Dopamine

The popular equation of dopamine with pleasure is an oversimplification. The clearest evidence comes from Berridge and Robinson's experiments with dopamine-depleted rats: when these animals were given sweet tastes, they showed normal positive hedonic reactions (tongue protrusions, licking) — indicating that pleasure itself was intact — but they made no effort to seek or obtain the reward. Dopamine appears to drive wanting — the motivational drive to pursue rewards — rather than the subjective pleasure of receiving them. Pleasure (liking) is mediated primarily by opioid signalling in the nucleus accumbens. This distinction matters clinically: the anhedonia of depression may involve opioid system dysfunction more than dopamine deficiency, while the compulsive drug-seeking of addiction involves sensitised dopaminergic wanting.

The dopamine hypothesis proposes that at least some symptoms of schizophrenia result from abnormal dopamine neurotransmission. The original version (van Rossum, 1966) simply noted that all drugs effective against psychosis block dopamine D2 receptors, and that dopamine-releasing drugs (amphetamines) can induce psychosis in healthy individuals. The revised hypothesis (Davis et al., 1991) distinguished between mesolimbic hyperdopaminergia — producing positive symptoms such as hallucinations and delusions — and mesocortical hypodopaminergia — producing negative symptoms and cognitive impairments. This dual model is now well-established, though it is widely recognised that dopamine dysregulation is one element of a more complex neurodevelopmental picture that also involves glutamate, serotonin, and GABAergic systems.

Antipsychotic drugs block dopamine D2 receptors to reduce mesolimbic hyperdopaminergia and alleviate positive symptoms. But D2 receptors are also present in the nigrostriatal pathway, which controls movement, and in the tuberoinfundibular pathway, which regulates prolactin. Blocking D2 receptors in the nigrostriatal system produces extrapyramidal side effects — parkinsonian symptoms (rigidity, tremor, bradykinesia), acute dystonia, and tardive dyskinesia with long-term use. Atypical antipsychotics have a lower propensity for these effects because they show faster dissociation from D2 receptors and additional antagonism at serotonin 5-HT2A receptors, allowing relatively selective action in limbic areas.

Repeated drug use progressively sensitises the mesolimbic dopamine system — the circuitry underlying incentive salience (wanting). Initially, drugs produce large dopamine releases in the nucleus accumbens, which the brain interprets as the arrival of an extraordinarily salient reward. Over time, tolerance develops to the hedonic effects, but the incentive salience attributed to drug cues (people, places, paraphernalia) remains — and can intensify. This explains the defining paradox of addiction: compulsive drug-seeking that persists even when the drug no longer produces pleasure. The cue-triggered dopamine release also explains why exposure to drug-associated stimuli reliably provokes craving and relapse even after prolonged abstinence.