Addiction (Substance Use Disorder)

Definition

Drug addiction is a chronically relapsing disorder characterised by compulsion to seek and take a drug, loss of control in limiting intake, and emergence of a negative emotional state (dysphoria, anxiety, irritability) when access to the drug is prevented.

DSM-5: Subsumed under Substance Use Disorders (SUD), combining former substance abuse and substance dependence into a single spectrum rated mild / moderate / severe based on number of criteria met.

Diagnostic Criteria (DSM-5, generalized)

Taking the substance in larger amounts or over longer periods than intended
Persistent desire or unsuccessful efforts to cut down
Significant time spent obtaining, using, or recovering
Craving or strong urge to use
Failure to fulfil major role obligations
Continued use despite interpersonal problems
Reduction of important activities due to use
Use in physically hazardous situations
Continued use despite known physical or psychological harm
Tolerance
Withdrawal

Three-Stage Cycle Framework (Koob & Volkow 2016)

Addiction follows a recurring three-stage cycle that progressively worsens and involves neuroplastic changes across three major circuits:

Stage	Core Feature	Primary Circuit	Key Neurochemistry
Binge/Intoxication	Reward, incentive salience, habit formation	Basal ganglia (ventral → dorsal striatum)	Dopamine, opioid peptides, glutamate
Withdrawal/Negative Affect	Dysphoria, stress, anti-reward	Extended amygdala	CRF, dynorphin, norepinephrine ↑; dopamine ↓
Preoccupation/Anticipation	Craving, executive dysfunction	Prefrontal cortex	Glutamate, D2 receptors, insula/CRF

Individuals shift from impulsivity (positive reinforcement, seeking pleasure) to compulsivity (negative reinforcement, avoiding withdrawal distress).

Heritability and Etiology

Heritability: 40–60%; remainder is environmental.
Vulnerability factors: adolescent onset (incomplete PFC myelination), stress, low socioeconomic status, parental drug use, poor parenting, peer influence.
Adolescent drug initiation is associated with more chronic, intensive use and higher SUD risk than adult onset.
Epigenetic modifications from adolescent alcohol use alter amygdalar gene expression, increasing adult anxiety susceptibility and alcohol intake. (Animal model evidence.)

Key Brain Regions

Nucleus accumbens (NAc): Core reward substrate; dopamine release central to drug reward.
Ventral tegmental area (VTA): Dopamine cell origin; modulated by glutamate, CRF, and other inputs.
Dorsal striatum: Habit formation; recruited as addiction progresses.
Extended amygdala (central nucleus of amygdala + bed nucleus of stria terminalis): CRF/norepinephrine stress system; withdrawal aversion; stress-induced reinstatement.
Prefrontal cortex (prelimbic, infralimbic, orbitofrontal, anterior cingulate, DLPFC): Executive control, decision making, inhibitory control; dysregulated in addiction.
Insula: Interoception; integrates autonomic/visceral states with motivation; lesions eliminate craving in smokers.
Habenula: Encodes aversive states; drives VTA dopamine neuron silencing.

Molecular Mechanisms

cAMP/PKA upregulation in NAc: Core neuroadaptation in established addiction.
CREB activation in NAc: Decreases reward value → dysphoric withdrawal state.
ΔFosB accumulation: Sustained transcription factor switch; increases drug sensitivity with repeated use. (See also Depression — ΔFosB manipulation in NAc linked to depressive behavior.)
Histone modifications (cocaine): Chromatin signatures alter pre-mRNA splicing; necessary for conditioned place preference. (See Histone Modifications.)
AMPA receptor recruitment in PFC→NAc circuits during craving incubation.
mTORC1 pathway activated by drug cues; blockade disrupts memory reconsolidation.

Behavioural Addictions

The three-stage cycle framework applies to non-drug (process) addictions including pathological gambling, binge-eating disorder, and internet addiction disorder. Similar neurobiological mechanisms observed: D2 deficits, reward hyposensitivity, stress sensitisation, impaired inhibitory control.