Assessment of lumateperone partial agonist activity at presynaptic dopamine D2 autoreceptors: reversal of haloperidol-induced tyrosine hydroxylase phosphorylation in mouse striatum

Background

Lumateperone is FDA-approved for the treatment of schizophrenia in adults, for the treatment of depressive episodes associated with bipolar I or II disorder (bipolar depression) in adults as monotherapy and as adjunctive therapy with lithium or valproate, and as an adjunctive treatment for major depressive disorder. Pharmacologically, lumateperone is a potent serotonin-2A receptor antagonist, a modest serotonin transporter inhibitor and an indirect enhancer of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) glutamatergic neurotransmission. A distinguishing feature of lumateperone is its dopaminergic profile, which includes presynaptic partial agonism while maintaining postsynaptic D₂ receptor antagonism at low receptor occupancy. This balanced modulation of dopaminergic tone may contribute to the low risk of extrapyramidal symptoms (EPS) and akathisia associated with its use. The hypothesis investigated here was that lumateperone, acting as a presynaptic partial agonist, would reduce the levels of haloperidol-induced phosphorylated tyrosine hydroxylase (p-TH), a marker of presynaptic dopaminergic activity, in mouse striatum.

Methods

To assess the D₂ agonist activity of lumateperone in an in vivo mouse model, we compared the effects of the (1) full D₂ agonist quinpirole, (2) partial D₂ agonists aripiprazole, brexpiprazole, and cariprazine, and (3) high-affinity D₂ antagonist haloperidol vs lumateperone. Phosphorylation of TH (the rate-limiting step in dopamine synthesis), a key indicator of presynaptic dopamine response, was used as an indicator of presynaptic dopaminergic response. Data from mouse striatal Western blots were analyzed by 1-way analysis of variance, and results are presented as mean ± SEM. Each treatment group was normalized to the control group.

Results

In mouse striatum, haloperidol significantly increased dopaminergic activity, inducing an ≈3-fold increase in p-TH serine 40 levels (P<.001). Co-administration of lumateperone significantly reduced phosphorylated tyrosine hydroxylase (p-TH) levels at 3 mg/kg (P<.01) and 6 mg/kg (P<.001) compared with haloperidol alone. This effect was replicated by the full D₂ agonist quinpirole, with a significant reduction observed with haloperidol + quinpirole co-injection versus haloperidol alone (P<.05), which did not affect basal levels of p-TH. Similarly, the partial D₂ agonists aripiprazole, brexpiprazole, and cariprazine reduced haloperidol-induced TH phosphorylation, with cariprazine showing a significant reduction (P<.0001). In contrast, lurasidone and quetiapine, which are antipsychotics with D₂ antagonist (but not agonist) activity, elevated basal p-TH alone and failed to suppress haloperidol-induced p-TH.

Conclusions

Lumateperone suppressed haloperidol-induced increases in striatal tyrosine hydroxylase phosphorylation at serine 40 in vivo. This effect closely mirrored the actions of full and partial dopamine D₂ receptor agonists at presynaptic dopamine D₂ receptors. These findings provide mechanistic insights supporting a balanced dopaminergic profile indicating that lumateperone acts as a dopamine D₂ receptor presynaptic partial agonist. The unique mechanism of action of lumateperone on the dopaminergic system may contribute to the low risk of EPS and akathisia, and overall favorable safety profile, observed with lumateperone in clinical trials.

References

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