Neurobiology, Etiology, and Pharmacology of Addictive Disorders
Reward circuitry and reinforcement
Addiction is best understood as a disorder of motivated learning, not simply of pleasure. Mesolimbic dopamine projections from the ventral tegmental area to the nucleus accumbens encode incentive salience and reward prediction error; dopamine signals “worth pursuing” and “better than expected,” which is why cues acquire power. Opioids, alcohol, and nicotine also engage endogenous opioid, GABA, and nicotinic systems. Repeated use produces tolerance, sensitization, and allostasis-an opponent-process shift in which withdrawal and negative affect (mediated partly by CRF and dynorphin) drive continued use.
Etiology
Heritability for alcohol use disorder is roughly 50%; family history, early age of first use, trauma, impulsivity, and psychiatric comorbidity all raise risk. Genetic variation in alcohol dehydrogenase and aldehyde dehydrogenase alters flushing and risk. Environmental access, cost, and peer norms matter.
Pharmacology
Know mechanisms and kinetics: naltrexone is a competitive opioid antagonist; acamprosate modulates glutamate and is renally excreted; disulfiram blocks aldehyde dehydrogenase; buprenorphine is a partial mu agonist with a ceiling on respiratory depression; methadone is a full agonist with long, variable half-life and QT risk; varenicline is a nicotinic partial agonist; bupropion inhibits dopamine and norepinephrine reuptake.
Traps
Questions test “dopamine equals pleasure” (false), “disulfiram reduces craving” (it does not), “acamprosate needs hepatic monitoring” (renal dosing matters), and “naltrexone can be started during opioid use” (it precipitates withdrawal).
Rule of thumb
Before adding a medication, ask what else is inducing or inhibiting CYP3A4: rifampin can precipitate methadone or buprenorphine withdrawal, while azoles and macrolides raise levels.