Neurological Factors: Reward Circuit, Receptor Actions, and Damage
Neurological Factors asks how drugs act on the brain: the reward circuit, the receptor action of each class, and the neurological damage chronic use causes. Items test mechanisms and syndrome recognition rather than psychosocial treatment.
The reward circuit
Dopaminergic neurons in the ventral tegmental area project to the nucleus accumbens and prefrontal cortex. Nearly all addictive drugs raise accumbens dopamine, though by different routes: cocaine and amphetamine block or reverse dopamine transporters; opioids disinhibit dopamine cells through mu receptors in the VTA; nicotine acts on nicotinic receptors; alcohol and benzodiazepines act indirectly. Repeated surges produce receptor downregulation and blunted baseline dopamine - the substrate of tolerance and of anhedonia during withdrawal.
Receptor actions that get tested
- Alcohol: GABA-A positive modulation plus NMDA antagonism. Chronic use upregulates NMDA receptors, so withdrawal is a glutamate storm - tremor, seizures, DT.
- Benzodiazepines: GABA-A modulation at the benzodiazepine site; flumazenil reverses.
- Opioids: mu agonism; naloxone reverses.
- Cocaine: blocks DAT, NET, and SERT; amphetamines reverse transporters and deplete vesicular stores.
- Cannabis: CB1 agonism; classic hallucinogens: 5-HT2A agonism.
Damage syndromes
- Thiamine deficiency in alcohol use: Wernicke encephalopathy (confusion, ataxia, ophthalmoplegia) and Korsakoff syndrome (anterograde amnesia, confabulation). Give thiamine before glucose.
- Alcohol: cerebellar vermis atrophy, peripheral neuropathy, Marchiafava-Bignami disease of the corpus callosum.
- Methamphetamine: striatal dopamine terminal damage, psychosis, "meth mouth."
- MDMA: serotonergic toxicity, hyperthermia, hyponatremia.
- Toluene: white matter damage with cognitive decline.
Worked example
A 38-year-old with long-standing heavy drinking presents confused with ataxia and nystagmus, then develops dense amnesia for new events. Reasoning: the triad plus nystagmus is Wernicke encephalopathy from thiamine deficiency; untreated, it progresses to Korsakoff syndrome with anterograde amnesia and confabulation. Treatment is parenteral thiamine, and glucose should not be given first.
Traps
- Reversing the glutamate/GABA story in alcohol withdrawal.
- Assuming all addictive drugs bind dopamine receptors directly.
- Withholding thiamine until after a glucose load.