This comprehensive review synthesizes decades of neuroscience research to map how casual substance use progresses to compulsive addiction via a three-stage cycle—binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. Each stage corresponds to distinct neuroadaptations: heightened incentive salience (dorsal striatum/basal ganglia), recruitment of stress circuits and diminished reward (extended amygdala), and executive-function deficits (prefrontal cortex). The authors argue that addiction involves a shift from voluntary “seeking pleasure” to involuntary “avoiding distress,” driven by progressively dysregulated brain reward and stress systems Neurobiology of Addicti….

Dopamine & Incentive Salience
Addictive drugs hijack dopamine signaling in the nucleus accumbens, mimicking phasic bursts that reinforce drug-taking and conditioned cues. Over time, dopamine D2 receptor down-regulation blunts the drug’s direct reward, while environmental and internal cues gain power to trigger intense craving via dorsal striatal circuits. This cue-driven dopamine release underlies the compulsive, habitual nature of drug seeking Neurobiology of Addicti….

Stress Systems & the “Dark Side”
Chronic use engages brain stress peptides—corticotropin-releasing factor (CRF) and dynorphin—in the extended amygdala, producing a dysphoric withdrawal state that reinforces negative-reinforcement drug taking. Antagonists of CRF or kappa-opioid receptors selectively reduce withdrawal-induced drug seeking, highlighting stress-neurotransmitter systems as targets for alleviating the “dark side” of addiction Neurobiology of Addicti….

Glutamate & Synaptic Plasticity
Drug cues induce excessive glutamate spillover in the nucleus accumbens, triggering matrix-metalloproteinase-mediated synaptic remodeling that entrenches drug-seeking engrams. Restoring glutamate transporter (GLT-1) function or inhibiting downstream plasticity enzymes (e.g., MMP9) reverses these changes and blocks relapse in animal models, pointing to glutamatergic regulation as crucial for preventing reinstatement Neurobiology of Addicti….

Implications for Prevention & Treatment
By detailing the neural circuits and molecular players across addiction’s stages, the review underlines the need for multi-modal interventions: dopamine-modulating agents, stress-system antagonists, glutamate-homeostasis restorers (e.g., N-acetylcysteine), and neuromodulation techniques. It also emphasizes critical developmental windows—particularly adolescence—when immature prefrontal control and elevated reward sensitivity heighten vulnerability. Understanding these mechanisms supports personalized, stage-specific therapies to foster resilience and durable recovery Neurobiology of Addicti….