2 Neuroscience2.11 Integrated neurobiology of syndromes and states
2.11.3 Drug use, addiction, tolerance, withdrawal and relapse
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Written by Resident Doctor Committee · Published
Reward circuitry
The ventral tegmental area holds the cell bodies of the dopamine neurones that drugs of abuse activate, and projects to the nucleus accumbens, the terminal field of the mesolimbic pathway.
The nucleus accumbens (ventral striatum) is the hub where this dopamine meets glutamate from prefrontal cortex, amygdala and hippocampus on accumbal gamma-aminobutyric acid neurones that shape drug seeking.
It is the region most implicated in cocaine reward and the move to dependence.
Stimulants
Drug | Action | Detail |
|---|---|---|
Cocaine | Blocks the presynaptic dopamine transporter, raising mesolimbic dopamine | Euphoria and addiction come from this, not its noradrenergic, sodium channel or glutamatergic effects |
Amphetamines | Release monoamines | Act most directly on striatal dopamine terminals (caudate and putamen), where methamphetamine users lose dopamine transporter binding |
Khat | Cathinone, its alkaloid, releases dopamine and noradrenaline from nerve terminals | Amphetamine-like stimulant |
Tolerance
Tolerance is a smaller effect from the same dose after repeated exposure, through receptor desensitisation, compensatory signalling with opioids, enzyme induction with alcohol, or conditioning.
Tolerance falls during abstinence, so overdose risk rises when people return to use.
Dependence and withdrawal
Physical dependence is not addiction: prescribed opioids cause withdrawal without compulsive use, and stimulants cause addiction without autonomic withdrawal.
Drug | Withdrawal | Danger |
|---|---|---|
Alcohol | Tremor, sweating; seizures at 12 to 48 hours, delirium tremens at 48 to 72 hours | Can be fatal; give benzodiazepines and thiamine |
Benzodiazepines | Anxiety, perceptual hypersensitivity, seizures | Can be fatal; taper gradually |
Opioids | Lacrimation, yawning, piloerection, mydriasis, diarrhoea | Rarely life-threatening alone |
Stimulants | Crash: hypersomnia, hyperphagia, anhedonia, craving | Suicide risk |
Reinforcement and relapse
In Koob and Volkow's model, use moves from positive reinforcement by intoxication to negative reinforcement by relief of withdrawal, a stage based in the extended amygdala.
Drug cues, stress and a priming dose trigger relapse.
Extinction adds competing learning rather than erasing the drug association, so renewal, spontaneous recovery and reinstatement can follow.
Alcohol genetics
Alcohol dependence is moderately heritable, with a small shared-environment share and similar heritability in both sexes.
Its best-replicated risk loci are variants in alcohol-metabolising enzyme genes.
The ALDH2*2 allele, a loss-of-function variant of aldehyde dehydrogenase 2, lets acetaldehyde build up and cause flushing, nausea and tachycardia, so drinking becomes aversive and dependence less likely.
Its protective effect is larger than that of the faster alcohol dehydrogenase 1B (ADH1B) alleles.