Mechanism of Action of Haloperidol on Dopamine Receptors
Haloperidol primarily acts as a dopamine D2 receptor antagonist, blocking postsynaptic D2 receptors which leads to its antipsychotic effects. 1
Primary Mechanism
- Haloperidol functions as a central nervous system (CNS) dopamine receptor antagonist, with its main action occurring at the D2 receptors 1
- The blockade of D2 receptors in the nigrostriatal pathways and spinal cord via extrapyramidal pathways produces muscle rigidity and tremor, which explains some of haloperidol's side effects 1
- Haloperidol's antagonism of D2 receptors in the hypothalamus affects temperature regulation by producing an increased set point and loss of heat-dissipating mechanisms 1
Receptor Specificity
- Haloperidol is classified as a "high-potency" typical antipsychotic, which means it has strong D2 receptor blocking effects with less sedation but higher risk of extrapyramidal symptoms compared to "low-potency" agents 1
- Unlike atypical antipsychotics, haloperidol does not significantly block serotonin receptors, which explains its different side effect profile 1
- Haloperidol binds to postsynaptic D2 receptors with high affinity, disrupting dopaminergic neurotransmission 2
Cellular and Molecular Effects
- Haloperidol can increase cAMP formation and prolactin release in cells expressing dopamine D2 receptors, suggesting it may act as an inverse agonist rather than a neutral antagonist at the D2 receptor 2
- Chronic administration of haloperidol leads to an increase in striatal D2 receptor binding, which may contribute to its long-term effects 3
- Haloperidol increases the phosphorylation of tyrosine hydroxylase (the rate-limiting enzyme in dopamine synthesis) at Ser31 and Ser40 sites through blockade of D2 receptors and subsequent activation of ERK1/2 pathways 4
Acute vs. Chronic Effects
- Acute administration of haloperidol may initially enhance dopaminergic transmission due to relatively strong presynaptic actions (blocking presynaptic D2 autoreceptors) and relatively weaker postsynaptic blocking effects 5
- Chronic administration of haloperidol reduces the basal levels of phosphorylated tyrosine hydroxylase and decreases the drug's ability to stimulate further phosphorylation, which may relate to depressed dopaminergic transmission with long-term use 4
Clinical Implications of Receptor Binding
- Haloperidol's strong D2 receptor antagonism is responsible for its efficacy in treating acute agitation and psychosis 1
- The blockade of D2 receptors can lead to serious adverse effects like neuroleptic malignant syndrome (NMS), which is attributed to the lack of dopaminergic activity in the CNS 1
- Extrapyramidal symptoms such as drug-induced parkinsonism, akathisia, and tardive dyskinesia are direct consequences of D2 receptor blockade in the nigrostriatal pathway 1
Common Pitfalls and Caveats
- Haloperidol's D2 receptor antagonism can cause significant extrapyramidal side effects, which may require treatment with anticholinergic agents or dopaminergic agonists 1
- Haloperidol may also act on other receptor systems, including as a ligand for sigma1 receptors, which could contribute to its cardiac effects 6
- Haloperidol can disrupt D1/D2 receptor complexes in cardiac cells, which may explain some of its cardiovascular effects that are not seen with other D2 antagonists 6