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.
ReviewNeurobiology of addiction: a neurocircuitry analysis
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
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