Pathophysiology
Clinical meaning
Substance use disorders (SUDs) are chronic, relapsing brain disorders characterized by compulsive drug seeking and use despite harmful consequences. The neurobiological basis involves hijacking of the brain's reward circuitry โ the mesolimbic dopamine system (VTA โ nucleus accumbens). All addictive substances increase dopamine release in the nucleus accumbens (NAc), producing the reinforcing 'reward' signal: cocaine/amphetamines directly increase dopamine (blocking DAT or reversing it); opioids disinhibit VTA dopamine neurons by binding mu receptors on GABA interneurons (removing the GABA 'brake'); alcohol enhances GABA (inhibitory) and antagonizes NMDA glutamate (excitatory) receptors, indirectly increasing dopamine; nicotine directly stimulates nicotinic acetylcholine receptors on VTA dopamine neurons. Chronic exposure causes neuroadaptation: (1) Tolerance โ downregulation of dopamine receptors (D2) in the NAc, requiring more substance for the same effect; (2) Dependence โ opponent-process neuroadaptation creating a new homeostatic set point; removal of the substance unmasks the compensatory changes (withdrawal); (3) Sensitization of stress circuits (extended amygdala, CRF system) drives negative emotional states during abstinence, motivating continued use to avoid dysphoria ('negative reinforcement'). Importantly, prefrontal cortex executive function is impaired in addiction (reduced gray matter, impaired...