Elucidating the Diverse Mechanisms That Drive the Onset, Progression and Continuation of Addiction

Substance use disorder involves the progressive dysregulation of motivational circuits in the brain’s reward system, starting with acute and deliberate intoxication, rebound/negative effect, preoccupation and anticipatory reward. These stages involve different neurobiological mechanisms that drive addiction, conspire and result in exaggerated incentive salience (liking, wanting, needing), increasing anhedonia from the down regulation of the reward system, the upregulation of the human stress response, iconic and Pavlovian habit formation, and impairment in cognitive skills which most notably usurp focus, attention, memory and executive function.

Drilling deeper, the progressive impact of psychoactive drug use involves changes in dopamine and opioidergic volume in the basal ganglia to produce salience incentive and reward. The dysphoric and stress-like responses observed during drug rebound and forced temporary abstinence involve decreases in the dopamine function within the reward system and concurrent increase of neurotransmitters such as: Corticotrophin-releasing factor (CRF) and the endogenous opioid dynorphin within the neurocircuitry of the extended amygdala.

Preoccupation and anticipatory reward involve the disruption of key afferent projections from the prefrontal cortex and insula including glutamate signaling to the basal ganglia and extended amygdala. Molecular genetic studies have identified transduction and transcription factors that act in the neurocircuitry associated with the onset, progression and maintenance of addiction that might mediate initial vulnerability, maintenance and relapse associated with addiction.

These progressive stages and the diverse mechanisms that drive addiction, conspire in the transition from recreational to compulsive drug use in some individuals—but not others. We just don’t know why.

Why Does This Matter?Ask the Expert

Dr. Koob postulates the individual differences in the neurobiological systems that gird the processing of reward, incentive salience, stress, pain, preoccupation, and habitual behaviors may explain one’s “vulnerability to substance use disorder; the diversity of emotional, motivational, and cognitive profiles of individuals with substance use disorders and heterogeneous responses to cognitive and pharmacological treatments”.

Understanding and codifying the neuropsychological conditions and mechanisms that differentiate how addiction manifests in certain ways among certain individuals, and not in others, is the key to understanding how addiction develops and progresses. Knowing this could lead to the development of personalized pharmacotherapy.


George O, Koob GF. Individual differences in the neuropsychopathology of addiction. Dialogues Clin Neurosci. 2017 Sep;19(3):217-229.