Chapter 5: Targeting Dopamine and Serotonin Receptors for Psychosis, Mood, and Beyond: So-Called "Antipsychotics"

The therapeutic foundation rests on blocking dopamine D2 receptors in the mesolimbic and mesostriatal pathways to reduce positive psychotic symptoms such as hallucinations and delusions, which are theorized to arise from excessive dopaminergic signaling in these circuits. However, D2 antagonism produces significant liabilities across multiple brain regions: blockade in the nigrostriatal motor pathway generates extrapyramidal side effects including parkinsonism, acute dystonia, and akathisia, while chronic receptor antagonism triggers upregulation and receptor supersensitivity, precipitating tardive dyskinesia, a potentially irreversible hyperkinetic movement disorder. D2 inhibition in the tuberoinfundibular pathway disrupts dopamine's tonic inhibition of prolactin secretion, leading to hyperprolactinemia and associated sequelae like galactorrhea and menstrual disturbances. Furthermore, reduced dopaminergic tone in the mesocortical pathway exacerbates negative, cognitive, and affective symptoms already compromised by illness. Modern pharmacological strategies mitigate these adverse effects through serotonin receptor mechanisms: 5HT2A antagonism and 5HT1A partial agonism enhance dopamine availability in motor and prefrontal regions, thereby reducing motor toxicity while improving cognition and affective domains. D2 partial agonists like aripiprazole stabilize dopaminergic signaling by occupying receptors with reduced blocking intensity, lowering motor side effects and hyperprolactinemia risk. Beyond monoamine systems, these agents engage muscarinic, histaminergic, and adrenergic receptors, producing anticholinergic and sedating effects. Significant metabolic concerns include weight gain and insulin dysregulation stemming from histamine H1 and serotonin 5HT2C receptor blockade, substantially elevating cardiometabolic morbidity. Emerging therapeutic targets include trace amine-associated receptor type one agonists, which selectively bias dopamine signaling away from psychosis-producing pathways, and muscarinic M4 and M1 receptor agonists. Treatment of established tardive dyskinesia employs vesicular monoamine transporter type two inhibitors such as valbenazine and deutetrabenazine, which deplete intrasynaptic dopamine stores to counteract pathological receptor supersensitivity.