure to a wide variety of abused drugs upregulates cAMP formation, cAMP-dependent protein kinase A (PKA) activity, and PKA-dependent protein

Developmental exposure as a key component of vulnerability for drug and alcohol use disorders

Normal developmental processes might result in higher risk for drug use at some stages of the lifecycle than others. Experimentation, as well as the process of addiction, most often starts in adolescence,166 a period during which the brain undergoes important developmental changes.167 Beginning in preadolescence and continuing into the mid-20s, cortical grey matter volumes reduce, which reflects a normal pruning process;168 white matter volume increases over the course of adolescence,

Relevance to behavioural addictive disorders

The three stages of the addiction cycle are pervasive and form common domains in non-drug addictions, also known as process addictions,179 such as pathological gambling, binge-eating disorder, compulsive buying, and internet addiction disorder.180 Non-drug addictions elaborate self-regulation failures similarly to drug addictions, with transitions from impulsivity to compulsivity and a chronic relapsing trajectory. Similar brain mechanisms, particularly with regard to reward deficits, stress

Implications for medication development

Our contention is that the field of the neurobiology of addiction has excellent and validated animal models and well developed clinical models that, combined with the neurocircuitry analysis herein, will provide a unique approach to medication development that emphasises excessive incentive salience, the loss of brain reward function, and the gain of stress function that drive negative reinforcement (ie, the dark side of addiction) and the dysregulation of executive function, all of which are

Conclusions and future directions

We elaborate here a heuristic framework based on the behavioural and imaging phenotypes of addiction as three stages linked by three functional domains that are mediated by three major neurobiological circuits (basal ganglia, extended amygdala, and prefrontal cortex) and numerous microcircuits of neuroplasticity. We outline 18 neurochemically defined mini circuits that can independently or interactively load the outputs of the major common neurobiological circuits to produce incentive salience

Search strategy and selection criteria

We identified seminal articles published in peer-reviewed journals and reports that were pertinent to the neurobiology of addiction using in-house expertise, consultations with other experts in the field, and searches of key databases, including PubMed. The exclusion and inclusion criteria for the articles were deliberately kept flexible. The scope of the review was expanded based on findings from the review of key papers and reports.

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